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Muñoz-Osses M, Navarrete E, Morales P, Quiroz J, Silva M, Torres-González S, Vásquez-Martínez Y, Godoy F, Mascayano C. Substituted aryl piperazine ligands as new dual 5-hLOX/COX-2 inhibitors. Synthesis, biological and computational studies. Bioorg Chem 2025; 159:108398. [PMID: 40174530 DOI: 10.1016/j.bioorg.2025.108398] [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: 01/13/2025] [Revised: 03/10/2025] [Accepted: 03/18/2025] [Indexed: 04/04/2025]
Abstract
Two series of cyano (1a-l) and amino (2a-l) aryl piperazines were synthesized and evaluated for their inhibitory activity against 5-lipoxygenase (5-hLOX) and cyclooxygenase-2 (COX-2). The newly designed derivatives feature diphenyl methyl (a-d), phenyl (e-h), or methoxyphenyl (i-l) groups, respectively, and demonstrated significant inhibition of 5-hLOX. Noteworthy were compounds 1b, 1 g, 1 k, 2f, and 2 g, exhibiting IC50 values ranging from 2.2 to 3.3 μM. The most potent inhibitors (1b, 1 g, 1 k, 2c, and 2f) were characterized by a competitive inhibition mechanism, with Ki values ranging between 1.77 μM and 9.50 μM. Additionally, compounds 2a, 2b, 2 g, and 2 h displayed promising dual inhibition of 5-hLOX and COX-2, with IC50 values below 15 μM. Cytotoxicity assessments against HEK293 cells revealed that the cyano derivatives (1a-l) were non-cytotoxic (CC50 > 200 μM), whereas the amino derivatives (2a-l) exhibited moderate cytotoxicity (CC50 < 50 μM). Notably, the most active derivatives against both targets were non-cytotoxic at their respective inhibitory concentrations. Computational studies, including docking and molecular dynamics simulations, indicated that compound 1 g demonstrated greater stability within the catalytic site of 5-hLOX compared to compound 2f, correlating with the higher affinity observed in kinetic assays. Furthermore, quantitative structure-activity relationship (QSAR) analyses revealed strong correlations between theoretical and experimental IC50 values (97 % for 1a-l and 93 % for 2a-l). These findings, combined with absorption, distribution, metabolism, and excretion (ADME) predictions, suggest that these derivatives are promising candidates as dual inhibitors of 5-hLOX and COX-2.
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Affiliation(s)
| | | | - Pilar Morales
- Departamento Ciencias del Ambiente, Universidad de Santiago de Chile, Chile
| | - Javiera Quiroz
- Departamento Ciencias del Ambiente, Universidad de Santiago de Chile, Chile
| | - Maite Silva
- Departamento Química de los Materiales, Universidad de Santiago de Chile, Chile
| | | | - Yesseny Vásquez-Martínez
- Programa Centro de Investigaciones Biomédicas y Aplicadas (CIBAP), Escuela de Medicina, Facultad de Ciencias Médicas, Universidad de Santiago de Chile, Chile
| | - Fernando Godoy
- Departamento Química de los Materiales, Universidad de Santiago de Chile, Chile
| | - Carolina Mascayano
- Departamento Ciencias del Ambiente, Universidad de Santiago de Chile, Chile
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Martis GJ, Gaonkar SL. Advances in isoxazole chemistry and their role in drug discovery. RSC Adv 2025; 15:8213-8243. [PMID: 40103991 PMCID: PMC11912359 DOI: 10.1039/d4ra08339c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 03/03/2025] [Indexed: 03/20/2025] Open
Abstract
Isoxazoles are a class of five-membered heterocyclic compounds that have gained significant attention in medicinal chemistry due to their diverse biological activities and therapeutic potential. Recent advances in isoxazole chemistry have led to the development of novel synthetic strategies, enabling the creation of a wide array of isoxazole derivatives with enhanced bioactivity and selectivity. This review explores the latest progress in isoxazole synthesis, highlighting key methodologies such as transition metal-catalyzed cycloadditions, green chemistry approaches, and regioselective functionalization techniques. These advances have not only improved the efficiency of isoxazole synthesis but have also facilitated the design of more complex and bioactive derivatives. In addition to their synthetic advances, isoxazoles have demonstrated a broad spectrum of biological activities, including antimicrobial, anticancer, anti-inflammatory, and neuroprotective effects, making them attractive candidates in drug discovery. This review discusses the structural modifications that enhance their pharmacological properties and their potential for developing therapies for diseases such as cancer, neurodegenerative disorders, and infections. Moreover, we examine the emerging trends in isoxazole-based drug discovery, such as the development of multi-targeted therapies and personalized medicine approaches. The evolving role of isoxazoles in drug discovery underscores their continued importance in modern pharmaceutical research and their potential to address unmet medical needs.
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Affiliation(s)
- Glanish Jude Martis
- Department of Chemistry, Manipal Institute of Technology, Manipal Academy of Higher Education Manipal 576104 Karnataka India
| | - Santosh L Gaonkar
- Department of Chemistry, Manipal Institute of Technology, Manipal Academy of Higher Education Manipal 576104 Karnataka India
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3
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Rahmawati SI, Indriani DW, Ningsih FN, Hardhiyuna M, Firdayani F, Ahmadi P, Rosyidah A, Septiana E, Dharmayanti NLPI, Bayu A, Putra MY. Dual anti-inflammatory activities of COX-2/5-LOX driven by kratom alkaloid extracts in lipopolysaccharide-induced RAW 264.7 cells. Sci Rep 2024; 14:28993. [PMID: 39578527 PMCID: PMC11584675 DOI: 10.1038/s41598-024-79229-x] [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: 09/03/2024] [Accepted: 11/07/2024] [Indexed: 11/24/2024] Open
Abstract
Cyclooxygenase (COX) and lipoxygenase (LOX) enzymes play a pivotal role in producing pro-inflammatory eicosanoids, including prostaglandins (PGs) and leukotrienes (LTs), in the inflammation process. Mitragynine is a primary alkaloid contained in the kratom's leaves and has been reported to show anti-inflammatory activity by suppressing COX-2 mRNA translation to lowering PGs synthesis. In this study, the Kratom's alkaloid extract containing ~ 46% mitragynine was found to exhibit dual inhibition activity towards COX-2/5-LOX enzymes at concentrations below 25 ppm in the LPS-induced RAW 264.7 macrophage cells. At these levels, no cell toxicity was observed while the cells became death (e.g., 10-46% viability at 50-100 ppm) and only COX-2 inhibition activity was observed after exposed with more than 25 ppm of alkaloid extract. In contrast, the methanolic-crude extract of Kratom's leaf containing ~ 5% mitragynine showed no inhibition toward COX-2/5-LOX enzymes and did not toxic onto the cells, even after treated at 100 ppm. The alkaloid extract suppressed several antiinflammation parameters, including ROS (64% reduction at 25 ppm), NO (30% reduction at 25 ppm), TNF-α (~ 50% reduction at 25 ppm), and IL-6 production (60% reduction at 6.25 ppm). In silico molecular studies indicated strong binding affinity of Kratom alkaloids to COX-2 and 5-LOX active sites, supporting the Kratom's alkaloids to have great potential dual inhibition activity towards COX-2/5-LOX enzymes and to be developed as a safer NSAIDs with fewer side effects.
