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Ferreira LM, García-García P, García PA, Castro MÁ. A review on quinolines: New green synthetic methods and bioactive potential. Eur J Pharm Sci 2025; 209:107097. [PMID: 40221058 DOI: 10.1016/j.ejps.2025.107097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 03/25/2025] [Accepted: 04/07/2025] [Indexed: 04/14/2025]
Abstract
Quinolines have been an interest of study for a few decades due to the importance of this system in natural and pharmaceutical products. Since their discovery in the nineteenth century, many medicinal properties have been found for quinoline compounds. Firstly, as an anti-parasitic agent against malaria and then against many other diseases, such as, other parasitic infections, HIV, bacterial infections and cancer. Consequently, many synthetic methods have been developed to afford the quinoline ring. In this review we look back at traditional methods and look forward to the most recent and promising "green" methods for the synthesis of quinolines. Also, we review the newest advances in therapeutic compounds based on the quinoline skeleton for the treatment of parasitic and cancer diseases and the most recent applications of quinoline derivatives in drug delivery systems.
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Affiliation(s)
- Laura M Ferreira
- Departamento de Ciencias Farmacéuticas, Facultad de Farmacia, CIETUS/IBSAL, Universidad de Salamanca, Campus Miguel de Unamuno Salamanca, 37007, Spain
| | - Pilar García-García
- Departamento de Ciencias Farmacéuticas, Facultad de Farmacia, CIETUS/IBSAL, Universidad de Salamanca, Campus Miguel de Unamuno Salamanca, 37007, Spain.
| | - Pablo A García
- Departamento de Ciencias Farmacéuticas, Facultad de Farmacia, CIETUS/IBSAL, Universidad de Salamanca, Campus Miguel de Unamuno Salamanca, 37007, Spain
| | - María Ángeles Castro
- Departamento de Ciencias Farmacéuticas, Facultad de Farmacia, CIETUS/IBSAL, Universidad de Salamanca, Campus Miguel de Unamuno Salamanca, 37007, Spain.
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2
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Ma C, Zhang H, Liu Z, Meng X, Chen S, Zhang J, Li Y, Huang X. Treatment options of nitrogen heterocyclic compounds in industrial wastewater: From fundamental technologies to energy valorization applications and future process design strategies. WATER RESEARCH 2025; 281:123575. [PMID: 40179728 DOI: 10.1016/j.watres.2025.123575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 03/28/2025] [Accepted: 03/29/2025] [Indexed: 04/05/2025]
Abstract
Nitrogen heterocyclic compounds (NHCs) widely exist in industrial wastewater and presented significant environmental and health risks due to their toxicity and persistence. This review addressed the challenges in treating NHCs in industrial wastewater, focusing on developing sustainable and efficient treatment processes. While various technologies, including adsorption, advanced oxidation/reduction processes (AOPs/ARPs), and microbial treatments, have been studied at the experimental stage of treating synthetic wastewater, scale-up for industrial applications is imperative. After analyzing the characteristics of NHCs and evaluating different treatment methods with the aid of efficiency and cost-benefit analysis, efficient detoxification while maximizing energy recovery constitutes a critical requirement in treating NHC-containing wastewater. Hence, we proposed a comprehensive strategy combining hydrolysis-acidification pretreatment enhanced by electro-assisted micro-aeration with methanogenic anaerobic digestion as core treatment units. The process design for NHC-containing wastewater treatment should consider the dynamic balance between removal efficiency, energy consumption, and ammonia recovery, incorporating environmental and economic impacts through life cycle assessment and technical-economic analysis. The potential of machine learning in optimizing operational parameters, predicting effluent quality, and supporting process design decisions is promising. To develop interpretable and practical solutions, the integration of data-driven approaches with mechanistic understanding and prior knowledge is indispensable. This review provided novel insights into sustainable NHC treatment strategies in the context of energy valorization and artificial intelligence advancement, offering guidance for future research and industrial applications.
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Affiliation(s)
- Chao Ma
- Innovation Demonstration Base of Ecological Environment Geotechnical and Ecological Restoration of Rivers and Lakes, Hubei University of Technology, Wuhan 430068, PR China
| | - Huiqin Zhang
- Innovation Demonstration Base of Ecological Environment Geotechnical and Ecological Restoration of Rivers and Lakes, Hubei University of Technology, Wuhan 430068, PR China
| | - Ziwei Liu
- State Key Joint Laboratory of Environment Simulation and Pollution Control, School of Environment, Tsinghua University, Beijing 100084, PR China.
| | - Xinran Meng
- State Key Joint Laboratory of Environment Simulation and Pollution Control, School of Environment, Tsinghua University, Beijing 100084, PR China
| | - Sijia Chen
- State Key Joint Laboratory of Environment Simulation and Pollution Control, School of Environment, Tsinghua University, Beijing 100084, PR China
| | - Jingsong Zhang
- CITIC Envirotech Pte. (Guangzhou) Ltd., Guangzhou 511455, PR China
| | - Yeqiang Li
- CITIC Envirotech Pte. (Guangzhou) Ltd., Guangzhou 511455, PR China
| | - Xia Huang
- State Key Joint Laboratory of Environment Simulation and Pollution Control, School of Environment, Tsinghua University, Beijing 100084, PR China; Research and Application Center for Membrane Technology, School of Environment, Tsinghua University, Beijing 100084, PR China.
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3
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Soltani M, Ahmadzadeh N, Rajabi S, Besharati N, Khatamian N, Homayouni Tabrizi M. Efficacy of graphene quantum dot-hyaluronic acid nanocomposites containing quinoline for target therapy against cancer cells. Sci Rep 2025; 15:8494. [PMID: 40074749 PMCID: PMC11904204 DOI: 10.1038/s41598-024-81604-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 11/27/2024] [Indexed: 03/14/2025] Open
Abstract
The study aims to assess the impact of graphene quantum dot-hyaluronic acid-quinoline nanocomposites (GQD-HA-Qu NCs) on MCF-7, HT-29, A2780, PANC-1, and HeLa cell lines. The GQD-HA-Qu NCs were characterized using dynamic light scattering (DLS), field emission scanning electron microscopy (FESEM), and Fourier-transform infrared (FTIR) spectroscopy. MTT assays and flow cytometry evaluated the cytotoxic and apoptotic effects of synthesized NCs. Additionally, real-time PCR was utilized to assess apoptotic gene expression. The DLS assay revealed a particle size of 224.96 nm with a polydispersity index (PDI) of 0.3. The FESEM analysis also confirmed the uniform spherical morphology of NCs. The MTT assessment demonstrated significant cytotoxicity in all cell lines, with MCF-7 and A2780 exhibiting pronounced sensitivity (P < 0.001). The flow cytometry analyses also revealed a dose-dependent increase in late apoptosis at higher concentrations of GQD-HA-Qu NCs. Notably, p53 expression was significantly upregulated compared to the untreated cells (P < 0.01), while caspases 8 and 9 showed no substantial change. This finding indicates that the p53 pathway is predominant in mediating GQD-HA-Qu NCs-induced apoptosis. The present study suggests that GQD-HA-Qu NCs are a promising treatment with selective cytotoxicity against cancer cells and robust antioxidant activity. These findings warrant further investigation for potential clinical applications.
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Affiliation(s)
- Mozhgan Soltani
- Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran.
| | - Negar Ahmadzadeh
- Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Sarah Rajabi
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Royan Institute, Tehran, Iran
- Department of Cell Engineering, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Nazanin Besharati
- Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Niloufar Khatamian
- Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran
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Bouria H, Alliouche H, Chouiter MI, Belfaitah A, Pacheco T, Gala V, Pereira D, Silva AMS. Synthesis of novel quinoline-thiazolobenzimidazolone hybrids as anticancer agents through caspase-dependent apoptosis. Future Med Chem 2025; 17:543-555. [PMID: 40008604 PMCID: PMC11901420 DOI: 10.1080/17568919.2025.2470112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
AIM This work explores the synthesis of new bi-heterocyclic hybrid compounds based on quinoline ring and investigates their potential as anticancer agents. MATERIALS & METHODS The novel fused quinoline-thiazolo[3,2-a] benzimidazole-3(2 h)one hybrids were prepared by regioselective nucleophilic ring opening of the corresponding quinolinyl-oxiranes. In vitro cytotoxic activity was evaluated against human lung (A549) and gastric (AGS) cancer cell lines. RESULTS Global results showed that all tested compounds have promising inhibitory properties. Compounds 17 and 18 bearing two methoxy groups on the quinoline ring have exhibited remarkable and interesting activities. The investigation of the cell death process showed that these compounds activated a caspase-dependent apoptosis pathway. Results were further supported by molecular docking studies. CONCLUSION Both compounds exhibited good drug-like characteristics, which make them promising drug candidates.
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Affiliation(s)
- Houria Bouria
- Equipe de Synthèse de Molécules à Objectif Thérapeutique (SMOTH), Laboratoire des Produits Naturels d’Origine Végétale et de Synthèse Organique. Faculté des Sciences Exactes, Campus de Chaabat Ersas, Université Frères Mentouri-Constantine1, Constantine, Algeria
| | - Hayette Alliouche
- Equipe de Synthèse de Molécules à Objectif Thérapeutique (SMOTH), Laboratoire des Produits Naturels d’Origine Végétale et de Synthèse Organique. Faculté des Sciences Exactes, Campus de Chaabat Ersas, Université Frères Mentouri-Constantine1, Constantine, Algeria
| | - Mohamed Imed Chouiter
- Equipe de Synthèse de Molécules à Objectif Thérapeutique (SMOTH), Laboratoire des Produits Naturels d’Origine Végétale et de Synthèse Organique. Faculté des Sciences Exactes, Campus de Chaabat Ersas, Université Frères Mentouri-Constantine1, Constantine, Algeria
| | - Ali Belfaitah
- Equipe de Synthèse de Molécules à Objectif Thérapeutique (SMOTH), Laboratoire des Produits Naturels d’Origine Végétale et de Synthèse Organique. Faculté des Sciences Exactes, Campus de Chaabat Ersas, Université Frères Mentouri-Constantine1, Constantine, Algeria
| | - Teresa Pacheco
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Viktor Gala
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
- Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic
| | - David Pereira
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Artur M. S. Silva
- LAQV-REQUIMTE & Department of Chemistry, University of Aveiro, Aveiro, Portugal
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5
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La Monica G, Bono A, Alamia F, Martorana A, Lauria A. Design, Synthesis, and In Silico Insights of new 4-Piperazinylquinolines as Antiproliferative Agents against NCI Renal Cancer Cell Lines. ChemistryOpen 2025:e202400518. [PMID: 39910865 DOI: 10.1002/open.202400518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/20/2025] [Indexed: 02/07/2025] Open
Abstract
In the search for new anticancer compounds, quinoline and piperazine moieties represent the most promising pharmacophoric fragments for the development of more effective drugs. A particularly interesting approach in medicinal chemistry is molecular hybridization, where different known components are integrated into a single chemical entity, resulting in hybrid molecules with enhanced biological activity. In this study, we have developed a new series of 4-(4-benzoylpiperazin-1-yl)-6-nitroquinoline-3-carbonitrile compounds (8 a-l), with potential anticancer effect, by combining the quinoline, the piperazinyl and the benzoylamino moieties. The rationalized compounds (8 a-l) were first evaluated in silico to assess the ADMET and drug-likeness profiles, synthesized using appropriate synthetic strategies and then tested in vitro under the National Cancer Institute DTP-NCI60 program. The entire series exhibited potent anticancer activity against the renal cell carcinoma (RCC) cell line UO-31, with compounds 8 c and 8 g effectively inhibiting cancer cell growth without excessive cytotoxic effects (growth percentages of -7 and -19, respectively). In silico induced fit docking (IFD) and molecular dynamics (MD) studies provided further insights into the putative mechanisms of action for both compounds, which were predicted to strongly bind key oncogenic proteins involved in RCC progression. The promising in vitro and in silico results herein presented provide a solid foundation for the development of a new series of small heterocyclic molecules with anticancer activity.
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Affiliation(s)
- Gabriele La Monica
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, Ed. 17, I-90128, Palermo, Italy
| | - Alessia Bono
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, Ed. 17, I-90128, Palermo, Italy
| | - Federica Alamia
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, Ed. 17, I-90128, Palermo, Italy
| | - Annamaria Martorana
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, Ed. 17, I-90128, Palermo, Italy
| | - Antonino Lauria
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, Ed. 17, I-90128, Palermo, Italy
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Ramasamy SS, Adhigaman K, Nandakumar V, Sundarasamy A, Jagadeesan S, Saravanakumar M, Malecki JG, Easwaran N, Thangaraj S. In-Silico exploration: Unraveling the anti-cancer potential of 8-Nitroquinoline hydrazides. J Mol Struct 2025; 1321:140218. [DOI: 10.1016/j.molstruc.2024.140218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Pastuch-Gawołek G, Szreder J. Effect of Glycoconjugation on Cytotoxicity and Selectivity of 8-Aminoquinoline Derivatives Compared to 8-Hydroxyquinoline. Molecules 2025; 30:427. [PMID: 39860296 PMCID: PMC11767929 DOI: 10.3390/molecules30020427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 01/13/2025] [Accepted: 01/17/2025] [Indexed: 01/27/2025] Open
Abstract
Numerous emerging chemotherapeutic agents incorporate N-heterocyclic fragments in their structures, with the quinoline skeleton being particularly significant. Our recent works have focused on glycoconjugates of 8-hydroxyquinoline (8-HQ), which demonstrated enhanced bioavailability and solubility compared to their parent compounds, although they fell short in selectivity. In this study, our objective was to improve the selectivity of glycoconjugates by replacing the oxygen atom with nitrogen by substituting the 8-HQ moiety with 8-aminoquinoline (8-AQ). The 8-AQ derivatives were functionalized through the amino group and linked to sugar derivatives (D-glucose or D-galactose) that were modified with an azide, alkylazide, or propargyl group at the anomeric position by copper(I)-catalyzed 1,3-dipolar azido-alkyne cycloaddition (CuAAC). The resulting glycoconjugates, as well as their potential metabolites, were evaluated for their ability to inhibit the proliferation of cancer cell lines (including HCT 116 and MCF-7) and a healthy cell line (NHDF-Neo). Two of the synthesized glycoconjugates (17 and 18) demonstrated higher cytotoxicity than their oxygen-containing counterparts and showed improved selectivity for cancer cells, thus enhancing their anticancer potential. Furthermore, it was found that glycoconjugates exhibited greater cytotoxicity in comparison to their potential metabolites.