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Affiliation(s)
- Siti Irma Rahmawati
- Research Center for Vaccine and Drugs, Research Organization for Health, National Research and Innovation Agency (BRIN), Jalan Raya Jakarta-Bogor Km. 46, 16911, Jakarta, West Java, Indonesia.
| | - Dwi Wahyu Indriani
- Research Center for Vaccine and Drugs, Research Organization for Health, National Research and Innovation Agency (BRIN), Jalan Raya Jakarta-Bogor Km. 46, 16911, Jakarta, West Java, Indonesia.
| | - Febby Nurdiya Ningsih
- Research Center for Vaccine and Drugs, Research Organization for Health, National Research and Innovation Agency (BRIN), Jalan Raya Jakarta-Bogor Km. 46, 16911, Jakarta, West Java, Indonesia
| | - Mutia Hardhiyuna
- Research Center for Vaccine and Drugs, Research Organization for Health, National Research and Innovation Agency (BRIN), Jalan Raya Jakarta-Bogor Km. 46, 16911, Jakarta, West Java, Indonesia
| | - Firdayani Firdayani
- Research Center for Vaccine and Drugs, Research Organization for Health, National Research and Innovation Agency (BRIN), Jalan Raya Jakarta-Bogor Km. 46, 16911, Jakarta, West Java, Indonesia
| | - Peni Ahmadi
- Research Center for Vaccine and Drugs, Research Organization for Health, National Research and Innovation Agency (BRIN), Jalan Raya Jakarta-Bogor Km. 46, 16911, Jakarta, West Java, Indonesia
| | - A'liyatur Rosyidah
- Research Center for Vaccine and Drugs, Research Organization for Health, National Research and Innovation Agency (BRIN), Jalan Raya Jakarta-Bogor Km. 46, 16911, Jakarta, West Java, Indonesia
| | - Eris Septiana
- Research Center for Vaccine and Drugs, Research Organization for Health, National Research and Innovation Agency (BRIN), Jalan Raya Jakarta-Bogor Km. 46, 16911, Jakarta, West Java, Indonesia
| | - Ni Luh Putu Indi Dharmayanti
- Research Organization for Health, National Research and Innovation Agency (BRIN), Jalan Raya Jakarta-Bogor Km. 46, 16911, Jakarta, West Java, Indonesia
| | - Asep Bayu
- Research Center for Vaccine and Drugs, Research Organization for Health, National Research and Innovation Agency (BRIN), Jalan Raya Jakarta-Bogor Km. 46, 16911, Jakarta, West Java, Indonesia
| | - Masteria Yunovilsa Putra
- Research Center for Vaccine and Drugs, Research Organization for Health, National Research and Innovation Agency (BRIN), Jalan Raya Jakarta-Bogor Km. 46, 16911, Jakarta, West Java, Indonesia.
- Faculty of Pharmacy, Universitas Indonesia, Jalan Prof. DR. Mahar Mardjono, Pondok Cina, Beji, Depok, 16424, Jakarta, West Java, Indonesia.
- National Metabolomics Collaborative Research Center, Universitas Indonesia, Kampus UI, Depok, 16424, Jakarta, West Java, Indonesia.
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Elewa M, Shehda M, Hanna PA, Said MM, Ramadan S, Barakat A, Abdel Aziz YM. Development of a selective COX-2 inhibitor: from synthesis to enhanced efficacy via nano-formulation. RSC Adv 2024; 14:32721-32732. [PMID: 39429925 PMCID: PMC11484160 DOI: 10.1039/d4ra06295g] [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: 08/31/2024] [Accepted: 09/19/2024] [Indexed: 10/22/2024] Open
Abstract
Non-steroidal anti-inflammatory drugs NSAIDs are widely used for managing various conditions including pain, inflammation, arthritis and many musculoskeletal disorders. NSAIDs exert their biological effects by inhibiting the cyclooxygenase (COX) enzyme, which has two main isoforms COX-1 and COX-2. The COX-2 isoform is believed to be directly related to inflammation. Based on structure-activity relationship (SAR) studies of known selective COX-2 inhibitors, our aim is to design and synthesize a novel series of 2-benzamido-N-(4-substituted phenyl)thiophene-3-carboxamide derivatives. These derivatives are intended to be selective COX-2 inhibitors through structural modification of diclofenac and celecoxib. The compound 2-benzamido-5-ethyl-N-(4-fluorophenyl)thiophene-3-carboxamide VIIa demonstrated selective COX-2 inhibition with an IC50 value of 0.29 μM and a selectivity index 67.24. This is compared to celecoxib, which has an IC50 value of 0.42 μM and a selectivity index 33.8. Molecular docking studies for compound VIIa displayed high binding affinity toward COX-2. Additionally, the suppression of protein denaturation with respect to albumin was performed as an indicative measure of the potential anti-inflammatory efficacy of the novel compounds. Compound VIIa showed potent anti-inflammatory activity with 93% inhibition and an IC50 value 0.54 μM. In comparison, celecoxib achieved 94% inhibition with an IC50 value 0.89 μM. Although molecule VIIa demonstrated significant in vitro anti-inflammatory activity, adhered to Lipinski's "five rules" (RO5) and exhibited promising drug-like properties, it showed indications of poor in vivo activity. This limitation is likely due to poor aqueous solubility, which impacts its bioavailability. This issue could be addressed by incorporating the drug in niosomal nanocarrier. Niosomes were prepared using the thin-film hydration technique. These niosomes exhibited a particle size of less than 200 nm, high entrapment efficiency, and an appropriate drug loading percentage. Transmission electron microscopy (TEM) and differential scanning calorimetry (DSC) studies revealed that the niosomes were spherical and demonstrated compatibility of all of its components. The drug release study indicated that the pure drug had limited practicality for in vivo use. However, incorporating the drug into niosomes significantly improved its release profile, making it more suitable for practical use.
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Affiliation(s)
- Marwa Elewa
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University Ismailia Egypt
| | - Mohamed Shehda
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt New Damietta Egypt
| | - Pierre A Hanna
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Suez Canal University Ismailia 41522 Egypt
| | - Mohamed M Said
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University Ismailia Egypt
| | - Sherif Ramadan
- Chemistry Department, Michigan State University East Lansing MI 48824 USA
- Department of Chemistry, Benha University Benha Egypt
| | - Assem Barakat
- Department of Chemistry, College of Science, King Saud University P. O. Box 2455 Riyadh 11451 Saudi Arabia
| | - Yasmine M Abdel Aziz
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University Ismailia Egypt
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Meneguelli TS, Wendling AL, Kravchychyn ACP, Rocha DMUP, Dionísio AP, Bressan J, Martino HSD, Tako E, Hermsdorff HHM. Effects of Cashew Nuts ( Anacardium occidentale L.) and Cashew Nut Oil on Intestinal Permeability and Inflammatory Markers during an Energy-Restricted 8-Week Intervention: A Randomized Controlled Trial (Brazilian Nuts Study). Foods 2024; 13:2917. [PMID: 39335845 PMCID: PMC11431763 DOI: 10.3390/foods13182917] [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: 08/11/2024] [Revised: 09/05/2024] [Accepted: 09/11/2024] [Indexed: 09/30/2024] Open
Abstract
Cashew nuts can contribute to improving intestinal permeability and inflammation as they contain essential nutrients and bioactive compounds, but no clinical trials have evaluated these potential effects. This randomized trial aimed to assess the effects of cashew nuts and their oil on intestinal permeability and inflammatory markers. Sixty-four adults with overweight or obesity were allocated into three groups receiving energy restriction (-500 kcal/day): control (CT, free nuts), cashew nuts (CN, 30 g/day), or cashew nut oil (OL, 30 mL/day). Urine lactulose and mannitol, plasma zonulin and the lipopolysaccharide-binding protein (LBP), plasma interleukins (IL-6, TNF-α, IL-10, IL-1β, IL-8, and IL-12p70), and C-reactive proteins were analyzed. Energy restriction reduced body fat and other indicators of adiposity without differences between the groups. Only the control group increased LBPs after an 8-week intervention. There were no statistically significant differences found between the groups in terms of intestinal permeability and inflammatory markers. In conclusion, incorporating cashew nuts or cashew nut oil into an energy-restricted 8-week dietary intervention did not change intestinal permeability and inflammatory markers. As studies evaluating cashew nuts on these markers remain scarce, further research is needed, perhaps with a longer study period and a higher concentration of cashew nuts and oil.
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Affiliation(s)
- Talitha Silva Meneguelli
- Laboratory of Clinical Analysis and Genomics (LACEG), Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa 36570-200, MG, Brazil; (T.S.M.); (A.L.W.); (A.C.P.K.); (D.M.U.P.R.); (J.B.)
- Laboratory of Energy Metabolism and Body Composition (LAMECC), Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa 36570-200, MG, Brazil
| | - Aline Lage Wendling
- Laboratory of Clinical Analysis and Genomics (LACEG), Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa 36570-200, MG, Brazil; (T.S.M.); (A.L.W.); (A.C.P.K.); (D.M.U.P.R.); (J.B.)
- Laboratory of Energy Metabolism and Body Composition (LAMECC), Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa 36570-200, MG, Brazil
| | - Ana Claudia Pelissari Kravchychyn
- Laboratory of Clinical Analysis and Genomics (LACEG), Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa 36570-200, MG, Brazil; (T.S.M.); (A.L.W.); (A.C.P.K.); (D.M.U.P.R.); (J.B.)
- Laboratory of Energy Metabolism and Body Composition (LAMECC), Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa 36570-200, MG, Brazil
| | - Daniela Mayumi Usuda Prado Rocha
- Laboratory of Clinical Analysis and Genomics (LACEG), Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa 36570-200, MG, Brazil; (T.S.M.); (A.L.W.); (A.C.P.K.); (D.M.U.P.R.); (J.B.)
- Laboratory of Energy Metabolism and Body Composition (LAMECC), Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa 36570-200, MG, Brazil
| | - Ana Paula Dionísio
- Brazilian Agricultural Research Corporation (Embrapa) Agroindústria Tropical—CNPAT, Fortaleza 60511-110, CE, Brazil;
| | - Josefina Bressan
- Laboratory of Clinical Analysis and Genomics (LACEG), Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa 36570-200, MG, Brazil; (T.S.M.); (A.L.W.); (A.C.P.K.); (D.M.U.P.R.); (J.B.)
- Laboratory of Energy Metabolism and Body Composition (LAMECC), Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa 36570-200, MG, Brazil
| | - Hércia Stampini Duarte Martino
- Laboratory of Experimental Nutrition, Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa 36570-200, MG, Brazil;
| | - Elad Tako
- Trace Minerals and Nutrition Laboratory, Department of Food Science, Cornell University, Ithaca, NY 14850, USA;
| | - Helen Hermana Miranda Hermsdorff
- Laboratory of Clinical Analysis and Genomics (LACEG), Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa 36570-200, MG, Brazil; (T.S.M.); (A.L.W.); (A.C.P.K.); (D.M.U.P.R.); (J.B.)
- Laboratory of Energy Metabolism and Body Composition (LAMECC), Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa 36570-200, MG, Brazil
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Fadaly WAA, Elshaier YAMM, Ali FEM, El-Bahrawy AH, Abdellatif KRA, Nemr MTM. Vicinal diaryl pyrazole with tetrazole/urea scaffolds as selective angiotensin converting enzyme-1/cyclooxygenase-2 inhibitors: Design, synthesis, anti-hypertensive, anti-fibrotic, and anti-inflammatory. Drug Dev Res 2024; 85:e22217. [PMID: 38845214 DOI: 10.1002/ddr.22217] [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: 04/04/2024] [Revised: 05/05/2024] [Accepted: 05/18/2024] [Indexed: 06/15/2024]
Abstract
As a hybrid weapon, two novel series of pyrazoles, 16a-f and 17a-f, targeting both COX-2 and ACE-1-N-domain, were created and their anti-inflammatory, anti-hypertensive, and anti-fibrotic properties were evaluated. In vitro, 17b and 17f showed COX-2 selectivity (SI = 534.22 and 491.90, respectively) compared to celecoxib (SI = 326.66) and NF-κB (IC50 1.87 and 2.03 μM, respectively). 17b (IC50 0.078 μM) and 17 f (IC50 0.094 μM) inhibited ACE-1 comparable to perindopril (PER) (IC50 0.048 μM). In vivo, 17b decreased systolic blood pressure by 18.6%, 17b and 17f increased serum NO levels by 345.8%, and 183.2%, respectively, increased eNOS expression by 0.97 and 0.52 folds, respectively and reduced NF-κB-p65 and P38-MAPK expression by -0.62, -0.22, -0.53, and -0.24 folds, respectively compared to l-NAME (-0.34, -0.45 folds decline in NF-κB-p65 and P38-MAPK, respectively). 17b reduced ANG-II expression which significantly reversed the cardiac histological changes induced by L-NAME.
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Affiliation(s)
- Wael A A Fadaly
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Yaseen A M M Elshaier
- Organic & Medicinal Chemistry Department, Faculty of Pharmacy, University of Sadat City, Menoufia, Egypt
| | - Fares E M Ali
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, Egypt
| | - Ali H El-Bahrawy
- Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, Egypt
| | - Khaled R A Abdellatif
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
- Pharmaceutical Sciences Department, Ibn Sina National College for Medical Studies, Jeddah, Kingdom of Saudi Arabia
| | - Mohamed T M Nemr
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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Said MF, Moussa BA, Mahrouse MA, Marie SM, Mohamed NM. Exploring new imines as anti-inflammatory COX and 5-LOX inhibitors with an improved pharmacokinetic profile. Future Med Chem 2024; 16:311-334. [PMID: 38293746 DOI: 10.4155/fmc-2023-0280] [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: 09/26/2023] [Accepted: 01/11/2024] [Indexed: 02/01/2024] Open
Abstract
Background: Dual COX/5-LOX inhibition is a bright strategy for developing new potent and safe anti-inflammatory agents. Methods: New imines were synthesized and evaluated for their anti-inflammatory activity. The most active compounds were further investigated for their safety profile. Their molecular docking and physicochemical parameters were assessed. A new LC-MS/MS method was developed for the quantification of compound 4d in rat plasma. Results: Synthesized compounds were found to have anti-inflammatory activity (77-88% edema inhibition). In addition, 4d, 5m and 7d showed analgesic activity (92.50, 95.71 and 96.28% protection, respectively). 4d showed dual COX-2/5-LOX activity. Molecular docking expected the binding pattern of compounds in COX-1, COX-2 and 5-LOX active sites. The in vivo pharmacokinetic parameters of compound 4d were also obtained.
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Affiliation(s)
- Mona F Said
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, PO Box 11562, Egypt
| | - Bahia A Moussa
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, PO Box 11562, Egypt
| | - Marianne A Mahrouse
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, PO Box 11562, Egypt
| | - Sarah M Marie
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, PO Box 11562, Egypt
| | - Nada M Mohamed
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Modern University for Technology & Information MTI, Cairo, Egypt
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Mittal R, Sharma S, Mittal A, Kushwah AS. Novel Dual COX-2/5-LOX Inhibitory Activity by Chalcone Derivatives: A Safe and Efficacious Anti-inflammatory Agent. Antiinflamm Antiallergy Agents Med Chem 2024; 23:174-186. [PMID: 38939991 DOI: 10.2174/0118715230301176240605072113] [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: 01/17/2024] [Revised: 04/10/2024] [Accepted: 05/03/2024] [Indexed: 06/29/2024]
Abstract
BACKGROUND Non-communicable diseases are chronic systemic inflammation in humans that occurs because of enhanced inflammatory mediators of the arachidonic acid cascade. We aimed to explore whether the lead chalcone compounds could exhibit anti-inflammatory activity via dual blockage of COX-2/5-LOX enzymes and their regulatory mechanism. METHODS RAW 264.7 macrophages were collected from NCC, Pune, for in-vitro experiments. The IC50 values of chalcone compounds C45 and C64 were calculated. RAW 264.7 macrophages were treated with C45 and C64 (10%, 5%, 2.5%, 0.125%, and 0.0625% concentration). The cell viability was carried out with an MTT assay. The COX-1, COX-2, 5-LOX, PGE2, and LTB4 levels were detected by ELISA-based kits. The in-vivo evaluation was carried out in Male Wistar rats (250-300 g, 7-8 weeks old) with acute and chronic anti-inflammatory models and histopathological studies on the stomach, liver, and kidney. RESULTS The present study described the in-vitro and in-vivo biological evaluation of dual COX-2/5-LOX inhibitors in chalcone derivatives (C45 and C64) compounds showed the most effective COX-2 and 5-LOX inhibition with IC50 values 0.092 and 0.136 μM respectively. Simultaneously, compound C64 showed comparable selectivity towards COX-2 with a Selectivity Index (SI) of 68.43 compared to etoricoxib, with an SI of 89.32. In-vivo carrageenaninduced rat paw oedema activity, the compound C64 showed a significant reduction in oedema with 78.28% compared to indomethacin with 88.07% inhibition. Furthermore, cotton pelletinduced granuloma activity revealed that compound C64 significantly reduced 32.85% compared with standard 40.13% granuloma inhibition. CONCLUSION The chalcone compound C64, (E)-1-(4-Amino-2-hydroxyphenyl)-3-(3,4,5-trimethoxyphenyl)- prop-2-en-1-one was proved to be a potent and novel Dual COX-2/5-LOX inhibitor with improved gastric safety profiling.