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Affiliation(s)
- Gabriela Pastuch-Gawołek
- Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, B. Krzywoustego 4, 44-100 Gliwice, Poland;
- Biotechnology Center, Silesian University of Technology, B. Krzywoustego 8, 44-100 Gliwice, Poland
| | - Julia Szreder
- Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, B. Krzywoustego 4, 44-100 Gliwice, Poland;
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Prejanò M, Romeo I, Felipe Hernández‐Ayala L, Gabriel Guzmán‐López E, Alcaro S, Galano A, Marino T. Evaluating Quinolines: Molecular Dynamics Approach to Assess Their Potential as Acetylcholinesterase Inhibitors for Alzheimer's Disease. Chemphyschem 2025; 26:e202400653. [PMID: 39301943 PMCID: PMC11747580 DOI: 10.1002/cphc.202400653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 09/06/2024] [Accepted: 09/20/2024] [Indexed: 09/22/2024]
Abstract
Quinoline represents a promising scaffold for developing potential drugs because of the wide range of biological and pharmacological activities that it exhibits. In the present study, quinoline derivatives obtained from CADMA-Chem docking protocol were investigated in the mean of molecular dynamics simulations as potential inhibitors of acetylcholinesterase enzyme. The examined species can be partitioned between neutral, dq815 (2,3 dihydroxyl-quinoline-4-carbaldehyde), dq829 (2,3 dihydroxyl-quinoline-8-carboxylic acid methane ester), dq1356 (3,4 dihydroxyl-quinoline-6-carbaldehyde), dq1368 (3,4 dihydroxyl-quinoline-8-carboxylic acid methane ester) and dq2357 (5,6 dihydroxyl-quinoline-8-carboxylic acid methane ester), and deprotonated, dq815_dep, dq829_dep, dq1356_dep and dq2357_dep. Twelve molecular dynamics simulations were performed including those of natural acetylcholine, of the well-known donepezil inhibitor and of the founder quinoline chosen as reference. Key intermolecular interactions were detected and discussed to describe the different dynamic behavior of all the considered species. Binding energies calculation from MMPBSA well accounts for the dynamic behavior observed in the simulation time proposing dq1368 as promising candidate for the inhibition of acetylcholinesterase. Retrosynthetic route for the production of the investigated compounds is also proposed.
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Affiliation(s)
- Mario Prejanò
- Dipartimento di Chimica e Tecnologie ChimicheUniversità della Calabria87036Arcavacata di RendeItaly
| | - Isabella Romeo
- Dipartimento di Scienze della Salute and Net4Science Academic Spin-OffUniversità degli Studi“Magna Græcia” di Catanzaro88100CatanzaroItaly
| | - Luis Felipe Hernández‐Ayala
- Departamento de QuímicaUniversidad Autónoma Metropolitana-IztapalapaAv. Ferrocarril San Rafael Atlixco 186Col. Leyes de Reforma 1 A SecciónAlcaldía Iztapalapa, Mexico City09310Mexico
- Consejo Nacional de Humanidades Ciencias y TecnologíasCiudad de México03940México
| | - Eduardo Gabriel Guzmán‐López
- Departamento de QuímicaUniversidad Autónoma Metropolitana-IztapalapaAv. Ferrocarril San Rafael Atlixco 186Col. Leyes de Reforma 1 A SecciónAlcaldía Iztapalapa, Mexico City09310Mexico
| | - Stefano Alcaro
- Dipartimento di Scienze della Salute and Net4Science Academic Spin-OffUniversità degli Studi“Magna Græcia” di Catanzaro88100CatanzaroItaly
| | - Annia Galano
- Departamento de QuímicaUniversidad Autónoma Metropolitana-IztapalapaAv. Ferrocarril San Rafael Atlixco 186Col. Leyes de Reforma 1 A SecciónAlcaldía Iztapalapa, Mexico City09310Mexico
| | - Tiziana Marino
- Dipartimento di Chimica e Tecnologie ChimicheUniversità della Calabria87036Arcavacata di RendeItaly
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Soniya N, Soumya V, Shivlingrao MD, M M, Meeramol C. Therapeutic Potental of Quinolin-2 H-one Hybrids as Anticancer Agents. Mini Rev Med Chem 2025; 25:386-402. [PMID: 39323349 DOI: 10.2174/0113895575305597240912192037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 07/31/2024] [Accepted: 08/09/2024] [Indexed: 09/27/2024]
Abstract
The statistical data related to cancer in recent years has shown a great increase in the number of cases and is likely to further increase in the future. Even after seeking thorough knowledge on the aetiology of cancer and related disorders and attempting to cure it by various methods like gene therapy, T cell therapy, chemotherapy, surgery, hormone therapy, and photodynamic therapy, there has always been disappointment concerning the survival rate. Hence, there is still a great urge for the discovery of novel drugs for the treatment of cancer. Chemotherapy being one of the widely used methods, several drug entities possessing anticancer properties are already in the market but none of them is known to show good efficacy which necessitates researchers to design newer drugs for the treatment of cancer. The urge to synthesize novel anticancer entities directed researchers towards molecular hybridization as one of the novel methods for designing newer drugs. Literature reveals wide research carried out on quinolin-2-one hybrids, possessing anticancer properties through different mechanisms. Tipifarnib and Dovitinib are quinolin-2-one hybrids used to treat cancer, possessing imidazole and benzimidazole heterocyclic rings. Different heterocyclic scaffolds such as pyrone, pyrrole, pyrimidine, pyridine, thiazole, and pyrazole in combination with heterocyclic quinolin-2-one have shown high potential to become lead for newer anticancer agents with better and wider therapeutic properties and lesser side effects. The current review presents information on the different quinolin-2-one hybrids and their effect on different cancer cell lines. It also imparts knowledge of the structural requirements for designing novel anticancer agents.
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Affiliation(s)
- Naik Soniya
- Department of Pharmaceutical Chemistry, Sri Ramachandra Faculty of Pharmacy, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, 600116, India
- Department of Pharmaceutical Chemistry, PESs Rajaram and Tarabai Bandekar College of Pharmacy, Farmagudi, Ponda, Goa, 403 401, India
| | - Vasu Soumya
- Department of Pharmaceutical Chemistry, Sri Ramachandra Faculty of Pharmacy, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, 600116, India
| | - Mamle Desai Shivlingrao
- Department of Pharmaceutical Chemistry, Sri Ramachandra Faculty of Pharmacy, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, 600116, India
| | - Manickavasagam M
- Department of Oncology, SRMC & RI, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, 600116, India
| | - Chellappan Meeramol
- Department of Pharmaceutical Chemistry, Sri Ramachandra Faculty of Pharmacy, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, 600116, India
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10
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Zhao Y, Zhang C, Liu W, Guo Z, Zhang Y, Wu Y, Wei C, Wu J, Yang X. Quinolines: A Promising Heterocyclic Scaffold for Cancer Therapeutics. Curr Med Chem 2025; 32:958-973. [PMID: 37877504 DOI: 10.2174/0109298673258512231013060222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 08/14/2023] [Accepted: 08/17/2023] [Indexed: 10/26/2023]
Abstract
The quinoline scaffold is a widely recognized heterocycle with applications across various disease categories, ranging from malaria and viral infections to bacterial infections, high cholesterol, and even tumors. Consequently, quinoline plays a crucial role in the development of new drugs, and the field greatly benefits from advancements in computer-aided drug design. This review aims to provide insights into the evolution of quinoline and its derivatives, offering a comprehensive exploration of both marketed and developing drugs. Furthermore, the function and mechanism of quinoline compounds are introduced. Many studies rely on cell experiments to demonstrate drug cytotoxicity. In the concluding section of this review, the interaction between quinoline compounds and targets is simulated using computer-aided drug design methods. A thorough analysis is conducted on the potential influencing factors affecting the binding state between quinoline compounds and targets. Notably, the Pi-Alkyl interaction emerges as a significant contributor, while hydrogen bonding is identified as a pivotal bond in these interactions. This review serves as a valuable overview of the potential contributions of quinoline compounds to cancer treatment. It seamlessly combines the essential functions of marketed quinoline drugs with the promise held by emerging quinoline-based compounds. Additionally, the simulation of interactions between quinoline compounds and proteins through computer-aided design enhances our understanding of these compounds' efficacy.
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Affiliation(s)
- Yinshen Zhao
- College of Life Science, Henan Normal University, Xinxiang 453007, China
| | - Chaoyang Zhang
- College of Life Science, Henan Normal University, Xinxiang 453007, China
| | - Wan Liu
- College of Life Science, Henan Normal University, Xinxiang 453007, China
| | - Zhiyuan Guo
- College of Life Science, Henan Normal University, Xinxiang 453007, China
| | - Yuqi Zhang
- College of Life Science, Henan Normal University, Xinxiang 453007, China
| | - Yuqi Wu
- College of Life Science, Henan Normal University, Xinxiang 453007, China
| | - Chenyu Wei
- College of Life Science, Henan Normal University, Xinxiang 453007, China
| | - Jianing Wu
- College of Life Science, Henan Normal University, Xinxiang 453007, China
| | - Xianguang Yang
- College of Life Science, Henan Normal University, Xinxiang 453007, China
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang 453007, China
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11
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La Monica G, Gallo A, Bono A, Alamia F, Lauria A, Alduina R, Martorana A. Novel Antibacterial 4-Piperazinylquinoline Hybrid Derivatives Against Staphylococcus aureus: Design, Synthesis, and In Vitro and In Silico Insights. Molecules 2024; 30:28. [PMID: 39795086 PMCID: PMC11720749 DOI: 10.3390/molecules30010028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/21/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
Molecular hybridization, which consists of the combination of two or more pharmacophores into a single molecule, is an innovative approach in drug design to afford new chemical entities with enhanced biological activity. In the present study, this strategy was pursued to develop a new series of 6,7-dimethoxy-4-piperazinylquinoline-3-carbonitrile derivatives (5a-k) with potential antibiotic activity by combining the quinoline, the piperazinyl, and the benzoylamino moieties, three recurrent frameworks in antimicrobial research. Initial in silico evaluations were conducted on the designed compounds, highlighting favorable ADMET and drug-likeness properties, which were synthesized through a multistep strategy, isolated, and fully characterized. The whole set was tested in vitro against Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 10145 representative Gram-positive and Gram-negative strains, respectively. Notably, 5k exhibited potent and selective activity against S. aureus (MIC 10 μM), with a dose- and time-dependent response and capability to affect cell membrane integrity. On the other hand, no significant activity was observed against P. aeruginosa. Further in silico docking and molecular dynamics studies highlighted strong interactions of 5k with bacterial enzymes, such as tyrosyl-tRNA synthetase, pyruvate kinase, and DNA gyrase B, suggesting potential modes of action. These findings underscore the value of the hybridization approach in producing new antimicrobial agents, guiding future optimization for broader-spectrum activity.
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Affiliation(s)
- Gabriele La Monica
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; (G.L.M.); (A.G.); (A.B.); (F.A.); (A.L.); (R.A.)
| | - Annamaria Gallo
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; (G.L.M.); (A.G.); (A.B.); (F.A.); (A.L.); (R.A.)
| | - Alessia Bono
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; (G.L.M.); (A.G.); (A.B.); (F.A.); (A.L.); (R.A.)
| | - Federica Alamia
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; (G.L.M.); (A.G.); (A.B.); (F.A.); (A.L.); (R.A.)
| | - Antonino Lauria
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; (G.L.M.); (A.G.); (A.B.); (F.A.); (A.L.); (R.A.)
- NBFC, National Biodiversity Future Center, Piazza Marina 61, 90133 Palermo, Italy
| | - Rosa Alduina
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; (G.L.M.); (A.G.); (A.B.); (F.A.); (A.L.); (R.A.)
- NBFC, National Biodiversity Future Center, Piazza Marina 61, 90133 Palermo, Italy
| | - Annamaria Martorana
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; (G.L.M.); (A.G.); (A.B.); (F.A.); (A.L.); (R.A.)
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12
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Zhou J, Chen Q, Ren R, Yang J, Liu B, Horton JR, Chang C, Li C, Maksoud L, Yang Y, Rotili D, Jain AK, Zhang X, Blumenthal RM, Chen T, Gao Y, Valente S, Mai A, Cheng X. Quinoline-based compounds can inhibit diverse enzymes that act on DNA. Cell Chem Biol 2024; 31:2112-2127.e6. [PMID: 39437789 DOI: 10.1016/j.chembiol.2024.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 08/07/2024] [Accepted: 09/25/2024] [Indexed: 10/25/2024]
Abstract
DNA methylation, as exemplified by cytosine-C5 methylation in mammals and adenine-N6 methylation in bacteria, is a key epigenetic process. Developing non-nucleoside inhibitors to cause DNA hypomethylation is crucial for treating various conditions without the toxicities associated with existing cytidine-based hypomethylating agents. This study characterized fifteen quinoline-based analogs, particularly compounds with additions like a methylamine (9) or methylpiperazine (11), which demonstrate similar low micromolar inhibitory potency against human DNMT1 and Clostridioides difficile CamA. These compounds (9 and 11) intercalate into CamA-bound DNA via the minor groove, causing a conformational shift that moves the catalytic domain away from the DNA. This study adds to the limited examples of DNA methyltransferases being inhibited by non-nucleotide compounds through DNA intercalation. Additionally, some quinoline-based analogs inhibit other DNA-interacting enzymes, such as polymerases and base excision repair glycosylases. Finally, compound 11 elicits DNA damage response via p53 activation in cancer cells.
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Affiliation(s)
- Jujun Zhou
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Qin Chen
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ren Ren
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jie Yang
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Bigang Liu
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - John R Horton
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Caleb Chang
- Department of Biosciences, Rice University, Houston, TX 77005, USA
| | - Chuxuan Li
- Department of Biosciences, Rice University, Houston, TX 77005, USA
| | - Leora Maksoud
- Department of Biosciences, Rice University, Houston, TX 77005, USA
| | - Yifei Yang
- Department of Biosciences, Rice University, Houston, TX 77005, USA
| | - Dante Rotili
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy
| | - Abhinav K Jain
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Xing Zhang
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Robert M Blumenthal
- Department of Medical Microbiology and Immunology, and Program in Bioinformatics, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
| | - Taiping Chen
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yang Gao
- Department of Biosciences, Rice University, Houston, TX 77005, USA
| | - Sergio Valente
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy
| | - Antonello Mai
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy; Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy
| | - Xiaodong Cheng
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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13
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Long Y, Yang X, Xu Y, Liu L, Wang N, Chu Y, Deng J, Ji Q. Design and synthesis of spiro[pyrrolidine-3,3'-quinoline]-2,2'-dione derivatives as novel antifungal agents targeting chitin synthase. Eur J Med Chem 2024; 279:116895. [PMID: 39316847 DOI: 10.1016/j.ejmech.2024.116895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 09/07/2024] [Accepted: 09/17/2024] [Indexed: 09/26/2024]
Abstract
A novel spiro [pyrrolidine-3',3'-quinoline]-2,2'-dione scaffold was constructed using fragments of quinoline and pyrrolidine. Subsequently, two series of derivatives were designed based on this scaffold. The enzyme inhibition experiments revealed that all designed compounds had moderate to good inhibitory activity against chitin synthase (CHS). The inhibitory effects of compounds 5i, 5j, 8i and 8n were approximately equal to that of control drug polyoxin B (PB, IP = 86.4 ± 2.9 %, IC50 = 0.082 ± 0.013 mM) which is a well-established CHS inhibitor. The results from enzyme kinetic parameters assays proved that these compounds act as non-competitive inhibitors of CHS. The sorbitol protection experiments demonstrated the tested compounds disrupted the synthesis of cell wall, which further verified that the target of these compounds is CHS. The experiments of antimicrobial showed that compounds 5b, 5f, 5i, 5j, 8f, 8i, 8m, 8n and 8o had strong antifungal activity against the four tested pathogenic fungi strains frequently emerging in clinical setting, with MIC values ranging from 4 to 32 μg/mL, which were either superior to or comparable with those of PB or fluconazole. Furthermore, these compounds displayed synergistic or additive effects when combined with fluconazole and these active compounds also showed promising activity against fluconazole-resistant and micafungin-resistant fungi variants. The result of antimicrobial experiments indicated that these compounds had minimal activity to tested bacterial strains. This suggests that they had selective antifungal activity. The results of ADME prediction, in conjunction with the cytotoxicity assay results, indicated that these compounds had favorable pharmacokinetic profiles and low toxicity. In addition, molecular docking studies illustrated that the compound had a strong affinity with the CHS, which was consistent with the results of enzymatic assays. These findings indicated that the designed compounds are non-competitive inhibitors of CHS with good selectivity and broad-spectrum antifungal activity, and possess significant antifungal activity against drug-resistant fungi, suggesting their potential as lead compounds for the development of novel drugs against drug-resistant fungi.
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Affiliation(s)
- Yan Long
- School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, PR China
| | - Xinglong Yang
- School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, PR China
| | - Yajie Xu
- School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, PR China
| | - Lige Liu
- School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, PR China
| | - Nan Wang
- School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, PR China
| | - Yiwen Chu
- Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, 610106, PR China
| | - Junfeng Deng
- Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, 610106, PR China.
| | - Qingggang Ji
- School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, PR China.
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14
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Wang K, Wang R, Yan Z, Li Y, Shi Y, Ge JY, Bai Y, Chen Z, Zhang L. Rational Design of a Highly Sensitive Carboxylesterase Probe and Its Application in High-Throughput Screening for Uncovering Carboxylesterase Inhibitors. J Org Chem 2024; 89:14650-14657. [PMID: 38720168 DOI: 10.1021/acs.joc.4c00699] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2024]
Abstract
Tracking carboxylesterases (CESs) through noninvasive and dynamic imaging is of great significance for diagnosing and treating CES-related metabolic diseases. Herein, three BODIPY-based fluorescent probes with a pyridine unit quaternarized via an acetoxybenzyl group were designed and synthesized to detect CESs based on the photoinduced electron transfer process. Notably, among these probes, BDPN2-CES exhibited a remarkable 182-fold fluorescence enhancement for CESs within 10 min. Moreover, BDPN2-CES successfully enabled real-time imaging of endogenous CES variations in living cells. Using BDPN2-CES, a visual high-throughput screening method for CES inhibitors was established, culminating in the discovery of an efficient inhibitor, WZU-13, sourced from a chemical library. These findings suggest that BDPN2-CES could provide a new avenue for diagnosing CES-related diseases, and WZU-13 emerges as a promising therapeutic candidate for CES-overexpression pathological processes.
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Affiliation(s)
- Kexin Wang
- College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, P. R. China
| | - Ruoxi Wang
- College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, P. R. China
| | - Zihui Yan
- School of Pharmacy, Changzhou University, Changzhou 213164, P. R. China
| | - Yi Li
- School of Pharmacy, Changzhou University, Changzhou 213164, P. R. China
| | - Yangchen Shi
- College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, P. R. China
| | - Jing-Yuan Ge
- College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, P. R. China
| | - Yang Bai
- School of Pharmacy, Changzhou University, Changzhou 213164, P. R. China
| | - Zhongyan Chen
- College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, P. R. China
- Key Lab of Biohealth Materials and Chemistry of Wenzhou, Wenzhou University, Wenzhou 325035, P. R. China
| | - Lei Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, P. R. China
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15
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Prats Luján A, Faizan Bhat M, Acosta Marko EE, Fodran P, Poelarends GJ. Exploiting Nitroreductases for the Tailored Photoenzymatic Synthesis of Structurally Diverse Heterocyclic Compounds. Chemistry 2024; 30:e202402380. [PMID: 39011613 DOI: 10.1002/chem.202402380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 07/15/2024] [Accepted: 07/16/2024] [Indexed: 07/17/2024]
Abstract
N-heterocyclic compounds have a broad range of applications and their selective synthesis is very appealing for the pharmaceutical and agrochemical industries. Herein we report the usage of the flavin-dependent nitroreductase BaNTR1 for the photoenzymatic synthesis of various anthranils and quinolines from retro-synthetically designed o-nitrophenyl-substituted carbonyl substrates, achieving high conversions (up to >99 %) and good product yields (up to 96 %). Whereas the effective production of anthranils required the inclusion of H2O2 in the reaction mixtures to accumulate the needed hydroxylamine intermediates, the formation of quinolines required the use of anaerobic or reducing conditions to efficiently generate the essential amine intermediates. Critical to our success was the high chemoselectivity of BaNTR1, performing selective reduction of the nitro group without reduction of the carbonyl moiety or the activated carbon-carbon double bond. The results highlight the usefulness of an innocuous chlorophyll- and nitroreductase-based photoenzymatic system for the tailored synthesis of diverse N-heterocycles from simple nitro compounds.
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Affiliation(s)
- Alejandro Prats Luján
- Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands
| | - Mohammad Faizan Bhat
- Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands
| | - Edgar Eduardo Acosta Marko
- Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands
| | - Peter Fodran
- Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands
| | - Gerrit J Poelarends
- Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands
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16
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Díaz I, Salido S, Nogueras M, Cobo J. Synthesis of Ethyl Pyrimidine-Quinolincarboxylates Selected from Virtual Screening as Enhanced Lactate Dehydrogenase (LDH) Inhibitors. Int J Mol Sci 2024; 25:9744. [PMID: 39273691 PMCID: PMC11396203 DOI: 10.3390/ijms25179744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 08/29/2024] [Accepted: 09/06/2024] [Indexed: 09/15/2024] Open
Abstract
The inhibition of the hLDHA (human lactate dehydrogenase A) enzyme has been demonstrated to be of great importance in the treatment of cancer and other diseases, such as primary hyperoxalurias. In that regard, we have designed, using virtual docking screening, a novel family of ethyl pyrimidine-quinolinecarboxylate derivatives (13-18)(a-d) as enhanced hLDHA inhibitors. These inhibitors were synthesised through a convergent pathway by coupling the key ethyl 2-aminophenylquinoline-4-carboxylate scaffolds (7-12), which were prepared by Pfitzinger synthesis followed by a further esterification, to the different 4-aryl-2-chloropyrimidines (VIII(a-d)) under microwave irradiation at 150-170 °C in a green solvent. The values obtained from the hLDHA inhibition were in line with the preliminary of the preliminary docking results, the most potent ones being those with U-shaped disposition. Thirteen of them showed IC50 values lower than 5 μM, and for four of them (16a, 18b, 18c and 18d), IC50 ≈ 1 μM. Additionally, all compounds with IC50 < 10 μM were also tested against the hLDHB isoenzyme, resulting in three of them (15c, 15d and 16d) being selective to the A isoform, with their hLDHB IC50 > 100 μM, and the other thirteen behaving as double inhibitors.
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Affiliation(s)
| | | | | | - Justo Cobo
- Facultad de Ciencias Experimentales, Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, E-23071 Jaén, Spain; (I.D.); (S.S.); (M.N.)
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17
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La Monica G, Bono A, Alamia F, Lauria A, Martorana A. Bioisosteric heterocyclic analogues of natural bioactive flavonoids by scaffold-hopping approaches: State-of-the-art and perspectives in medicinal chemistry. Bioorg Med Chem 2024; 109:117791. [PMID: 38870715 DOI: 10.1016/j.bmc.2024.117791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 05/13/2024] [Accepted: 06/05/2024] [Indexed: 06/15/2024]
Abstract
The flavonoid family is a set of well-known bioactive natural molecules, with a wide range of potential therapeutic applications. Despite the promising results obtained in preliminary in vitro/vivo studies, their pharmacokinetic and pharmacodynamic profiles are severely compromised by chemical instability. To address this issue, the scaffold-hopping approach is a promising strategy for the structural optimization of natural leads to discover more potent analogues. In this scenario, this Perspective provides a critical analysis on how the replacement of the chromon-4-one flavonoid core with other bioisosteric nitrogen/sulphur heterocycles might affect the chemical, pharmaceutical and biological properties of the resulting new chemical entities. The investigated derivatives were classified on the basis of their biological activity and potential therapeutic indications. For each session, the target(s), the specific mechanism of action, if available, and the key pharmacophoric moieties were highlighted, as revealed by X-ray crystal structures and in silico structure-based studies. Biological activity data, in vitro/vivo studies, were examined: a particular focus was given on the improvements observed with the new heterocyclic analogues compared to the natural flavonoids. This overview of the scaffold-hopping advantages in flavonoid compounds is of great interest to the medicinal chemistry community to better exploit the vast potential of these natural molecules and to identify new bioactive molecules.
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Affiliation(s)
- Gabriele La Monica
- Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, University of Palermo, Viale delle Scienze, Ed. 17, I-90128 Palermo, Italy
| | - Alessia Bono
- Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, University of Palermo, Viale delle Scienze, Ed. 17, I-90128 Palermo, Italy
| | - Federica Alamia
- Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, University of Palermo, Viale delle Scienze, Ed. 17, I-90128 Palermo, Italy
| | - Antonino Lauria
- Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, University of Palermo, Viale delle Scienze, Ed. 17, I-90128 Palermo, Italy
| | - Annamaria Martorana
- Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, University of Palermo, Viale delle Scienze, Ed. 17, I-90128 Palermo, Italy.
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18
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Côrte-Real L, Sergi B, Yildirim B, Colucas R, Starosta R, Fontrodona X, Romero I, André V, Acilan C, Correia I. Enhanced selectivity towards melanoma cells with zinc(II)-Schiff bases containing imidazole derivatives. Dalton Trans 2024; 53:9416-9432. [PMID: 38758025 DOI: 10.1039/d4dt00733f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2024]
Abstract
Zinc(II)-complexes with the general formula [Zn(L)2] containing 8-hydroxyquinoline Schiff bases functionalized with 1-(3-aminopropyl)imidazole or 1-(3-aminopropyl)-2-methyl-1H-imidazole on 2-position and their respective ligands (HL1 or HL2) were synthesized and characterized by NMR, UV-Vis, FTIR and CD spectroscopies as well as ESI-MS spectrometry. Single crystals of HL2 and [Zn(L1)2]n were analysed by SC-XRD. [Zn(L1)2]n shows a 1D polymeric chain structure of alternating Zn(II) cations and bridging Schiff base ligands, in contrast to previously reported monomeric structures of analogous complexes. DFT calculations were performed to rationalize the polymeric X-ray structure of Zn(L1)2. Results showed that the ligands can bind as bi- or tridentate to Zn(II) and there is the possibility of a dynamic behavior for the complexes in solution. Both ligands and complexes present limited stability in aqueous media, however, in the presence of bovine serum albumin the complexes are stable. Molecular docking simulations and circular dichroism spectroscopic studies suggest binding to this protein in close proximity to the Trp213 residue. Biological studies on a panel of cancer cells revealed that the Zn(II)-complexes have a lower impact on cell viability than cisplatin, except for triple-negative breast cancer cells in which they were comparable. Notwithstanding, they display much higher selectivity towards cancer cells vs. normal cells, than cisplatin. They induce the generation of ROS and DNA double-strand breaks, primarily through apoptosis as the mode of cell death. Overall, the novel Zn(II)-complexes demonstrate improved induction of apoptosis and higher selectivity, particularly for melanoma cells, compared to previously reported analogues, making them promising candidates for clinical application.