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Affiliation(s)
- Roopal Mittal
- Department of Pharmacy, IK Gujral Punjab Technical University, Jalandhar Punjab, 144601, India
- R.K.S.D. College of Pharmacy, Kaithal Haryana, 136027, India
| | - Shailesh Sharma
- Department of Pharmaceutics, Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial College of Pharmacy, Bela Ropar, Punjab, 140111, India
| | - Amit Mittal
- Department of Pharmaceutical Chemistry, School of Pharmacy, Lovely Professional University, Jalandhar - Delhi G.T. Road, Phagwara, Punjab, India
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Desh Bhagat University, Amloh Road, Mandi Gobindgarh, Fatehgarh Sahib, Punjab, 147301, India
| | - Ajay Singh Kushwah
- Department of Pharmacology, Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial College of Pharmacy, Bela Ropar, Punjab, 140111, India
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Fiorucci S, Sepe V, Biagioli M, Fiorillo B, Rapacciuolo P, Distrutti E, Zampella A. Development of bile acid activated receptors hybrid molecules for the treatment of inflammatory and metabolic disorders. Biochem Pharmacol 2023; 216:115776. [PMID: 37659739 DOI: 10.1016/j.bcp.2023.115776] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/29/2023] [Accepted: 08/30/2023] [Indexed: 09/04/2023]
Abstract
The farnesoid-x-receptor (FXR) and the G protein bile acid activated receptor (GPBAR)1 are two bile acid activated receptors highly expressed in entero-hepatic, immune, adipose and cardiovascular tissues. FXR and GPBAR1 are clinically validated targets in the treatment of metabolic disorders and FXR agonists are currently trialled in patients with non-alcoholic steato-hepatitis (NASH). Results of these trials, however, have raised concerns over safety and efficacy of selective FXR ligands suggesting that the development of novel agent designed to impact on multiple targets might have utility in the treatment of complex, multigenic, disorders. Harnessing on FXR and GPBAR1 agonists, several novel hybrid molecules have been developed, including dual FXR and GPBAR1 agonists and antagonists, while exploiting the flexibility of FXR agonists toward other nuclear receptors, dual FXR and peroxisome proliferators-activated receptors (PPARs) and liver-X-receptors (LXRs) and Pregnane-X-receptor (PXR) agonists have been reported. In addition, modifications of FXR agonists has led to the discovery of dual FXR agonists and fatty acid binding protein (FABP)1 and Leukotriene B4 hydrolase (LTB4H) inhibitors. The GPBAR1 binding site has also proven flexible to accommodate hybrid molecules functioning as GPBAR1 agonist and cysteinyl leukotriene receptor (CYSLTR)1 antagonists, as well as dual GPBAR1 agonists and retinoid-related orphan receptor (ROR)γt antagonists, dual GPBAR1 agonist and LXR antagonists and dual GPBAR1 agonists endowed with inhibitory activity on dipeptidyl peptidase 4 (DPP4). In this review we have revised the current landscape of FXR and GPBAR1 based hybrid agents focusing on their utility in the treatment of metabolic associated liver disorders.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy.
| | - Valentina Sepe
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | - Bianca Fiorillo
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Pasquale Rapacciuolo
- Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, Naples I-80131, Italy
| | | | - Angela Zampella
- Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, Naples I-80131, Italy
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10
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Tiwari R, Mishra S, Danaboina G, Pratap Singh Jadaun G, Kalaivani M, Kalaiselvan V, Dhobi M, Raghuvanshi RS. Comprehensive chemo-profiling of coumarins enriched extract derived from Aegle marmelos (L.) Correa fruit pulp, as an anti-diabetic and anti-inflammatory agent. Saudi Pharm J 2023; 31:101708. [PMID: 37564748 PMCID: PMC10410585 DOI: 10.1016/j.jsps.2023.101708] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 07/19/2023] [Indexed: 08/12/2023] Open
Abstract
Aegle marmelos (L.) Correa is an Indian medicinal plant known for its vast therapeutic activities. In Ayurveda, the plant is known to balance "vata," "pitta," and "kapha" dosh. Recent studies suggest anti-inflammatory, anti-microbial, and anti-diabetic potential but lack in defining the dosage over the therapeutic activities. This study aims to determine the chemical profile of Aegle marmelos fruit extract; identification, enrichment, and characterization of the principal active component(s) having anti-inflammatory and anti-diabetic potential. Targeted enrichment of total coumarins, focusing on marmelosin, marmesin, aegeline, psoralen, scopoletin, and umbelliferone, was done from Aegle marmelos fruit pulp, and characterized using advanced high-throughput techniques. In vitro and in silico anti-diabetic and anti-inflammatory activities were assessed to confirm their efficacy and affinity as anti-diabetic and anti-inflammatory agents. The target compounds were also analysed for toxicity by in silico ADMET study and in vitro MTT assay on THP-1 and A549 cell lines. The coumarins enrichment process designed, was found specific for coumarins isolation as it resulted into 48.61% of total coumarins enrichment, which includes 31.2% marmelosin, 8.9% marmesin, 4% psoralen, 2% scopoletin, 1.7% umbelliferone, and 0.72% aegeline. The quantification with HPTLC and qNMR was found to be correlated with the HPLC assay results. The present study validates the potential use of Aegle marmelos as an anti-inflammatory and anti-diabetic agent. Coumarins enriched from the plant fruit have good therapeutic activity and can be used for Phytopharmaceutical ingredient development. The study is novel, in which coumarins were enriched and characterized by a simple and sophisticated methodology.
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Affiliation(s)
- Ritu Tiwari
- Indian Pharmacopoeia Commission, Ministry of Health & Family Welfare, Government of India, Raj Nagar, Ghaziabad 201002, India
- Department of Pharmacognosy and Phytochemistry, Delhi Pharmaceutical Sciences and Research University, New Delhi 110017, India
| | - Smita Mishra
- Indian Pharmacopoeia Commission, Ministry of Health & Family Welfare, Government of India, Raj Nagar, Ghaziabad 201002, India
| | - Gnanabhaskar Danaboina
- Indian Pharmacopoeia Commission, Ministry of Health & Family Welfare, Government of India, Raj Nagar, Ghaziabad 201002, India
| | - Gaurav Pratap Singh Jadaun
- Indian Pharmacopoeia Commission, Ministry of Health & Family Welfare, Government of India, Raj Nagar, Ghaziabad 201002, India
| | - M. Kalaivani
- Indian Pharmacopoeia Commission, Ministry of Health & Family Welfare, Government of India, Raj Nagar, Ghaziabad 201002, India
| | - Vivekanandan Kalaiselvan
- Indian Pharmacopoeia Commission, Ministry of Health & Family Welfare, Government of India, Raj Nagar, Ghaziabad 201002, India
| | - Mahaveer Dhobi
- Department of Pharmacognosy and Phytochemistry, Delhi Pharmaceutical Sciences and Research University, New Delhi 110017, India
| | - Rajeev S Raghuvanshi
- Indian Pharmacopoeia Commission, Ministry of Health & Family Welfare, Government of India, Raj Nagar, Ghaziabad 201002, India
- Drugs Controller General of India, Central Drugs Standard Control Organization, FDA Bhawan, Kotla Road, New Delhi 110002, India
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11
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Mishra AK, Anjali K, Singh H, Mishra A, Kumar A. Synthesis and in silico studies of some new pyrrolidine derivatives and their biological evaluation for analgesic and anti-inflammatory activity. ANNALES PHARMACEUTIQUES FRANÇAISES 2023; 81:801-813. [PMID: 36931432 DOI: 10.1016/j.pharma.2023.03.002] [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: 12/15/2022] [Revised: 03/10/2023] [Accepted: 03/10/2023] [Indexed: 03/17/2023]
Abstract
BACKGROUND An array of commercially viable intermediate molecules necessary for the synthesis of a variety of bioactive molecules are chemically synthesized by pyrrolidine and its derivatives, which play a significant role in drug design and development process. AIM The aim of the present research work was to explore the synthesis of some new pyrrolidine derivatives and to perform their in silico studies and finally evaluation of analgesic and anti-inflammatory activity. OBJECTIVE The purpose of this study was to synthesis new pyrrolidine derivatives, examine how they affected the COX-1 and COX-2 enzymes computationally, and to screen their in vivo analgesic and anti-inflammatory activity on laboratory animals. METHOD The new pyrrolidine derivatives were synthesized by condensing N-(3-acetylphenyl)-2-(pyrrolidin-1-yl)acetamide with substituted aniline in ethanol in the presence of catalytic amounts of glacial acetic acid. The structures of novel pyrrolidine derivatives were characterised using IR, NMR, and mass spectroscopy. Several molecular properties of the newly synthesized derivatives were calculated in order to evaluate the nature of the drug-like candidate. A specific reference cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzyme was used to dock the newly synthesized pyrrolidine derivatives. RESULTS From the observed data, it was noted that amongst all newly synthesized compounds, A-1 and A-4 exhibited the highest anti-inflammatory and analgesic effects, respectively. CONCLUSION On the basis of findings of present research, it was concluded that A-1 and A-4 might be utilized as a promising new lead compound for Non-Steroidal Anti-Inflammatory Drug (NSAIDs) development.
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Affiliation(s)
- A K Mishra
- Drug Design Laboratory, Pharmacy Academy, IFTM University, 244001 Moradabad, India.
| | - Km Anjali
- Drug Design Laboratory, School of Pharmaceutical Sciences, IFTM University, 244001 Moradabad, India
| | - H Singh
- Drug Design Laboratory, School of Pharmaceutical Sciences, IFTM University, 244001 Moradabad, India
| | - A Mishra
- School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences & Research University, 110017 New Delhi, India
| | - A Kumar
- Drug Design Laboratory, School of Pharmaceutical Sciences, IFTM University, 244001 Moradabad, India
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12
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Hawash M, Jaradat N, Sabobeh R, Abualhasan M, Qaoud MT. New Thiazole Carboxamide Derivatives as COX Inhibitors: Design, Synthesis, Anticancer Screening, In Silico Molecular Docking, and ADME Profile Studies. ACS OMEGA 2023; 8:29512-29526. [PMID: 37599929 PMCID: PMC10433355 DOI: 10.1021/acsomega.3c03256] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 07/20/2023] [Indexed: 08/22/2023]
Abstract
The goal of this work was to create and test a new series of thiazole carboxamide derivatives for their cyclooxygenase (COX) suppressor and anticancer effects. The compounds were characterized using 1H, 13C NMR, and HRMS spectrum analysis, and their selectivity toward COX-1 and COX-2 was assessed using an in vitro COX inhibition assay kit. Cytotoxicity was assessed using an MTS assay against a panel of cancer and normal cell lines. The docking studies were aided by the Prime MM-GBSA method for estimating binding affinities. The density functional theory (DFT) analysis was performed to assess compound chemical reactivity, which was calculated by computing the border orbital energy of both HOMO and LUMO orbitals, as well as the HOMO-LUMO energy gap. For ADME-T analysis, the QiKProp module was employed. Furthermore, using human X-ray crystal structures, molecular docking studies were carried out to discover the probable binding patterns of these drugs within both COX-1 and COX-2 isozymes. The results demonstrated that the most effective compound against the COX-1 enzyme was 2b with an IC50 of 0.239 μM. It also showed potent activity against COX-2 with an IC50 value of 0.191 μM and a selectivity ratio of 1.251. The highest selectivity ratio was 2.766 for compound 2a against COX-2 with an IC50 dose of 0.958 μM relating to the celecoxib ratio of 23.8 and its IC50 against COX-2 of 0.002 μM. Compound 2j also showed good selectivity toward COX-2 (1.507) with an IC50 value of 0.957 μM. All compounds showed negligible cytotoxic activity against the evaluated normal cell lines, and the IC50 values were more than 300 μM, except for compound 2b, whose IC50 values were 203.71 ± 1.89 and 116.96 ± 2.05 μM against LX-2 and Hek293t cell lines, respectively. Moreover, compound 2b showed moderate anticancer activity against COLO205 and B16F1 cancer cell lines with IC50 values of 30.79 and 74.15 μM, respectively.
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Affiliation(s)
- Mohammed Hawash
- Department
of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus 400, Palestine
| | - Nidal Jaradat
- Department
of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus 400, Palestine
| | - Rozan Sabobeh
- Department
of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus 400, Palestine
| | - Murad Abualhasan
- Department
of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus 400, Palestine
| | - Mohammed T. Qaoud
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Etiler, 06330 Ankara, Turkey
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13
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Rudrapal M, Eltayeb WA, Rakshit G, El-Arabey AA, Khan J, Aldosari SM, Alshehri B, Abdalla M. Dual synergistic inhibition of COX and LOX by potential chemicals from Indian daily spices investigated through detailed computational studies. Sci Rep 2023; 13:8656. [PMID: 37244921 PMCID: PMC10224994 DOI: 10.1038/s41598-023-35161-0] [Citation(s) in RCA: 62] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 05/13/2023] [Indexed: 05/29/2023] Open
Abstract
Cyclooxygenase (COX) and Lipoxygenase (LOX) are essential enzymes for arachidonic acid (AA) to eicosanoids conversion. These AA-derived eicosanoids are essential for initiating immunological responses, causing inflammation, and resolving inflammation. Dual COX/5-LOX inhibitors are believed to be promising novel anti-inflammatory agents. They inhibit the synthesis of prostaglandins (PGs) and leukotrienes (LTs), but have no effect on lipoxin formation. This mechanism of combined inhibition circumvents certain limitations for selective COX-2 inhibitors and spares the gastrointestinal mucosa. Natural products, i.e. spice chemicals and herbs, offer an excellent opportunity for drug discovery. They have proven anti-inflammatory properties. However, the potential of a molecule to be a lead/ drug candidate can be much more enhanced if it has the property of inhibition in a dual mechanism. Synergistic activity is always a better option than the molecule's normal biological activity. Herein, we have explored the dual COX/5-LOX inhibition property of the three major potent phytoconsituents (curcumin, capsaicin, and gingerol) from Indian spices using in silico tools and biophysical techniques in a quest to identify their probable inhibitory role as anti-inflammatory agents. Results revealed the dual COX/5-LOX inhibitory potential of curcumin. Gingerol and capsaicin also revealed favorable results as dual COX/5-LOX inhibitors. Our results are substantiated by target similarity studies, molecular docking, molecular dynamics, energy calculations, DFT, and QSAR studies. In experimental inhibitory (in vitro) studies, curcumin exhibited the best dual inhibitory activities against COX-1/2 and 5-LOX enzymes. Capsaicin and gingerol also showed inhibitory potential against both COX and LOX enzymes. In view of the anti-inflammatory potential these spice chemicals, this research could pave the way for more scientific exploration in this area for drug discovery.
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Affiliation(s)
- Mithun Rudrapal
- Department of Pharmaceutical Sciences, School of Biotechnology and Pharmaceutical Sciences, Vignan's Foundation for Science, Technology & Research (Deemed to Be University), Guntur, 522213, India.
| | - Wafa Ali Eltayeb
- Biotechnology Department, Faculty of Science and Technology, Shendi University, Shendi, 414601, Sudan
| | - Gourav Rakshit
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Ranchi, 835215, India
| | - Amr Ahmed El-Arabey
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, 11651, Egypt
| | - Johra Khan
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al'Majmaah, 11952, Saudi Arabia.
- Health and Basic Sciences Research Center, Majmaah University, Al'Majmaah, 11952, Saudi Arabia.
| | - Sahar M Aldosari
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al'Majmaah, 11952, Saudi Arabia
- Health and Basic Sciences Research Center, Majmaah University, Al'Majmaah, 11952, Saudi Arabia
| | - Bader Alshehri
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al'Majmaah, 11952, Saudi Arabia
- Health and Basic Sciences Research Center, Majmaah University, Al'Majmaah, 11952, Saudi Arabia
| | - Mohnad Abdalla
- Pediatric Research Institute, Children's Hospital Affiliated to Shandong University, Jinan, 250022, People's Republic of China.