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Affiliation(s)
- Leonor Côrte-Real
- Centro de Química Estrutural, Institute of Molecular Sciences, and Department of Chemical Engineering, Instituto Superior Técnico, Universidade de Lisboa, Avenida Rovisco Pais 1, 1049-001 Lisboa, Portugal.
| | - Baris Sergi
- Koç University, Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey
| | - Busra Yildirim
- Koç University, Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey
| | - Raquel Colucas
- Centro de Química Estrutural, Institute of Molecular Sciences, and Department of Chemical Engineering, Instituto Superior Técnico, Universidade de Lisboa, Avenida Rovisco Pais 1, 1049-001 Lisboa, Portugal.
| | - Radosław Starosta
- Centro de Química Estrutural, Institute of Molecular Sciences, and Department of Chemical Engineering, Instituto Superior Técnico, Universidade de Lisboa, Avenida Rovisco Pais 1, 1049-001 Lisboa, Portugal.
- Faculty of Chemistry, University of Wrocław, ul. F. Joliot-Curie 14, 50-383 Wrocław, Poland
| | - Xavier Fontrodona
- Departament de Química and Serveis Técnicas de Recerca, Universitat de Girona, Spain
| | - Isabel Romero
- Departament de Química and Serveis Técnicas de Recerca, Universitat de Girona, Spain
| | - Vânia André
- Centro de Química Estrutural, Institute of Molecular Sciences, and Department of Chemical Engineering, Instituto Superior Técnico, Universidade de Lisboa, Avenida Rovisco Pais 1, 1049-001 Lisboa, Portugal.
| | - Ceyda Acilan
- Koç University, School of Medicine, Sariyer, Istanbul, Turkey.
- Koç University, Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey
| | - Isabel Correia
- Centro de Química Estrutural, Institute of Molecular Sciences, and Department of Chemical Engineering, Instituto Superior Técnico, Universidade de Lisboa, Avenida Rovisco Pais 1, 1049-001 Lisboa, Portugal.
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19
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Zinman PS, Welsh A, Omondi RO, Khan S, Prince S, Nordlander E, Smith GS. Aminoquinoline-based Re(I) tricarbonyl complexes: Insights into their antiproliferative activity and mechanisms of action. Eur J Med Chem 2024; 266:116094. [PMID: 38219660 DOI: 10.1016/j.ejmech.2023.116094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 12/13/2023] [Accepted: 12/21/2023] [Indexed: 01/16/2024]
Abstract
In an effort to develop new potent anticancer agents, two Schiff base rhenium(I) tricarbonyl complexes, containing the ubiquitous aminoquinoline scaffold, were synthesized. Both aminoquinoline ligands and Re(I) complexes showed adequate stability over a 48-h incubation period. Furthermore, the cytotoxic activity of the precursor ligands and rhenium(I) complexes were evaluated against the hormone-dependent MCF-7 and hormone-independent triple negative MDA-MB-231 breast cancer cell lines. Inclusion of the [Re(CO)3Cl]+ entity significantly enhanced the cytotoxicity of the aminoquinoline Schiff base ligands against the tested cancer cell lines. Remarkably, the incorporation of the Schiff-base iminoquinolyl entity notably enhanced the cytotoxic activity of the Re(I) complexes, in comparison with the iminopyridyl entity. Notably, the quinolyl-substituted complex showed up to three-fold higher activity than cisplatin against breast cancer cell lines, underpinning the significance of the quinoline pharmacophore in rational drug design. In addition, the most active Re(I) complex showed better selectivity towards the breast cancer cells over non-tumorigenic FG-0 cells. Western blotting revealed that the complexes increased levels of γH2AX, a key DNA damage response protein. Moreover, apoptosis was confirmed in both cell lines due to the detection of cleaved PARP. The complexes show favourable binding affinities towards both calf thymus DNA (CT-DNA), and bovine serum albumin (BSA), and the order of their interactions align with their cytotoxic effects. The in silico molecular simulations of the complexes were also performed with CT-DNA and BSA targets.
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Affiliation(s)
- Paige S Zinman
- Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa
| | - Athi Welsh
- Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa
| | - Reinner O Omondi
- Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa
| | - Saif Khan
- Department of Human Biology, University of Cape Town, Faculty of Health Science, Observatory, 7925, South Africa
| | - Sharon Prince
- Department of Human Biology, University of Cape Town, Faculty of Health Science, Observatory, 7925, South Africa
| | - Ebbe Nordlander
- Chemical Physics, Department of Chemistry, Lund University, Box 124, SE-221 00, Lund, Sweden
| | - Gregory S Smith
- Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa.
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20
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Adhikari S, Nath P, Das A, Datta A, Baildya N, Duttaroy AK, Pathak S. A review on metal complexes and its anti-cancer activities: Recent updates from in vivo studies. Biomed Pharmacother 2024; 171:116211. [PMID: 38290253 DOI: 10.1016/j.biopha.2024.116211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 12/22/2023] [Accepted: 01/22/2024] [Indexed: 02/01/2024] Open
Abstract
Research into cancer therapeutics has uncovered various potential medications based on metal-containing scaffolds after the discovery and clinical applications of cisplatin as an anti-cancer agent. This has resulted in many metallodrugs that can be put into medical applications. These metallodrugs have a wider variety of functions and mechanisms of action than pure organic molecules. Although platinum-based medicines are very efficient anti-cancer agents, they are often accompanied by significant side effects and toxicity and are limited by resistance. Some of the most studied and developed alternatives to platinum-based anti-cancer medications include metallodrugs based on ruthenium, gold, copper, iridium, and osmium, which showed effectiveness against many cancer cell lines. These metal-based medicines represent an exciting new category of potential cancer treatments and sparked a renewed interest in the search for effective anti-cancer therapies. Despite the widespread development of metal complexes touted as powerful and promising in vitro anti-cancer therapeutics, only a small percentage of these compounds have shown their worth in vivo models. Metallodrugs, which are more effective and less toxic than platinum-based drugs and can treat drug-resistant cancer cells, are the focus of this review. Here, we highlighted some of the most recently developed Pt, Ru, Au, Cu, Ir, and Os complexes that have shown significant in vivo antitumor properties between 2017 and 2023.
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Affiliation(s)
- Suman Adhikari
- Department of Chemistry, Govt. Degree Collage, Dharmanagar, Tripura (N) 799253, India.
| | - Priyatosh Nath
- Department of Human Physiology, Tripura University, Suryamaninagar, West Tripura 799022, India
| | - Alakesh Das
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai 603103, India
| | - Abhijit Datta
- Department of Botany, Ambedkar College, Fatikroy, Unakoti 799290, Tripura, India
| | - Nabajyoti Baildya
- Department of Chemistry, Milki High School, Milki, Malda 732209, India
| | - Asim K Duttaroy
- Department of Nutrition, Institute of Medical Sciences, Faculty of Medicine, University of Oslo, Norway.
| | - Surajit Pathak
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai 603103, India
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21
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Liang JW, Gao ZC, Yang LL, Zhang W, Chen MZ, Meng FH. Development of Acridone Derivatives: Targeting c-MYC Transcription in Triple-Negative Breast Cancer with Inhibitory Potential. Antioxidants (Basel) 2023; 13:11. [PMID: 38275631 PMCID: PMC10812579 DOI: 10.3390/antiox13010011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/10/2023] [Accepted: 12/12/2023] [Indexed: 01/27/2024] Open
Abstract
Breast cancer, especially the aggressive triple-negative subtype, poses a serious health threat to women. Unfortunately, effective targets are lacking, leading to a grim prognosis. Research highlights the crucial role of c-MYC overexpression in this form of cancer. Current inhibitors targeting c-MYC focus on stabilizing its G-quadruplex (G4) structure in the promoter region. They can inhibit the expression of c-MYC, which is highly expressed in triple-negative breast cancer (TNBC), and then regulate the apoptosis of breast cancer cells induced by intracellular ROS. However, the clinical prospects for the application of such inhibitors are not promising. In this research, we designed and synthesized 29 acridone derivatives. These compounds were assessed for their impact on intracellular ROS levels and cell activity, followed by comprehensive QSAR analysis and molecular docking. Compound N8 stood out, significantly increasing ROS levels and demonstrating potent anti-tumor activity in the TNBC cell line, with excellent selectivity shown in the docking results. This study suggests that acridone derivatives could stabilize the c-MYC G4 structure. Among these compounds, the small molecule N8 shows promising effects and deserves further investigation.
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Affiliation(s)
- Jing-Wei Liang
- School of Pharmacy, China Medical University, Shenyang 110000, China; (J.-W.L.); (Z.-C.G.); (L.-L.Y.); (W.Z.)
- School of Pharmacy, Hainan Medical University, Haikou 570100, China
| | - Zhi-Chao Gao
- School of Pharmacy, China Medical University, Shenyang 110000, China; (J.-W.L.); (Z.-C.G.); (L.-L.Y.); (W.Z.)
- Department of Medical Oncology, Cancer Hospital of China Medical University, Shenyang 110044, China
| | - Lu-Lu Yang
- School of Pharmacy, China Medical University, Shenyang 110000, China; (J.-W.L.); (Z.-C.G.); (L.-L.Y.); (W.Z.)
| | - Wei Zhang
- School of Pharmacy, China Medical University, Shenyang 110000, China; (J.-W.L.); (Z.-C.G.); (L.-L.Y.); (W.Z.)
| | - Ming-Zhe Chen
- School of Pharmacy, China Medical University, Shenyang 110000, China; (J.-W.L.); (Z.-C.G.); (L.-L.Y.); (W.Z.)
| | - Fan-Hao Meng
- School of Pharmacy, China Medical University, Shenyang 110000, China; (J.-W.L.); (Z.-C.G.); (L.-L.Y.); (W.Z.)
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22
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Kwon HC, Lee DH, Yoon M, Nayab S, Lee H, Han JH. Novel Cu(II) complexes as DNA-destabilizing agents and their DNA nuclease activity. Dalton Trans 2023; 52:16802-16811. [PMID: 37902974 DOI: 10.1039/d3dt02615a] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2023]
Abstract
Here, we report a series of four novel Cu complexes, namely 2-(piperidin-1-ylmethyl)quinoline copper(II) nitrate, [LACu(NO3)2] (Cu1), 4-(quinolin-2-ylmethyl)morpholine copper(II) nitrate, [LBCu(NO3)2] (Cu2), 4-(quinolin-2-ylmethyl)morpholine copper(II) chloride, [LBCuCl2] (Cu3), and 2-(piperidin-1-ylmethyl)pyridine copper(II) chloride, [LCCu(μ-Cl)Cl]2 (Cu4). X-ray diffraction studies revealed that the geometry around the Cu(II) center could be best described as distorted octahedral in Cu1 and Cu2, whereas Cu3 and Cu4 showed distorted tetrahedral and square pyramidal geometries, respectively. DNA binding studies showed that Cu complexes Cu1-3 containing quinoline interacted via minor groove binding, whereas the Cu4 complex containing pyridine interacted via intercalation. All Cu complexes containing quinoline and pyridine caused destabilization of DNA at specific homogeneous G-C regions. The Cu1-3 complexes as groove binders destabilized the DNA structure much more than the Cu4 complex as an intercalator. Regarding groove binders, the Cu2 complex containing quinoline and morpholine caused the highest distortion and destabilization of the DNA structure, leading to high DNA cleavage efficiency.
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Affiliation(s)
- Hee Chang Kwon
- Department of Chemical and Biological Engineering, Andong National University, 1375 Gyeongdong-ro, Andong, Gyeongbuk, Korea, 36729.
| | - Da Hyun Lee
- Department of Chemical and Biological Engineering, Andong National University, 1375 Gyeongdong-ro, Andong, Gyeongbuk, Korea, 36729.
| | - Minyoung Yoon
- Department of Chemistry and Green-Nano Materials Research Center, Kyungpook National University, 80 Daehakro, Bukgu, Daegu 41566, Republic of Korea.
| | - Saira Nayab
- Department of Chemistry and Green-Nano Materials Research Center, Kyungpook National University, 80 Daehakro, Bukgu, Daegu 41566, Republic of Korea.
- Department of Chemistry, Shaheed Benazir Bhutto University (SBBU), Sheringal Upper Dir (18050), Khyber Pakhtunkhwa, Islamic Republic of Pakistan
| | - Hyosun Lee
- Department of Chemistry and Green-Nano Materials Research Center, Kyungpook National University, 80 Daehakro, Bukgu, Daegu 41566, Republic of Korea.
| | - Ji Hoon Han
- Department of Chemical and Biological Engineering, Andong National University, 1375 Gyeongdong-ro, Andong, Gyeongbuk, Korea, 36729.
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Zhang S, Mo M, Lv M, Xia W, Liu K, Yu G, Yu J, Xu G, Zeng X, Cheng S, Xu B, Luo H, Meng X. Design, synthesis and bioevaluation of novel trifluoromethylquinoline derivatives as tubulin polymerization inhibitors. Future Med Chem 2023; 15:1967-1986. [PMID: 37937524 DOI: 10.4155/fmc-2023-0151] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2023] Open
Abstract
Aim: A series of novel trifluoromethylquinoline derivatives were designed, synthesized and evaluated for antitumor activities. Methodology: All compounds were evaluated for antiproliferative activity against four human cancer cell lines. Results: Among them, 5a, 5m, 5o and 6b exhibited remarkable antiproliferative activities against all the tested cell lines at nanomolar concentrations. Mechanism of action studies demonstrated that 6b targeted the colchicine binding site, potentially inhibiting tubulin polymerization, and further studies indicated that 6b could arrest LNCaP cells in the G2/M phase and induce cell apoptosis. Molecular docking confirmed that 6b could bind to the colchicine binding site. Conclusion: Results suggested that 6b could serve as a promising lead compound for the development of novel tubulin polymerization inhibitors and cancer therapy.
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Affiliation(s)
- Sisi Zhang
- State Key Laboratory of Functions & Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China
- Natural Products Research Center of Guizhou Province, Guiyang, 550014, China
- School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 550025, China
| | - Min Mo
- State Key Laboratory of Functions & Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China
- Natural Products Research Center of Guizhou Province, Guiyang, 550014, China
- School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 550025, China
| | - Mengfan Lv
- State Key Laboratory of Functions & Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China
- Natural Products Research Center of Guizhou Province, Guiyang, 550014, China
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, PR China
| | - Wen Xia
- Guizhou Bailing Enterprise Group Pharmaceutical Co. Ltd, Anshun Guizhou, 561000, China
| | - Kun Liu
- State Key Laboratory of Functions & Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China
- Natural Products Research Center of Guizhou Province, Guiyang, 550014, China
| | - Gang Yu
- State Key Laboratory of Functions & Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China
- Natural Products Research Center of Guizhou Province, Guiyang, 550014, China
| | - Jia Yu
- State Key Laboratory of Functions & Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China
- Natural Products Research Center of Guizhou Province, Guiyang, 550014, China
| | - Guangcan Xu
- State Key Laboratory of Functions & Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China
- Natural Products Research Center of Guizhou Province, Guiyang, 550014, China
| | - Xiaoping Zeng
- State Key Laboratory of Functions & Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China
- Natural Products Research Center of Guizhou Province, Guiyang, 550014, China
| | - Sha Cheng
- State Key Laboratory of Functions & Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China
- Natural Products Research Center of Guizhou Province, Guiyang, 550014, China
| | - Bixue Xu
- State Key Laboratory of Functions & Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China
- Natural Products Research Center of Guizhou Province, Guiyang, 550014, China
| | - Heng Luo
- State Key Laboratory of Functions & Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China
- Natural Products Research Center of Guizhou Province, Guiyang, 550014, China
| | - Xueling Meng
- State Key Laboratory of Functions & Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China
- Natural Products Research Center of Guizhou Province, Guiyang, 550014, China
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24
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La Monica G, Pizzolanti G, Baiamonte C, Bono A, Alamia F, Mingoia F, Lauria A, Martorana A. Design and Synthesis of Novel Thieno[3,2- c]quinoline Compounds with Antiproliferative Activity on RET-Dependent Medullary Thyroid Cancer Cells. ACS OMEGA 2023; 8:34640-34649. [PMID: 37779971 PMCID: PMC10536062 DOI: 10.1021/acsomega.3c03578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 07/25/2023] [Indexed: 10/03/2023]
Abstract
RET kinase gain-of-function mutations represent the main cause of the high aggressiveness and invasiveness of medullary thyroid cancer (MTC). The selective inhibition of the RET kinase is a suitable strategy for the treatment of this endocrine neoplasia. Herein, we performed an innovative ligand-based virtual screening protocol using the DRUDITonline web service, focusing on the RET kinase as a biological target. In this process, thieno[3,2-c]quinolines 6a-e and 7a-e were proposed as new potential RET inhibitors. The selected compounds were synthetized by appropriate synthetic strategies, and in vitro evaluation of antiproliferative properties conducted on the particularly aggressive MTC cell line TT(C634R) identified compounds 6a-d as promising anticancer agents, with IC50 values in the micromolar range. Further structure-based computational studies revealed a significant capability of the most active compounds to the complex RET tyrosine kinase domain. The interesting antiproliferative results supported by in silico predictions suggest that these compounds may represent a starting point for the development of a new series of small heterocyclic molecules for the treatment of MTC.
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Affiliation(s)
- Gabriele La Monica
- Dipartimento di Scienze e
Tecnologie Biologiche Chimiche e Farmaceutiche, University of Palermo, viale delle Scienze, Ed.17, 90128 Palermo, Italy
| | - Giuseppe Pizzolanti
- Dipartimento di Scienze e
Tecnologie Biologiche Chimiche e Farmaceutiche, University of Palermo, viale delle Scienze, Ed.17, 90128 Palermo, Italy
| | - Concetta Baiamonte
- Dipartimento di Scienze e
Tecnologie Biologiche Chimiche e Farmaceutiche, University of Palermo, viale delle Scienze, Ed.17, 90128 Palermo, Italy
| | - Alessia Bono
- Dipartimento di Scienze e
Tecnologie Biologiche Chimiche e Farmaceutiche, University of Palermo, viale delle Scienze, Ed.17, 90128 Palermo, Italy
| | - Federica Alamia
- Dipartimento di Scienze e
Tecnologie Biologiche Chimiche e Farmaceutiche, University of Palermo, viale delle Scienze, Ed.17, 90128 Palermo, Italy
| | - Francesco Mingoia
- Dipartimento di Scienze e
Tecnologie Biologiche Chimiche e Farmaceutiche, University of Palermo, viale delle Scienze, Ed.17, 90128 Palermo, Italy
| | - Antonino Lauria
- Dipartimento di Scienze e
Tecnologie Biologiche Chimiche e Farmaceutiche, University of Palermo, viale delle Scienze, Ed.17, 90128 Palermo, Italy
| | - Annamaria Martorana
- Dipartimento di Scienze e
Tecnologie Biologiche Chimiche e Farmaceutiche, University of Palermo, viale delle Scienze, Ed.17, 90128 Palermo, Italy
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25
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Carmona JA, Rodríguez-Salamanca P, Fernández R, Lassaletta JM, Hornillos V. Dynamic Kinetic Resolution of 2-(Quinolin-8-yl)Benzaldehydes: Atroposelective Iridium-Catalyzed Transfer Hydrogenative Allylation. Angew Chem Int Ed Engl 2023; 62:e202306981. [PMID: 37389578 DOI: 10.1002/anie.202306981] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/30/2023] [Accepted: 06/30/2023] [Indexed: 07/01/2023]
Abstract
An atroposelective Ir-catalyzed dynamic kinetic resolution (DKR) of 2-(quinolin-8-yl)benzaldehydes/1-naphthaldehydes by transfer hydrogenative coupling of allyl acetate is disclosed. The allylation reaction takes place with simultaneous installation of central and axial chirality, reaching high diastereoselectivities and excellent enantiomeric excesses when ortho-cyclometalated iridium-DM-BINAP is used as the catalyst. The racemization of the substrates occurs through a designed transient Lewis acid-base interaction between the quinoline nitrogen atom and the aldehyde carbonyl group.
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Affiliation(s)
- José A Carmona
- Instituto Investigaciones Químicas (CSIC-US) and Centro de Innovación en Química Avanzada (ORFEO-CINQA), C/Américo Vespucio 49, 41092, Sevilla, Spain
| | - Patricia Rodríguez-Salamanca
- Instituto Investigaciones Químicas (CSIC-US) and Centro de Innovación en Química Avanzada (ORFEO-CINQA), C/Américo Vespucio 49, 41092, Sevilla, Spain
| | - Rosario Fernández
- Departamento de Química Orgánica, Universidad de Sevilla and Centro de Innovación en Química Avanzada (ORFEO-CINQA), C/Prof. García González 1, 41012, Sevilla, Spain
| | - José M Lassaletta
- Instituto Investigaciones Químicas (CSIC-US) and Centro de Innovación en Química Avanzada (ORFEO-CINQA), C/Américo Vespucio 49, 41092, Sevilla, Spain
| | - Valentín Hornillos
- Instituto Investigaciones Químicas (CSIC-US) and Centro de Innovación en Química Avanzada (ORFEO-CINQA), C/Américo Vespucio 49, 41092, Sevilla, Spain
- Departamento de Química Orgánica, Universidad de Sevilla and Centro de Innovación en Química Avanzada (ORFEO-CINQA), C/Prof. García González 1, 41012, Sevilla, Spain
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26
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Nandakumar V, Sundarasamy A, Adhigaman K, Ramasamy SS, Paulpandi M, Kodiveri Muthukaliannan G, Narayanasamy A, Thangaraj S. Anti-proliferative activity of nitroquinolone fused acylhydrazones as non-small cell human lung cancer agents. RSC Med Chem 2023; 14:1331-1343. [PMID: 37484570 PMCID: PMC10357927 DOI: 10.1039/d3md00165b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 05/16/2023] [Indexed: 07/25/2023] Open
Abstract
A new series of 8-nitroquinolone-based aromatic heterocyclic acyl hydrazones have been synthesised and characterised through various spectroscopic techniques. They were theoretically examined for molecular docking with various proteins related to the apoptosis of the non-small cell lung cancer cell line A549. The results indicate that the possible modes of interaction of all the synthesised compounds are compatible for use as anti-proliferative drugs. Also, the drug-likeness of the compounds was examined through theoretical ADMET analysis, which indicated good gastrointestinal absorption as well as low toxicity. Selected compounds were evaluated for their in vitro anti-cancer activity using A549, MCF-7 and HeLa cell lines through an MTT assay to determine cytotoxicity. Compounds 3c, 3a and 11c exhibited significant cytotoxicity towards A549 cells in the order of 3c (15.3 ± 0.7) > 3a (15.8 ± 0.1) > 11c (17.1 ± 0.2), whereas all the compounds show insignificant toxicity on normal human embryonic kidney cells up to a concentration of 200 μM. The best compounds among the series (3c and 11c) were chosen for further detection of apoptosis through fluorescence microscopic techniques using AO/EtBr and DAPI. The reduced DNA synthesis during the cell cycle was also investigated through flow cytometric techniques. The results indicate that the compounds possess significant anticancer properties due to the activation of the mitochondrial mediated intrinsic pathway.
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Affiliation(s)
- Vandana Nandakumar
- School of Chemical Sciences, Department of Chemistry, Bharathiar University Coimbatore Tamil Nadu 641046 India
| | - Amsaveni Sundarasamy
- School of Chemical Sciences, Department of Chemistry, Bharathiar University Coimbatore Tamil Nadu 641046 India
| | - Kaviyarasu Adhigaman
- School of Chemical Sciences, Department of Chemistry, Bharathiar University Coimbatore Tamil Nadu 641046 India
| | - Sentamil Selvi Ramasamy
- School of Chemical Sciences, Department of Chemistry, Bharathiar University Coimbatore Tamil Nadu 641046 India
| | - Manickam Paulpandi
- Disease Proteomics laboratory, School of Life Sciences, Department of Zoology, Bharathiar University Coimbatore Tamil Nadu 641046 India
| | | | - Arul Narayanasamy
- Disease Proteomics laboratory, School of Life Sciences, Department of Zoology, Bharathiar University Coimbatore Tamil Nadu 641046 India
| | - Suresh Thangaraj
- School of Chemical Sciences, Department of Chemistry, Bharathiar University Coimbatore Tamil Nadu 641046 India
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27
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Sheir SK, Elmongy EI, Mohamad AH, Osman GY, Bendary SE, Ahmed AAS, Binsuwaidan R, El-Sayed IET. Molluscicidal and Larvicidal Potency of N-Heterocylic Analogs against Biomophalaria alexandrina Snails and Schistosoma mansoni Larval Stages. Pharmaceutics 2023; 15:pharmaceutics15041200. [PMID: 37111685 PMCID: PMC10142358 DOI: 10.3390/pharmaceutics15041200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/22/2023] [Accepted: 04/04/2023] [Indexed: 04/29/2023] Open
Abstract
This work describes the synthesis of quinoline-based N--heterocyclic arenes and their biological evaluation as molluscicides against adult Biomophalaria alexandrina snails as well as larvicides against Schistosoma mansoni larvae (miracidia and cercariae). Molecular docking studies were demonstrated to investigate their affinity for cysteine protease protein as an interesting target for antiparasitics. Compound AEAN showed the best docking results followed by APAN in comparison to the co-crystallized ligand D1R reflected by their binding affinities and RMSD values. The egg production, hatchability of B. alexandrina snails and ultrastructural topography of S. mansoni cercariae using SEM were assessed. Biological evaluations (hatchability and egg-laying capacity) revealed that the quinoline hydrochloride salt CAAQ was the most effective compound against adult B. alexandrina snails, whereas the indolo-quinoline derivative APAN had the most efficiency against miracidia, and the acridinyl derivative AEAA was the most effective against cercariae and caused 100% mortality. CAAQ and AEAA were found to modulate the biological responses of B. alexandrina snails with/without S. mansoni infection and larval stages that will affect S. mansoni infection. AEAA caused deleterious morphological effects on cercariae. CAAQ caused inhibition in the number of eggs/snail/week and reduced reproductive rate to 43.8% in all the experimental groups. CAAQ and AEAA can be recommended as an effective molluscicide of plant origin for the control program of schistosomiasis.
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Affiliation(s)
- Sherin K Sheir
- Zoology Department, Faculty of Science, Menoufia University, Shibin El Kom 32511, Egypt
| | - Elshaymaa I Elmongy
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Azza H Mohamad
- Zoology Department, Faculty of Science, Menoufia University, Shibin El Kom 32511, Egypt
| | - Gamalat Y Osman
- Zoology Department, Faculty of Science, Menoufia University, Shibin El Kom 32511, Egypt
| | - Shimaa E Bendary
- Zoology Department, Faculty of Science, Menoufia University, Shibin El Kom 32511, Egypt
| | - Abdullah A S Ahmed
- Chemistry Department, Faculty of Science, Menoufia University, Shibin El-Kom 32511, Egypt
| | - Reem Binsuwaidan
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
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28
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Shen WY, Jia CP, Liao LY, Chen LL, Yuan CC, Gu YQ, Liu YH, Liang H, Chen ZF. Copper(II) complex enhanced chemodynamic therapy through GSH depletion and autophagy flow blockade. Dalton Trans 2023; 52:3287-3294. [PMID: 36691961 DOI: 10.1039/d2dt04108a] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Three copper(II) complexes C1-C3 were synthesized and fully characterized as chemodynamic therapy (CDT) anticancer agents. C1-C3 showed greater cytotoxicity than their ligands toward SK-OV-3 and T24 cells. Particularly, C2 showed high cytotoxicity toward T24 cells and low cytotoxicity toward normal human HL-7702 and WI-38 cells. Mechanistic studies demonstrated that C2 oxidized GSH to GSSG and produced ˙OH, which induced mitochondrial dysfunction and ER stress, finally leading to apoptosis of T24 cells. In addition, C2 inhibited autophagy by blocking autophagy flow, thereby closing the self-protection pathway of oxidative stress to enhance CDT. Importantly, C2 significantly inhibited T24 tumor growth with 57.1% inhibition in a mouse xenograft model. C2 is a promising lead as a potential CDT anticancer agent.