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Sohail R, Mathew M, Patel KK, Reddy SA, Haider Z, Naria M, Habib A, Abdin ZU, Razzaq Chaudhry W, Akbar A. Effects of Non-steroidal Anti-inflammatory Drugs (NSAIDs) and Gastroprotective NSAIDs on the Gastrointestinal Tract: A Narrative Review. Cureus 2023; 15:e37080. [PMID: 37153279 PMCID: PMC10156439 DOI: 10.7759/cureus.37080] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/01/2023] [Indexed: 04/05/2023] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for their anti-inflammatory, antipyretic, and analgesic properties. However, their use is often associated with gastrointestinal tract (GIT) side effects due to the inhibition of both cyclooxygenase (COX)-1 and COX-2 enzymes, leading to a decrease in gastroprotective prostaglandins (PG). To minimize these adverse effects, various approaches have been explored, including selective COX-2 inhibitors, NO-NSAIDs (nitric oxide-releasing NSAIDs), and dual COX/LOX (lipoxygenase) NSAIDs. However, the effects of these gastroprotective NSAIDs on the GIT and their efficacy remains uncertain. This review aims to provide an overview of the current understanding of the effects of traditional NSAIDs and gastroprotective NSAIDs on GIT. We discuss the underlying mechanisms of GIT damage caused by NSAIDs, including mucosal injury, ulceration, and bleeding, and the potential of gastroprotective NSAIDs to mitigate these effects. We also summarize recent studies on the efficacy and safety of various gastroprotective NSAIDs and highlight the limitations and challenges of these approaches. The review concludes with recommendations for future research in this field.
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Affiliation(s)
- Rohab Sohail
- Internal Medicine, Quaid-e-Azam Medical College, Bahawalpur, PAK
| | - Midhun Mathew
- Department of Internal Medicine, Pennsylvania Hospital, Philadelphia, USA
| | - Khushbu K Patel
- Internal Medicine, Index Medical College Hospital & Research Center, Indore, IND
| | - Srija A Reddy
- Internal Medicine, Malla Reddy Institute of Medical Sciences, Hyderabad, IND
| | - Zaroon Haider
- Internal Medicine, Combined Military Hospital (CMH) Lahore Medical College and Institute of Dentistry, Lahore, PAK
| | - Mansi Naria
- Internal Medicine, American University of Barbados, Bridgetown, BRB
| | - Ayesha Habib
- Internal Medicine, Punjab Medical College, Faisalabad, PAK
| | - Zain U Abdin
- Medicine, District Head Quarter Hospital, Faisalabad, PAK
| | | | - Anum Akbar
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, USA
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15
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Design, synthesis, molecular docking studies and biological evaluation of thiazole carboxamide derivatives as COX inhibitors. BMC Chem 2023; 17:11. [PMID: 36879343 PMCID: PMC9987136 DOI: 10.1186/s13065-023-00924-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 02/25/2023] [Indexed: 03/08/2023] Open
Abstract
BACKGROUND Nonsteroidal anti-inflammatory drugs (NSAIDs) have been the most commonly used class of medications worldwide for the last three decades. OBJECTIVES This study aimed to design and synthesize a novel series of methoxyphenyl thiazole carboxamide derivatives and evaluate their cyclooxygenase (COX) suppressant and cytotoxic properties. METHODS The synthesized compounds were characterized using 1H, 13C-NMR, IR, and HRMS spectrum analysis and were evaluated for their selectivity towards COX-1 and COX-2 using an in vitro COX inhibition assay kit. Besides, their cytotoxicity was evaluated using the Sulforhodamine B (SRB) assay. Moreover, molecular docking studies were conducted to identify the possible binding patterns of these compounds within both COX-1 and COX-2 isozymes, utilizing human X-ray crystal structures. The density functional theory (DFT) analysis was used to evaluate compound chemical reactivity, which was determined by calculating the frontier orbital energy of both HOMO and LUMO orbitals, as well as the HOMO-LUMO energy gap. Finally, the QiKProp module was used for ADME-T analysis. RESULTS The results revealed that all synthesized molecules have potent inhibitory activities against COX enzymes. The percentage of inhibitory activities at 5 µM concentration against the COX2 enzyme was in the range of 53.9-81.5%, while the percentage against the COX-1 enzyme was 14.7-74.8%. That means almost all of our compounds have selective inhibition activities against the COX-2 enzyme, and the most selective compound was 2f, with selectivity ratio (SR) value of 3.67 at 5 µM concentration, which has a bulky group of trimethoxy on the phenyl ring that could not bind well with the COX-1 enzyme. Compound 2h was the most potent, with an inhibitory activity percentage at 5 µM concentration of 81.5 and 58.2% against COX-2 and COX-1, respectively. The cytotoxicity of these compounds was evaluated against three cancer cell lines: Huh7, MCF-7, and HCT116, and negligible or very weak activities were observed for all of these compounds except compound 2f, which showed moderate activities with IC50 values of 17.47 and 14.57 µM against Huh7 and HCT116 cancer cell lines, respectively. Analysis of the molecular docking suggests 2d, 2e, 2f, and 2i molecules were bound to COX-2 isozyme favorably over COX-1 enzyme, and their interaction behaviors within COX-1 and COX-2 isozymes were comparable to celecoxib, as an ideal selective COX-2 drug, which explained their high potency and COX-2 selectivity. The molecular docking scores and expected affinity using the MM-GBSA approach were consistent with the recorded biological activity. The calculated global reactivity descriptors, such as HOMO and LUMO energies and the HOMO-LUMO gaps, confirmed the key structural features required to achieve favorable binding interactions and thus improve affinity. The in silico ADME-T studies asserted the druggability of molecules and have the potential to become lead molecules in the drug discovery process. CONCLUSION In general, the series of the synthesized compounds had a strong effect on both enzymes (COX-1 and COX-2) and the trimethoxy compound 2f was more selective than the other compounds.
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16
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Mukhopadhyay N, Shukla A, Makhal PN, Kaki VR. Natural product-driven dual COX-LOX inhibitors: Overview of recent studies on the development of novel anti-inflammatory agents. Heliyon 2023; 9:e14569. [PMID: 37020932 PMCID: PMC10068128 DOI: 10.1016/j.heliyon.2023.e14569] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 03/02/2023] [Accepted: 03/10/2023] [Indexed: 03/14/2023] Open
Abstract
Inflammation is a complicated physiological process that results in a variety of disorders. Several inflammatory mediators are produced during this process, which is responsible for long-term inflammatory conditions like osteoarthritis, rheumatoid arthritis, asthma, cancer, and neurological disorders. Inflammatory mediators are produced by an arachidonic acid pathway that gives us several anti-inflammatory targets. The most commonly used medications are NSAIDs to treat inflammation by inhibiting cyclooxygenase (COX) and lipoxygenase enzymes (5-LOX). However, this therapy is associated with adverse events like gastrointestinal disorders, renal failure, etc., limiting its use. Therefore, novel, efficacious, and safer anti-inflammatory agents are prerequisites for inhibiting both cyclooxygenase and lipoxygenase pathways. Though several synthetic analogs are under development, natural products may act as a potential source to identify novel molecules and herbal remedies. Valuable contributions have been made in this direction by the scientific communities. This review article briefly discusses the implications of phytochemicals and bioactive fractions in the development of dual COX-LOX inhibitors while highlighting different classes of phytoconstituents such as tannins, steroids, flavonoids, alkaloids, terpenoids, among others, that showed significant dual COX-LOX inhibition.