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Affiliation(s)
- Wen-Ying Shen
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, P. R. China. .,Scientific Research Center, Guilin Medical University, Guilin, 541199, P. R China
| | - Chun-Peng Jia
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, P. R. China.
| | - Li-Yi Liao
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, P. R. China.
| | - Liu-Lin Chen
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, P. R. China.
| | - Cheng-Cheng Yuan
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, P. R. China.
| | - Yun-Qiong Gu
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, P. R. China.
| | - Yang-Han Liu
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, P. R. China.
| | - Hong Liang
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, P. R. China.
| | - Zhen-Feng Chen
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, P. R. China.
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29
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Pastuch-Gawołek G, Szreder J, Domińska M, Pielok M, Cichy P, Grymel M. A Small Sugar Molecule with Huge Potential in Targeted Cancer Therapy. Pharmaceutics 2023; 15:913. [PMID: 36986774 PMCID: PMC10056414 DOI: 10.3390/pharmaceutics15030913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/01/2023] [Accepted: 03/09/2023] [Indexed: 03/14/2023] Open
Abstract
The number of cancer-related diseases is still growing. Despite the availability of a large number of anticancer drugs, the ideal drug is still being sought that would be effective, selective, and overcome the effect of multidrug resistance. Therefore, researchers are still looking for ways to improve the properties of already-used chemotherapeutics. One of the possibilities is the development of targeted therapies. The use of prodrugs that release the bioactive substance only under the influence of factors characteristic of the tumor microenvironment makes it possible to deliver the drug precisely to the cancer cells. Obtaining such compounds is possible by coupling a therapeutic agent with a ligand targeting receptors, to which the attached ligand shows affinity and is overexpressed in cancer cells. Another way is to encapsulate the drug in a carrier that is stable in physiological conditions and sensitive to conditions of the tumor microenvironment. Such a carrier can be directed by attaching to it a ligand recognized by receptors typical of tumor cells. Sugars seem to be ideal ligands for obtaining prodrugs targeted at receptors overexpressed in cancer cells. They can also be ligands modifying polymers' drug carriers. Furthermore, polysaccharides can act as selective nanocarriers for numerous chemotherapeutics. The proof of this thesis is the huge number of papers devoted to their use for modification or targeted transport of anticancer compounds. In this work, selected examples of broad-defined sugars application for improving the properties of both already-used drugs and substances exhibiting anticancer activity are presented.
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Affiliation(s)
- Gabriela Pastuch-Gawołek
- Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, B. Krzywoustego 4, 44-100 Gliwice, Poland
- Biotechnology Centre, Silesian University of Technology, B. Krzywoustego 8, 44-100 Gliwice, Poland
| | - Julia Szreder
- Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, B. Krzywoustego 4, 44-100 Gliwice, Poland
| | - Monika Domińska
- Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, B. Krzywoustego 4, 44-100 Gliwice, Poland
| | - Mateusz Pielok
- Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, B. Krzywoustego 4, 44-100 Gliwice, Poland
| | - Piotr Cichy
- Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, B. Krzywoustego 4, 44-100 Gliwice, Poland
| | - Mirosława Grymel
- Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, B. Krzywoustego 4, 44-100 Gliwice, Poland
- Biotechnology Centre, Silesian University of Technology, B. Krzywoustego 8, 44-100 Gliwice, Poland
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Vera DR, Ardila DM, Palma A, Cobo J, Glidewell C. Conversion of 2-methyl-4-styrylquinolines into 2,4-distyrylquinolines: synthesis, and spectroscopic and structural characterization of five examples. Acta Crystallogr C Struct Chem 2023; 79:94-103. [PMID: 36871291 PMCID: PMC9985948 DOI: 10.1107/s2053229623001432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 02/16/2023] [Indexed: 02/24/2023] Open
Abstract
Four new 2,4-distyrylquinolines and one 2-styryl-4-[2-(thiophen-2-yl)vinyl]quinoline have been synthesized using indium trichloride condensation reactions between aromatic aldehydes and the corresponding 2-methylquinolines, which were themselves prepared using Friedländer annulation reactions between mono- or diketones and (2-aminophenyl)chalcones: the products have all been fully characterized by spectroscopic and crystallographic methods. 2,4-Bis[(E)-styryl]quinoline, C25H19N, (IIa), and its dichloro analogue, 2-[(E)-2,4-dichlorostyryl]-4-[(E)-styryl]quinoline, C25H17Cl2N, (IIb), exhibit different orientations of the 2-styryl unit relative to the quinoline nucleus. In each of the 3-benzoyl analogues {2-[(E)-4-bromostyryl]-4-[(E)-styryl]quinolin-3-yl}(phenyl)methanone, C32H22BrNO, (IIc), {2-[(E)-4-bromostyryl]-4-[(E)-4-chlorostyryl]quinolin-3-yl}(phenyl)methanone, C32H21BrClNO, (IId), and {2-[(E)-4-bromostyryl]-4-[(E)-2-(thiophen-2-yl)vinyl]quinolin-3-yl}(phenyl)methanone, C30H20BrNOS, (IIe), the orientation of the 2-styryl unit is similar to that in (IIa), but the orientation of the 4-arylvinyl units show considerable variation. The thiophene unit in (IIe) is disordered over two sets of atomic sites having occupancies of 0.926 (3) and 0.074 (3). There are no hydrogen bonds of any kind in the structure of (IIa), but in (IId), a single C-H...O hydrogen bond links the molecules into cyclic centrosymmetric R22(20) dimers. A combination of C-H...N and C-H...π hydrogen bonds links the molecules of (IIb) into a three-dimensional framework structure. A combination of three C-H...π hydrogen bonds links the molecules of (IIc) into sheets, and a combination of C-H...O and C-H...π hydrogen bonds forms sheets in (IIe). Comparisons are made with the structures of some related compounds.
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Affiliation(s)
- Diana R. Vera
- Laboratorio de Síntesis Orgánica, Escuela de Química, Universidad Industrial de Santander, AA 678, Bucaramanga, Colombia
| | - Diana M. Ardila
- Laboratorio de Síntesis Orgánica, Escuela de Química, Universidad Industrial de Santander, AA 678, Bucaramanga, Colombia
| | - Alirio Palma
- Laboratorio de Síntesis Orgánica, Escuela de Química, Universidad Industrial de Santander, AA 678, Bucaramanga, Colombia
| | - Justo Cobo
- Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, 23071 Jaén, Spain
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Christidou A, Zavalani K, Hatzidimitriou AG, Psomas G. Copper(II) complexes with 3,5-dihalogeno-salicylaldehydes: Synthesis, structure and interaction with DNA and albumins. J Inorg Biochem 2023; 238:112049. [PMID: 36327500 DOI: 10.1016/j.jinorgbio.2022.112049] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/12/2022] [Accepted: 10/21/2022] [Indexed: 11/21/2022]
Abstract
Eight copper(II) complexes of 3,5-dichloro-salicyladehyde or 3,5-dibromo-salicyladehyde (3,5-diX-saloH, X = Br or Cl) were synthesized in the absence or presence of a N,N'-donor co-ligand such as 2,2'-bipyridylamine, 1,10-phenanthroline, or 2,2'-bipyridine. The resultant compounds were formulated as [Cu(3,5-diX-salo)2(MeOH)2] (1-2) and [Cu(3,5-diX-salo)(N,N'-donor)Cl] (3-8) and were characterized by diverse techniques. The crystal structures of three complexes were determined by single-crystal X-ray crystallography. Diverse techniques were employed in order to investigate the interaction of the complexes with calf-thymus DNA which showed intercalation as the most possible mode of their interaction. The affinity of the complexes for bovine serum albumin and human serum albumin was evaluated by fluorescence emission spectroscopy in order to calculate the binding constants which suggested a tight and reversible binding. SYNOPSIS: A series of copper(II) complexes with 3,5-dihalogen-substituted salicylaldehydes as ligands were isolated and characterized. In vitro biological studies showed the intercalation of the compounds with calf-thymus DNA and their tight and reversible binding with serum albumins.
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Affiliation(s)
- Aphrodite Christidou
- Laboratory of Inorganic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, GR 54124 Thessaloniki, Greece
| | - Konstantina Zavalani
- Laboratory of Inorganic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, GR 54124 Thessaloniki, Greece
| | - Antonios G Hatzidimitriou
- Laboratory of Inorganic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, GR 54124 Thessaloniki, Greece
| | - George Psomas
- Laboratory of Inorganic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, GR 54124 Thessaloniki, Greece.
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El-Sheref EM, Tawfeek HN, Hassan AA, Bräse S, Elbastawesy MAI, Gomaa HAM, Mostafa YA, Youssif BGM. Synthesis of novel amidines via one-pot three component reactions: Selective topoisomerase I inhibitors with antiproliferative properties. Front Chem 2022; 10:1039176. [PMID: 36465858 PMCID: PMC9716094 DOI: 10.3389/fchem.2022.1039176] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/07/2022] [Indexed: 03/26/2024] Open
Abstract
Novel series of amidines were synthesized via the interaction between alicyclic amines, cyclic ketones, and a highly electrophilic 4-azidoquinolin-2(1H)-ones without any catalyst or additive. All the obtained products were elucidated based on NMR spectroscopy, mass spectrometry, and elemental analysis. The reaction conditions were optimized using cyclohexanone (2), piperidine (3a), and 4-azido-quinolin-2(1H)-one (1a) under an air atmosphere. The new compounds 4a-l and 5a-c were tested for antiproliferative activity against four cancer cell lines using doxorubicin as a reference drug. The most potent derivatives were compounds 4b, 4d, 4e, 4i, and 5c, with GI50 ranging from 1.00 µM to 1.50 µM. Compound 5c was the most effective derivative against the four cancer cell lines, outperforming doxorubicin. The compounds 4b, 4d, 4e, 4i, and 5c were studied further as topoisomerase I and IIα inhibitors. The compounds tested showed selective inhibition of topo I over topo IIα. Finally, docking studies explain why these compounds prefer topo I over topo IIα.
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Affiliation(s)
| | - Hendawy N. Tawfeek
- Chemistry Department, Faculty of Science, Minia University, El Minia, Egypt
| | - Alaa A. Hassan
- Chemistry Department, Faculty of Science, Minia University, El Minia, Egypt
| | - S. Bräse
- Institute of Biological and Chemical Systems, IBCS-FMS, Karlsruhe Institute of Technology, Karlsruhe, Germany
| | | | - Hesham A. M. Gomaa
- Pharmacology Department, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia
| | - Yaser A. Mostafa
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, Egypt
| | - Bahaa G. M. Youssif
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, Egypt
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Ardila DM, Rodríguez DF, Palma A, Díaz Costa I, Cobo J, Glidewell C. Synthesis, and spectroscopic and structural characterization of three new styrylquinoline-benzimidazole hybrids. Acta Crystallogr C Struct Chem 2022; 78:671-680. [PMID: 36331891 PMCID: PMC9635590 DOI: 10.1107/s2053229622010063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 10/17/2022] [Indexed: 11/10/2022] Open
Abstract
Three new 4-styrylquinoline-benzimidazole hybrids have been synthesized using a reaction sequence in which 2-methylquinoline precursors first undergo selective oxidation by selenium dioxide to form the corresponding 2-formylquinoline intermediates, followed by oxidative cyclocondensation reactions with benzene-1,2-diamine to yield the hybrid products. The formyl intermediates and the hybrid products have all been fully characterized using a combination of IR, 1H and 13C NMR spectroscopy, and high-resolution mass spectrometry, and the structures of the three hybrid products have been determined using single-crystal X-ray diffraction. Ethyl (E)-2-(1H-benzo[d]imidazol-2-yl)-4-(4-chlorostyryl)quinoline-3-carboxylate, C27H20ClN3O2, (IIIa), and ethyl (E)-2-(1H-benzo[d]imidazol-2-yl)-4-(2-methoxystyryl)quinoline-3-carboxylate, C28H23N3O3, (IIIb), both crystallize in the solvent-free form with Z' = 1, but ethyl (E)-2-(1H-benzo[d]imidazol-2-yl)-4-(4-methylstyryl)quinoline-3-carboxylate, C28H23N3O2, (IIIc), crystallizes as a partial hexane solvate with Z' = 3, and the ester group in one of the independent molecules is disordered over two sets of atomic sites having occupancies of 0.765 (7) and 0.235 (7). The molecules of (IIIc) enclose continuous channels which are occupied by disordered solvent molecules having partial occupancy. In all of the molecules of (IIIa)-(IIIc), the styrylquinoline fragment is markedly nonplanar. Different combinations of N-H...O and C-H...π hydrogen bonds generate supramolecular assemblies which are two-dimensional in (IIIb) and (IIIc), but three-dimensional in (IIIa). Comparisons are made with the structures of some related compounds.