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17
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Martins AN, de Souza Almeida D, Florentino IF, da Silva Moreira LK, Turones LC, Batista DC, Machado LS, Vaz BG, Lião LM, de Almeida Ribeiro Oliveira G, Martins JLR, Fajemiroye JO, Menegatti R, Costa EA, da Silva DPB. Pharmacological evaluation of antinociceptive and anti-inflammatory activities of LQFM202: a new piperazine derivative. Inflammopharmacology 2023; 31:411-422. [PMID: 36443517 DOI: 10.1007/s10787-022-01103-x] [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: 08/21/2022] [Accepted: 11/12/2022] [Indexed: 11/30/2022]
Abstract
Advances have been made in the search for new multi-target modulators to control pain and inflammation. Therefore, compound 3,5-di-tert-butyl-4-hydroxyphenyl)(4-methylpiperazin-1-yl)methanone (LQFM202) was synthesised and evaluated. First, in vitro assays were performed for COX-1, COX-2, and 5-LOX enzymes. Subsequently, adult female Swiss albino mice treated orally with LQFM202 at doses of 25-200 mg/kg were subjected to acetic acid-induced writhing, formalin-induced pain, carrageenan-induced hyperalgesia, carrageenan- or zymosan-induced paw oedema, or pleurisy. LQFM202 inhibited COX-1, COX-2, and LOX-5 (IC50 = 3499 µM, 1565 µM, and 1343 µM, respectively). In acute animal models, LQFM202 (50, 100, or 200 mg/kg) decreased the amount of abdominal writhing (29%, 52% and 48%, respectively). Pain in the second phase of the formalin test was reduced by 46% with intermediate dose. LQFM202 (100 mg/kg) reduced the difference in nociceptive threshold in all 4 h evaluated (46%, 37%, 30%, and 26%, respectively). LQFM202 (50 mg/kg) decreased the carrageenan-oedema from the second hour (27%, 31% and 25%, respectively); however, LQFM202 (100 mg/kg) decreased the carrageenan-oedema in all hours evaluated (35%, 42%, 48% and 50%, respectively). When using zymosan, LQFM202 (50 mg/kg) decreased the oedema in all hours evaluated (33%, 32%, 31% and 20%, respectively). In the carrageenan-pleurisy test, LQFM202 (50 mg/kg) reduced significantly the number of polymorphonuclear cells (34%), the myeloperoxidase activity (53%), TNF-α levels (47%), and IL-1β levels (58.8%). When using zymosan, LQFM202 (50 mg/kg) reduced the number of polymorphonuclear and mononuclear cells (54% and 79%, respectively); and the myeloperoxidase activity (46%). These results suggest antinociceptive and anti-inflammatory effects of LQFM202.
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Affiliation(s)
- Aline N Martins
- Institute of Biological Sciences, Department of Pharmacology, Federal University of Goiás, Campus Samambaia, Goiânia, GO, Brazil
| | - Dionys de Souza Almeida
- Institute of Biological Sciences, Department of Pharmacology, Federal University of Goiás, Campus Samambaia, Goiânia, GO, Brazil
| | - Iziara F Florentino
- Institute of Biological Sciences, Department of Pharmacology, Federal University of Goiás, Campus Samambaia, Goiânia, GO, Brazil
| | - Lorrane K da Silva Moreira
- Institute of Biological Sciences, Department of Pharmacology, Federal University of Goiás, Campus Samambaia, Goiânia, GO, Brazil
| | - Larissa C Turones
- Institute of Biological Sciences, Department of Pharmacology, Federal University of Goiás, Campus Samambaia, Goiânia, GO, Brazil
| | - Daniel C Batista
- Institute of Biological Sciences, Department of Pharmacology, Federal University of Goiás, Campus Samambaia, Goiânia, GO, Brazil
| | - Lucas S Machado
- Chemistry Institute, Federal University of Goiás, Campus Samambaia, Goiânia, GO, Brazil
| | - Boniek G Vaz
- Chemistry Institute, Laboratory of Chromatography and Mass Spectrometry, Federal University of Goiás, Goiânia, GO, Brazil
| | - Luciano M Lião
- Chemistry Institute, Federal University of Goiás, Campus Samambaia, Goiânia, GO, Brazil
| | | | - José Luís Rodrigues Martins
- Institute of Biological Sciences, Department of Pharmacology, Federal University of Goiás, Campus Samambaia, Goiânia, GO, Brazil
| | - James Oluwagbamigbe Fajemiroye
- Institute of Biological Sciences, Department of Pharmacology, Federal University of Goiás, Campus Samambaia, Goiânia, GO, Brazil
| | - Ricardo Menegatti
- Faculty of Pharmacy, Laboratory of Medicinal Pharmaceutical Chemistry, Federal University of Goiás, Goiânia, GO, Brazil
| | - Elson A Costa
- Institute of Biological Sciences, Department of Pharmacology, Federal University of Goiás, Campus Samambaia, Goiânia, GO, Brazil
| | - Daiany P B da Silva
- Institute of Biological Sciences, Department of Pharmacology, Federal University of Goiás, Campus Samambaia, Goiânia, GO, Brazil.
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Salamatullah AM. Antioxidant, Anti-Inflammatory, and Analgesic Properties of Chemically Characterized Polyphenol-Rich Extract from Withania adpressa Coss. ex Batt. LIFE (BASEL, SWITZERLAND) 2022; 13:life13010109. [PMID: 36676058 PMCID: PMC9861700 DOI: 10.3390/life13010109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/13/2022] [Accepted: 12/27/2022] [Indexed: 01/04/2023]
Abstract
The current work was undertaken to investigate the chemical composition, antioxidant, anti-inflammatory, and analgesic properties of a polyphenol-rich fraction from Withania adpressa Coss. ex Batt. After being extracted, the polyphenol-rich fraction was chemically characterized through use of high-performance liquid chromatography (HPLC). Antioxidant potency was assessed through the use of 2,2-diphenyl-1-picrylhydrazyl (DPPH) and total antioxidant capacity (TAC). Inflammatory and analgesic properties were assessed in vivo through the use of carrageenan and heat stimulus assays, respectively. Chromatographic analysis of polyphenol-rich fraction revealed the presence of potentially bioactive phenols including epicatechin, apigenin, luteolin, quercetin, caffeic acid, p-coumaric acid, and rosmarinic acid. The polyphenol-rich fraction showed interesting anti-free-radical potency with a calculated IC50 value of 27.84 ± 1.48 µg/mL. At the highest dose used (1000 µg/mL), the polyphenol-rich fraction scored good total antioxidant capacity with a calculated value of 924.0 ± 28.29 µg EAA/mg. The polyphenol-rich fraction strongly alleviated the inflammatory effect of carrageenan injected into the plantar fascia of rats resulting in inhibition up to 89.0 ± 2.08% at the highest tested dose (500 mg/kg). The polyphenol-rich fraction showed a good analgesic effect wherein the delay in reaction time to a thermal stimulus caused by 500 mg/kg had a highly similar effect to that induced by Tramadol used as a positive control. The findings of the current work highlight the importance of polyphenol-rich fractions from W. adpressa Coss. ex Batt. as an alternative source of natural antioxidant, inflammatory, and analgesic drugs to control relative diseases.