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Affiliation(s)
- Diana M. Ardila
- Laboratorio de Síntesis Orgánica, Escuela de Química, Universidad Industrial de Santander, AA 678, Bucaramanga, Colombia
| | - Diego F. Rodríguez
- Laboratorio de Síntesis Orgánica, Escuela de Química, Universidad Industrial de Santander, AA 678, Bucaramanga, Colombia
| | - Alirio Palma
- Laboratorio de Síntesis Orgánica, Escuela de Química, Universidad Industrial de Santander, AA 678, Bucaramanga, Colombia
| | - Iván Díaz Costa
- Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, 23071 Jaén, Spain
| | - Justo Cobo
- Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, 23071 Jaén, Spain
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Feng Q, Yang W, Peng Z, Wang G. Recent advances in the synthetic thymidine phosphorylase inhibitors for cancer therapy. Eur J Pharmacol 2022; 934:175319. [DOI: 10.1016/j.ejphar.2022.175319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 09/16/2022] [Accepted: 10/04/2022] [Indexed: 11/03/2022]
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Elmongy EI, Ahmed AAS, El Sayed IET, Fathy G, Awad HM, Salman AU, Hamed MA. Synthesis, Biocidal and Antibiofilm Activities of New Isatin-Quinoline Conjugates against Multidrug-Resistant Bacterial Pathogens along with Their In Silico Screening. Antibiotics (Basel) 2022; 11:1507. [PMID: 36358162 PMCID: PMC9686684 DOI: 10.3390/antibiotics11111507] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 10/24/2022] [Accepted: 10/24/2022] [Indexed: 07/29/2023] Open
Abstract
Isatin-quinoline conjugates 10a-f and 11a-f were assembled by the reaction of N-(bromobutyl) isatin derivatives 3a, b with aminoquinolines 6a-c and their corresponding hydrazinyl 9a-c in good yields. The structures of the resulting conjugates were established by spectroscopic tools and showed data consistent with the proposed structures. In vitro antibacterial activity against different bacterial strains was evaluated. All tested conjugates showed significant biocidal activity with lower MIC than the first line drugs chloramphenicol and ampicillin. Conjugates 10a, 10b and 10f displayed the most potent activity against all clinical isolates. The antibiofilm activity for all tested conjugates was screened against the reference drug vancomycin using the MRSA strain. The results revealed that all conjugates had an inhibitory activity against biofilm formation and conjugate. Conjugate 11a showed 83.60% inhibition at 10 mg/mL. In addition, TEM studies were used to prove the mechanism of antibacterial action of conjugates 10a and 11a against (MRSA). Modeling procedures were performed on 10a-f and 11a-f and interestingly the results were nearly consistent with the biological activities. In addition, in silico pharmacokinetic evaluation was performed and revealed that the synthesized compounds 10a-f and 11a-f were considered drug-like molecules with promising bioavailability and high GI absorption. The results confirmed that the title compounds caused the disruption of bacterial cell membranes and could be used as potential leads for the further development and optimization of antibacterial agents.
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Affiliation(s)
- Elshaymaa I. Elmongy
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Abdullah A. S. Ahmed
- Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Kom 32511, Egypt
| | | | - Ghady Fathy
- Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Kom 32511, Egypt
| | - Hanem M. Awad
- Department of Tanning Materials and Leather Technology, National Research Centre, Dokki, Giza 12611, Egypt
| | - Ayah Usama Salman
- Department of Botany and Microbiology, Faculty of Science, Menoufia University, Shebin El-Kom 32511, Egypt
| | - Mohamed A. Hamed
- Chemistry Department, Faculty of Science, Tanta University, Tanta 31511, Egypt
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36
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Joksimović N, Petronijević J, Radisavljević S, Petrović B, Mihajlović K, Janković N, Milović E, Milivojević D, Ilić B, Djurić A. Synthesis, characterization, antitumor potential, and investigation of mechanism of action of copper(ii) complexes with acylpyruvates as ligands: interactions with biomolecules and kinetic study. RSC Adv 2022; 12:30501-30513. [PMID: 36337968 PMCID: PMC9597287 DOI: 10.1039/d2ra05797b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 10/20/2022] [Indexed: 11/07/2022] Open
Abstract
Considering the urgency of finding a cure for vicious diseases such as tumors, we have synthesized and characterized a small series of new copper(ii) complexes with biologically important ligands such as acylpyruvate. In addition to this, we used another four copper(ii) complexes, with ligands of the same type to examine the antitumor potential. The antitumor potential of the copper(ii) complexes was examined on three tumor cell lines and one normal human cell line using the MTT assay. All seven tested complexes showed very good cytotoxic effects. Two copper complexes that showed the best antitumor potential were selected for further testing that showed the best potential for potential application in the future. The mechanism of activity of these complexes was examined in detail using tests such as cell cycle, ROS level, oxidative DNA damage, and proteins related to hypoxia analysis. In addition, we examined the binding abilities of these complexes with biomolecules (Guo, Ino, 5'-GMP, BSA, and DNA). The results showed that the tested compounds bind strongly to DNA molecules through intercalation. Also, it has been shown that the tested compounds adequately bind to the BSA molecule, which indicates an even greater potential for some future application of these compounds in clinical practice.
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Affiliation(s)
- Nenad Joksimović
- University of Kragujevac, Faculty of Science, Department of Chemistry Radoja Domanovića 12 34000 Kragujevac Serbia
| | - Jelena Petronijević
- University of Kragujevac, Faculty of Science, Department of Chemistry Radoja Domanovića 12 34000 Kragujevac Serbia
| | - Snežana Radisavljević
- University of Kragujevac, Faculty of Science, Department of Chemistry Radoja Domanovića 12 34000 Kragujevac Serbia
| | - Biljana Petrović
- University of Kragujevac, Faculty of Science, Department of Chemistry Radoja Domanovića 12 34000 Kragujevac Serbia
| | - Kristina Mihajlović
- University of Kragujevac, Faculty of Science, Department of Chemistry Radoja Domanovića 12 34000 Kragujevac Serbia
| | - Nenad Janković
- University of Kragujevac, Institute for Information Technologies Kragujevac, Department of Sciences Jovana Cvijića bb 34000 Kragujevac Serbia
| | - Emilija Milović
- University of Kragujevac, Institute for Information Technologies Kragujevac, Department of Sciences Jovana Cvijića bb 34000 Kragujevac Serbia
| | - Dušan Milivojević
- Vinča Institute of Nuclear Science University of Belgrade P.O. Box 522 11001 Belgrade Serbia
| | - Bojana Ilić
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia Belgrade Serbia
| | - Ana Djurić
- Institute of Oncology and Radiology of Serbia Pasterova 14 11000 Belgrade Serbia
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Glycoconjugation of Quinoline Derivatives Using the C-6 Position in Sugars as a Strategy for Improving the Selectivity and Cytotoxicity of Functionalized Compounds. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27206918. [PMID: 36296513 PMCID: PMC9607644 DOI: 10.3390/molecules27206918] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/10/2022] [Accepted: 10/13/2022] [Indexed: 11/19/2022]
Abstract
Based on the Warburg effect and the increased demand for glucose by tumor cells, a targeted drug delivery strategy was developed. A series of new glycoconjugates with increased ability to interact with GLUT transporters, responsible for the transport of sugars to cancer cells, were synthesized. Glycoconjugation was performed using the C-6 position in the sugar unit, as the least involved in the formation of hydrogen bonds with various aminoacids residues of the transporter. The carbohydrate moiety was connected with the 8-hydroxyquinoline scaffold via a 1,2,3-triazole linker. For the obtained compounds, several in vitro biological tests were performed using HCT-116 and MCF-7 cancer cells as well as NHDF-Neo healthy cells. The highest cytotoxicity of both cancer cell lines in the MTT test was noted for glycoconjugates in which the triazole-quinoline was attached through the triazole nitrogen atom to the d-glucose unit directly to the carbon at the C-6 position. These compounds were more selective than the analogous glycoconjugates formed by the C-1 anomeric position of d-glucose. Experiments with an EDG inhibitor have shown that GLUTs can be involved in the transport of glycoconjugates. The results of apoptosis and cell cycle analyses by flow cytometry confirmed that the new type of glycoconjugates shows pro-apoptotic properties, without significantly affecting changes in the distribution of the cell cycle. Moreover, glycoconjugates were able to decrease the clonogenic potential of cancer cells, inhibit the migration capacity of cells and intercalate with DNA.
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Quinoline-imidazole/benzimidazole derivatives as dual-/multi-targeting hybrids inhibitors with anticancer and antimicrobial activity. Sci Rep 2022; 12:16988. [PMID: 36216981 PMCID: PMC9551061 DOI: 10.1038/s41598-022-21435-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 09/27/2022] [Indexed: 12/29/2022] Open
Abstract
Two new classes of hybrid quinoline-imidazole/benzimidazole derivatives (the hybrid QIBS salts and QIBC cycloadducts) were designed and synthesized to evaluate their anticancer and antimicrobial activity. The strategy adopted for synthesis is straight and efficient, in four steps: N-acylation, N-alkylation, quaternization and a Huisgen 3 + 2 cycloaddition. The in vitro single-dose anticancer assay of forty six hybrid quinoline-benzimidazole compounds reveal that one QIBS salt (11h), has an excellent quasi nonselective activity against all type of cancer cell with an excellent PGI in the area of 90-100% and very good lethality. Three others quinoline-imidazole/benzimidazole hybrids (8h, 12h, 12f) has an excellent selective activity against some cancer cell lines: breast cancer MDA-MB-468 and Leukemia HL-60 TB). The five-dose assay screening confirms that compound 11h possesses excellent anti-proliferative activity, with GI50 in the range of nano-molar, against some cancer cell lines: Leukemia HL-60 TB, Leukemia K-526, Leukemia RPMI-8226, Breast cancer MDA-MB-468, Lung cancer HOP-92 and Ovarian cancer IGROV1. The antibacterial assay indicates that three hybrid QIBS salts (12f, 12c, 12d) have an excellent activity against Gram-negative bacteria E. coli (superior to control Gentamicin) while against Gram-positive bacteria S. aureus only one compound 8i (R2 = -CF3) exhibits a significant activity (superior to control Gentamicin). The MIC assay indicates that two other compounds (11h, 12h) are biologically active to a very low concentration, in the range of nano-molar. We believe that all these excellent assets related to anticancer and antibacterial activities, make from our hybrid quinoline-imidazole/benzimidazole compounds bearing a phenyl group (R2 = -C6H5) in the para (4)-position of the benzoyl moiety a good candidate for future drug developing.
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Hybrids of 1,4-Quinone with Quinoline Derivatives: Synthesis, Biological Activity, and Molecular Docking with DT-Diaphorase (NQO1). Molecules 2022; 27:molecules27196206. [PMID: 36234741 PMCID: PMC9572083 DOI: 10.3390/molecules27196206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/14/2022] [Accepted: 09/17/2022] [Indexed: 11/16/2022] Open
Abstract
Hybrids 1,4-quinone with quinoline were obtained by connecting two active structures through an oxygen atom. This strategy allows to obtain new compounds with a high biological activity and suitable bioavailability. Newly synthesized compounds were characterized by various spectroscopic methods. The enzymatic assay used showed that these compounds were a suitable DT-diaphorase (NQO1) substrates as evidenced by increasing enzymatic conversion rates relative to that of streptonigrin. Hybrids were tested in vitro against a panel of human cell lines including melanoma, breast, and lung cancers. They showed also a high cytotoxic activity depending on the type of 1,4-quinone moiety and the applied tumor cell lines. It was found that cytotoxic activity of the studied hybrids was increasing against the cell lines with higher NQO1 protein level, such as breast (MCF-7 and T47D) and lung (A549) cancers. Selected hybrids were tested for the transcriptional activity of the gene encoding a proliferation marker (H3 histone), cell cycle regulators (p53 and p21) and the apoptosis pathway (BCL-2 and BAX). The molecular docking was used to examine the probable interaction between the hybrids and NQO1 protein.
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40
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Guo Y, Gao Q. Recent advances in 3-aminoindazoles as versatile synthons for the synthesis of nitrogen heterocycles. Org Biomol Chem 2022; 20:7138-7150. [PMID: 36043318 DOI: 10.1039/d2ob01348g] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Nitrogen-based heterocycles are an important class of structural scaffolds distributed in biologically active natural products, medicinal chemistry, and agrochemicals. Hence, there is increasing interest in the development of novel synthetic strategies for the construction of these privileged structural motifs. Recently, 3-aminoindazoles have emerged as versatile synthons participating in a variety of condensation annulation, denitrogenative transannulation and rearrangement ring expansion reactions, which provide efficient synthetic routes for the formation of nitrogen heterocycles. This review systematically highlights for the first time the most recent advances in 3-aminoindazoles to provide a deep understanding of using 3-aminoindazoles as versatile synthons in organic transformations for synthetic and medicinal chemists.
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Affiliation(s)
- Yimei Guo
- School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, P. R. China.
| | - Qinghe Gao
- School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, P. R. China.
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Cesaretti A, Mencaroni L, Bonaccorso C, Botti V, Calzoni E, Carlotti B, Fortuna CG, Montegiove N, Spalletti A, Elisei F. Amphiphilicity-Controlled Localization of Red Emitting Bicationic Fluorophores in Tumor Cells Acting as Bio-Probes and Anticancer Drugs. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27123713. [PMID: 35744843 PMCID: PMC9230006 DOI: 10.3390/molecules27123713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/04/2022] [Accepted: 06/07/2022] [Indexed: 11/16/2022]
Abstract
Small organic molecules arouse lively interest for their plethora of possible biological applications, such as anticancer therapy, for their ability to interact with nucleic acids, or bioimaging, thanks to their fluorescence emission. Here, a panchromatic series of styryl-azinium bicationic dyes, which have already proved to exhibit high water-solubility and significant red fluorescence in water, were investigated through spectrofluorimetric titrations to assess the extent of their association constants with DNA and RNA. Femtosecond-resolved transient absorption spectroscopy was also employed to characterize the changes in the photophysical properties of these fluorophores upon interaction with their biological targets. Finally, in vitro experiments conducted on tumor cell lines revealed that some of the bicationic fluorophores had a peculiar localization within cell nuclei exerting important antiproliferative effects, others were instead found to localize in the cytoplasm without leading to cell death, being useful to mark specific organelles in light of live cell bioimaging. Interestingly, this molecule-dependent behavior matched the different amphiphilicity featured by these bioactive compounds, which are thus expected to be caught in a tug-of-war between lipophilicity, ensured by the presence of aromatic rings and needed to pass cell membranes, and hydrophilicity, granted by charged groups and necessary for stability in aqueous media.
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Affiliation(s)
- Alessio Cesaretti
- Department of Chemistry, Biology and Biotechnology and “Centro di Eccellenza Materiali Innovativi Nanostrutturati” (CEMIN), University of Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy; (A.C.); (V.B.); (E.C.); (B.C.); (N.M.); (A.S.); (F.E.)
| | - Letizia Mencaroni
- Department of Chemistry, Biology and Biotechnology and “Centro di Eccellenza Materiali Innovativi Nanostrutturati” (CEMIN), University of Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy; (A.C.); (V.B.); (E.C.); (B.C.); (N.M.); (A.S.); (F.E.)
- Correspondence: ; Tel.: +39-075-585-5590
| | - Carmela Bonaccorso
- Department of Chemical Sciences, University of Catania, Viale Andrea Doria 6, 95125 Catania, Italy; (C.B.); (C.G.F.)
| | - Valentina Botti
- Department of Chemistry, Biology and Biotechnology and “Centro di Eccellenza Materiali Innovativi Nanostrutturati” (CEMIN), University of Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy; (A.C.); (V.B.); (E.C.); (B.C.); (N.M.); (A.S.); (F.E.)
| | - Eleonora Calzoni
- Department of Chemistry, Biology and Biotechnology and “Centro di Eccellenza Materiali Innovativi Nanostrutturati” (CEMIN), University of Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy; (A.C.); (V.B.); (E.C.); (B.C.); (N.M.); (A.S.); (F.E.)
| | - Benedetta Carlotti
- Department of Chemistry, Biology and Biotechnology and “Centro di Eccellenza Materiali Innovativi Nanostrutturati” (CEMIN), University of Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy; (A.C.); (V.B.); (E.C.); (B.C.); (N.M.); (A.S.); (F.E.)
| | - Cosimo Gianluca Fortuna
- Department of Chemical Sciences, University of Catania, Viale Andrea Doria 6, 95125 Catania, Italy; (C.B.); (C.G.F.)
| | - Nicolò Montegiove
- Department of Chemistry, Biology and Biotechnology and “Centro di Eccellenza Materiali Innovativi Nanostrutturati” (CEMIN), University of Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy; (A.C.); (V.B.); (E.C.); (B.C.); (N.M.); (A.S.); (F.E.)
| | - Anna Spalletti
- Department of Chemistry, Biology and Biotechnology and “Centro di Eccellenza Materiali Innovativi Nanostrutturati” (CEMIN), University of Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy; (A.C.); (V.B.); (E.C.); (B.C.); (N.M.); (A.S.); (F.E.)
| | - Fausto Elisei
- Department of Chemistry, Biology and Biotechnology and “Centro di Eccellenza Materiali Innovativi Nanostrutturati” (CEMIN), University of Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy; (A.C.); (V.B.); (E.C.); (B.C.); (N.M.); (A.S.); (F.E.)
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Wu X, Zhang Y, Liu S, Liu C, Tang G, Cao X, Lei X, Peng J. Research applications of “linkers” in small molecule drugs design in fragment-based. Bioorg Chem 2022; 127:105921. [DOI: 10.1016/j.bioorg.2022.105921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 05/12/2022] [Accepted: 05/28/2022] [Indexed: 11/02/2022]
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Zaraei SO, Al-Ach NN, Anbar HS, El-Gamal R, Tarazi H, Tokatly RT, Kalla RR, Munther MA, Wahba MM, Alshihabi AM, Shehata MK, Sbenati RM, Shahin AI, El-Awady R, Al-Tel TH, El-Gamal MI. Design and synthesis of new quinoline derivatives as selective C-RAF kinase inhibitors with potent anticancer activity. Eur J Med Chem 2022; 238:114434. [PMID: 35551038 DOI: 10.1016/j.ejmech.2022.114434] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 04/28/2022] [Accepted: 04/29/2022] [Indexed: 11/04/2022]
Abstract
This article describes the design, synthesis, and biological screening of a new series of diarylurea and diarylamide derivatives including quinoline core armed with dimethylamino or morpholino side chain. Fifteen target compounds were selected by the National Cancer Institute (NCI, USA) for in vitro antiproliferative screening against a panel of 60 cancer cell lines of nine cancer types. Compounds 1j-l showed the highest mean inhibition percentage values over the 60-cell line panel at 10 μM with broad-spectrum antiproliferative activity. Subsequently, compounds 1j-l were subjected to a dose-response study to measure their GI50 and total growth inhibition (TGI) values against the cell lines. Three of the tested molecules exerted higher potency against most of the cell lines than the reference drug, sorafenib. Compound 1l indicated a higher potency than sorafenib against 53 of tested cancer cell lines. Compounds 1j-l demonstrated promising selectivity against cancer cells than normal cells. Moreover, compound 1l induced apoptosis and necrosis in RPMI-8226 cell line in a dose-dependent manner. In addition, compounds 1j-l were tested against C-RAF kinase as a potential molecular target. The three compounds showed high potency, and the most potent C-RAF kinase inhibitor was compound 1j with an IC50 value of 0.067 μM. In addition, Compounds 1j-l were further tested at 1 μM concentration against a panel of another twelve kinases and they showed a high selectivity for C-RAF kinase. Molecular modeling studies were performed to illuminate on the putative binding interactions of these motifs in the active site of C-RAF kinase. Additional studies were conducted to measure aqueous solubility, partition coefficient, and Caco-2 permeability of the most promising derivatives.
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Affiliation(s)
- Seyed-Omar Zaraei
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Nour N Al-Ach
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Hanan S Anbar
- Department of Clinical Pharmacy and Pharmacotherapeutics, Dubai Pharmacy College for Girls, Dubai, 19099, United Arab Emirates
| | - Randa El-Gamal
- Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Hamadeh Tarazi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Rimas T Tokatly
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Rawan R Kalla
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Mouna A Munther
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Marwa M Wahba
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Aya M Alshihabi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Mahmoud K Shehata
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Rawan M Sbenati
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Afnan I Shahin
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Raafat El-Awady
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Taleb H Al-Tel
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Mohammed I El-Gamal
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
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Acridine Based N-Acylhydrazone Derivatives as Potential Anticancer Agents: Synthesis, Characterization and ctDNA/HSA Spectroscopic Binding Properties. Molecules 2022; 27:molecules27092883. [PMID: 35566236 PMCID: PMC9100673 DOI: 10.3390/molecules27092883] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/19/2022] [Accepted: 04/22/2022] [Indexed: 02/06/2023] Open
Abstract
A series of novel acridine N-acylhydrazone derivatives have been synthesized as potential topoisomerase I/II inhibitors, and their binding (calf thymus DNA—ctDNA and human serum albumin—HSA) and biological activities as potential anticancer agents on proliferation of A549 and CCD-18Co have been evaluated. The acridine-DNA complex 3b (-F) displayed the highest Kb value (Kb = 3.18 × 103 M−1). The HSA-derivatives interactions were studied by fluorescence quenching spectra. This method was used for the calculation of characteristic binding parameters. In the presence of warfarin, the binding constant values were found to decrease (KSV = 2.26 M−1, Kb = 2.54 M−1), suggesting that derivative 3a could bind to HSA at Sudlow site I. The effect of tested derivatives on metabolic activity of A549 cells evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide or MTT assay decreased as follows 3b(-F) > 3a(-H) > 3c(-Cl) > 3d(-Br). The derivatives 3c and 3d in vitro act as potential dual inhibitors of hTopo I and II with a partial effect on the metabolic activity of cancer cells A594. The acridine-benzohydrazides 3a and 3c reduced the clonogenic ability of A549 cells by 72% or 74%, respectively. The general results of the study suggest that the novel compounds show potential for future development as anticancer agents.
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Bai YP, Yang CJ, Deng N, Zhang M, Zhang ZJ, Li L, Zhou Y, Luo XF, Xu CR, Zhang BQ, Ma Y, Liu YQ. Design and Synthesis of Novel 7-Ethyl-10-Fluoro-20-O-(Cinnamic Acid Ester)-Camptothecin Derivatives as Potential High Selectivity and Low Toxicity Topoisomerase I inhibitors for Hepatocellular Carcinoma. Biochem Pharmacol 2022; 200:115049. [DOI: 10.1016/j.bcp.2022.115049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/30/2022] [Accepted: 04/15/2022] [Indexed: 11/02/2022]
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Kakoulidou C, Chasapis CT, Hatzidimitriou AG, Fylaktakidou KC, Psomas G. Transition metal( ii) complexes of halogenated derivatives of ( E)-4-(2-(pyridin-2-ylmethylene)hydrazinyl)quinazoline: structure, antioxidant activity, DNA-binding DNA photocleavage, interaction with albumin and in silico studies. Dalton Trans 2022; 51:16688-16705. [DOI: 10.1039/d2dt02622h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Six transition metal(ii) complexes with halogenated quinazoline derivatives as ligands were characterized and evaluated for interaction with calf-thymus DNA, photocleavage of plasmid-DNA, affinity for bovine serum albumin, and antioxidant activity.
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Affiliation(s)
- Chrisoula Kakoulidou
- Department of General and Inorganic Chemistry, Faculty of Chemistry, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece
| | - Christos T. Chasapis
- NMR Facility, Instrumental Analysis Laboratory, School of Natural Sciences, University of Patras, Greece
| | - Antonios G. Hatzidimitriou
- Department of General and Inorganic Chemistry, Faculty of Chemistry, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece
| | - Konstantina C. Fylaktakidou
- Laboratory of Organic Chemistry, Faculty of Chemistry, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece
| | - George Psomas
- Department of General and Inorganic Chemistry, Faculty of Chemistry, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece
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Hammoud MM, Nageeb AS, Morsi MA, Gomaa EA, Elmaaty AA, Al-Karmalawy AA. Design, synthesis, biological evaluation, and SAR studies of novel cyclopentaquinoline derivatives as DNA intercalators, topoisomerase II inhibitors, and apoptotic inducers. NEW J CHEM 2022. [DOI: 10.1039/d2nj01646j] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Novel cyclopentaquinoline derivatives as promising DNA intercalators, topoisomerase II inhibitors, and apoptotic inducers.
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Affiliation(s)
- Mohamed M. Hammoud
- Department of Chemistry, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
- Department of Chemistry, Faculty of Science, Mansoura University, Mansoura 35516, Egypt
| | - Alaa S. Nageeb
- Department of Chemistry, Faculty of Science, Mansoura University, Mansoura 35516, Egypt
| | - M. A. Morsi
- Department of Chemistry, Faculty of Science, Mansoura University, Mansoura 35516, Egypt
| | - Esam A. Gomaa
- Department of Chemistry, Faculty of Science, Mansoura University, Mansoura 35516, Egypt
| | - Ayman Abo Elmaaty
- Department of Medicinal Chemistry, Faculty of Pharmacy, Port Said University, Port Said 42526, Egypt
| | - Ahmed A. Al-Karmalawy
- Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt
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Zaib S, Munir R, Younas MT, Kausar N, Ibrar A, Aqsa S, Shahid N, Asif TT, Alsaab HO, Khan I. Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer's Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis. Molecules 2021; 26:molecules26216573. [PMID: 34770983 PMCID: PMC8587653 DOI: 10.3390/molecules26216573] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/26/2021] [Accepted: 10/27/2021] [Indexed: 02/07/2023] Open
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. The limited pharmacological approaches based on cholinesterase inhibitors only provide symptomatic relief to AD patients. Moreover, the adverse side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with these drugs and numerous clinical trial failures present substantial limitations on the use of medications and call for a detailed insight of disease heterogeneity and development of preventive and multifactorial therapeutic strategies on urgent basis. In this context, we herein report a series of quinoline-thiosemicarbazone hybrid therapeutics as selective and potent inhibitors of cholinesterases. A facile multistep synthetic approach was utilized to generate target structures bearing multiple sites for chemical modifications and establishing drug-receptor interactions. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1H- and 13C-NMR). In vitro inhibitory results revealed compound 5b as a promising and lead inhibitor with an IC50 value of 0.12 ± 0.02 μM, a 5-fold higher potency than standard drug (galantamine; IC50 = 0.62 ± 0.01 μM). The synergistic effect of electron-rich (methoxy) group and ethylmorpholine moiety in quinoline-thiosemicarbazone conjugates contributes significantly in improving the inhibition level. Molecular docking analysis revealed various vital interactions of potent compounds with amino acid residues and reinforced the in vitro results. Kinetics experiments revealed the competitive mode of inhibition while ADME properties favored the translation of identified inhibitors into safe and promising drug candidates for pre-clinical testing. Collectively, inhibitory activity data and results from key physicochemical properties merit further research to ensure the design and development of safe and high-quality drug candidates for Alzheimer’s disease.
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Affiliation(s)
- Sumera Zaib
- Department of Biochemistry, Faculty of Life Sciences, University of Central Punjab, Lahore 54590, Pakistan;
- Correspondence: (S.Z.); (R.M.); (I.K.)
| | - Rubina Munir
- Department of Chemistry, Kinnaird College for Women, Lahore 54000, Pakistan; (S.A.); (N.S.); (T.T.A.)
- Correspondence: (S.Z.); (R.M.); (I.K.)
| | - Muhammad Tayyab Younas
- Department of Biochemistry, Faculty of Life Sciences, University of Central Punjab, Lahore 54590, Pakistan;
| | - Naghmana Kausar
- Department of Chemistry, University of Gujrat, Gujrat 50700, Pakistan;
| | - Aliya Ibrar
- Department of Chemistry, Faculty of Natural Sciences, The University of Haripur, Haripur 22620, Pakistan;
| | - Sehar Aqsa
- Department of Chemistry, Kinnaird College for Women, Lahore 54000, Pakistan; (S.A.); (N.S.); (T.T.A.)
| | - Noorma Shahid
- Department of Chemistry, Kinnaird College for Women, Lahore 54000, Pakistan; (S.A.); (N.S.); (T.T.A.)
| | - Tahira Tasneem Asif
- Department of Chemistry, Kinnaird College for Women, Lahore 54000, Pakistan; (S.A.); (N.S.); (T.T.A.)
| | - Hashem O. Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;
| | - Imtiaz Khan
- Department of Chemistry, Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK
- Correspondence: (S.Z.); (R.M.); (I.K.)
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