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Affiliation(s)
- Ahmad Mohammad Salamatullah
- Department of Food Science & Nutrition, College of Food and Agricultural Sciences, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia
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Abdellatif KR, Abdelall EK, Lamie PF, Labib MB, Abdelhakeem MM, Abdel-Fattah MM, El-Nahaas ES. Novel pyrazole-oxadiazole hybrids possessing methanesulphonyl pharmacophore with good gastric safety profile: Design, synthesis, cyclooxygenase inhibition, anti-inflammatory activity and histopathological studies. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.133529] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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20
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Emam M, Eslamloo K, Caballero-Solares A, Lorenz EK, Xue X, Umasuthan N, Gnanagobal H, Santander J, Taylor RG, Balder R, Parrish CC, Rise ML. Nutritional immunomodulation of Atlantic salmon response to Renibacterium salmoninarum bacterin. Front Mol Biosci 2022; 9:931548. [PMID: 36213116 PMCID: PMC9532746 DOI: 10.3389/fmolb.2022.931548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 08/12/2022] [Indexed: 11/18/2022] Open
Abstract
We investigated the immunomodulatory effect of varying levels of dietary ω6/ω3 fatty acids (FA) on Atlantic salmon (Salmo salar) antibacterial response. Two groups were fed either high-18:3ω3 or high-18:2ω6 FA diets for 8 weeks, and a third group was fed for 4 weeks on the high-18:2ω6 diet followed by 4 weeks on the high-18:3ω3 diet and termed "switched-diet". Following the second 4 weeks of feeding (i.e., at 8 weeks), head kidney tissues from all groups were sampled for FA analysis. Fish were then intraperitoneally injected with either a formalin-killed Renibacterium salmoninarum bacterin (5 × 107 cells mL-1) or phosphate-buffered saline (PBS control), and head kidney tissues for gene expression analysis were sampled at 24 h post-injection. FA analysis showed that the head kidney profile reflected the dietary FA, especially for C18 FAs. The qPCR analyses of twenty-three genes showed that both the high-ω6 and high-ω3 groups had significant bacterin-dependent induction of some transcripts involved in lipid metabolism (ch25ha and lipe), pathogen recognition (clec12b and tlr5), and immune effectors (znrf1 and cish). In contrast, these transcripts did not significantly respond to the bacterin in the "switched-diet" group. Concurrently, biomarkers encoding proteins with putative roles in biotic inflammatory response (tnfrsf6b) and dendritic cell maturation (ccl13) were upregulated, and a chemokine receptor (cxcr1) was downregulated with the bacterin injection regardless of the experimental diets. On the other hand, an inflammatory regulator biomarker, bcl3, was only significantly upregulated in the high-ω3 fed group, and a C-type lectin family member (clec3a) was only significantly downregulated in the switched-diet group with the bacterin injection (compared with diet-matched PBS-injected controls). Transcript fold-change (FC: bacterin/PBS) showed that tlr5 was significantly over 2-fold higher in the high-18:2ω6 diet group compared with other diet groups. FC and FA associations highlighted the role of DGLA (20:3ω6; anti-inflammatory) and/or EPA (20:5ω3; anti-inflammatory) vs. ARA (20:4ω6; pro-inflammatory) as representative of the anti-inflammatory/pro-inflammatory balance between eicosanoid precursors. Also, the correlations revealed associations of FA proportions (% total FA) and FA ratios with several eicosanoid and immune receptor biomarkers (e.g., DGLA/ARA significant positive correlation with pgds, 5loxa, 5loxb, tlr5, and cxcr1). In summary, dietary FA profiles and/or regimens modulated the expression of some immune-relevant genes in Atlantic salmon injected with R. salmoninarum bacterin. The modulation of Atlantic salmon responses to bacterial pathogens and their associated antigens using high-ω6/high-ω3 diets warrants further investigation.
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Affiliation(s)
- Mohamed Emam
- Department of Ocean Sciences, Memorial University of Newfoundland, St. John’s, NL, Canada
| | - Khalil Eslamloo
- Department of Ocean Sciences, Memorial University of Newfoundland, St. John’s, NL, Canada
| | | | - Evandro Kleber Lorenz
- Department of Ocean Sciences, Memorial University of Newfoundland, St. John’s, NL, Canada
| | - Xi Xue
- Department of Ocean Sciences, Memorial University of Newfoundland, St. John’s, NL, Canada
| | | | - Hajarooba Gnanagobal
- Marine Microbial Pathogenesis and Vaccinology Laboratory, Department of Ocean Sciences, Memorial University of Newfoundland, St. John’s, NL, Canada
| | - Javier Santander
- Marine Microbial Pathogenesis and Vaccinology Laboratory, Department of Ocean Sciences, Memorial University of Newfoundland, St. John’s, NL, Canada
| | | | - Rachel Balder
- Cargill Animal Nutrition and Health, Minneapolis, MN, United States
| | - Christopher C. Parrish
- Department of Ocean Sciences, Memorial University of Newfoundland, St. John’s, NL, Canada
| | - Matthew L. Rise
- Department of Ocean Sciences, Memorial University of Newfoundland, St. John’s, NL, Canada
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21
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Synthesis, analgesic, anti-inflammatory, ulcerogenic evaluation, and docking study of (benzoylphenoxy)-N-{5-[2-methylphenyl-6-chlorobenzoxazole]} acetamides as COX/5-LOX inhibitor. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.134240] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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22
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Nagesh KM, Prashanth T, Khamees HA, Khanum SA. Synthesis, analgesic, anti-inflammatory, COX/5-LOX inhibition, ulcerogenic evaluation, and docking study of benzimidazole bearing indole and benzophenone analogs. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.132741] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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23
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Xu HB, Yang YG, Xu HL, Yuan MM, Chen SZ, Song ZX, Tang ZS. Screening 5-lipoxygenase inhibitors from selected traditional Chinese medicines and isolation of the active compounds from Polygoni Cuspidati Rhizoma by an on-line bioactivity evaluation system. Biomed Chromatogr 2022; 36:e5426. [PMID: 35707928 DOI: 10.1002/bmc.5426] [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: 01/29/2022] [Revised: 06/11/2022] [Accepted: 06/13/2022] [Indexed: 11/08/2022]
Abstract
To identify natural products as new prototypes for 5-lipoxygenase (5-LOX), 12 traditional Chinese medicines (TCMs), were selected for screening their 5-LOX inhibition activities. The results showed that all of the methanol extracts of 12 selected TCMs possessed inhibitory activities of 5-LOX at 200 μg/mL, of which six extracts of the TCMs showed significant inhibitory effects with IC50 values ranged from 33.2 ± 1.4 μg/mL to 153.5 ± 1.7 μg/mL, and the extract of Polygoni Cuspidati Rhizoma (RPC) was the most active sample. An on-line UPLC-PDA-MSn -5-LOX-FLD method was applied to further identify the potential 5-LOX inhibitory constituents in RPC extracts, which resulted in the identification of 7 components with 5-LOX-binding activities. Finally, four compounds (polydatin, resveratrol, emodin-8-O-glucoside and emodin) were successfully purified from RPC extracts. The 5-LOX inhibition action was assayed in vitro, and the results showed that these compounds possessed potent inhibitory effects against 5-LOX with IC50 values of 15.3 ± 2.1, 4.5 ± 1.2, 23.8 ± 0.4 and 11.8 ± 1.5 μg/mL, respectively. This was the first study to reveal the 5-LOX inhibitory constituents of RPC, and the present investigation might provide a valuable approach for the rapid discovery of natural inhibitors from TCMs.
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Affiliation(s)
- Hong-Bo Xu
- Shaanxi Collaborative Innovation Center of Chinese Medicine Resources Industrialization, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center and College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, People's Republic of China
| | - Yuan-Gui Yang
- Shaanxi Collaborative Innovation Center of Chinese Medicine Resources Industrialization, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center and College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, People's Republic of China
| | - Huai-Li Xu
- Shaanxi Collaborative Innovation Center of Chinese Medicine Resources Industrialization, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center and College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, People's Republic of China
| | - Meng-Meng Yuan
- Shaanxi Collaborative Innovation Center of Chinese Medicine Resources Industrialization, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center and College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, People's Republic of China.,School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China
| | - Shi-Zhong Chen
- Shaanxi Collaborative Innovation Center of Chinese Medicine Resources Industrialization, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center and College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, People's Republic of China.,School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China
| | - Zhong-Xing Song
- Shaanxi Collaborative Innovation Center of Chinese Medicine Resources Industrialization, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center and College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, People's Republic of China
| | - Zhi-Shu Tang
- Shaanxi Collaborative Innovation Center of Chinese Medicine Resources Industrialization, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center and College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, People's Republic of China
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A Report on Multi-Target Anti-Inflammatory Properties of Phytoconstituents from Monochoria hastata (Family: Pontederiaceae). Molecules 2021; 26:molecules26237397. [PMID: 34885978 PMCID: PMC8658818 DOI: 10.3390/molecules26237397] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/29/2021] [Accepted: 12/02/2021] [Indexed: 12/22/2022] Open
Abstract
This study aims to investigate the potential analgesic properties of the crude extract of Monochoria hastata (MH) leaves using in vivo experiments and in silico analysis. The extract, in a dose-dependent manner, exhibited a moderate analgesic property (~54% pain inhibition in acetic acid-induced writhing test), which is significant (** p < 0.001) as compared to the control group. The complex inflammatory mechanism involves diverse pathways and they are inter-connected. Therefore, multiple inflammatory modulator proteins were selected as the target for in silico analysis. Computational analysis suggests that all the selected targets had different degrees of interaction with the phytochemicals from the extract. Rutin (RU), protocatechuic acid (PA), vanillic acid (VA), and ferulic acid (FA) could regulate multiple targets with a robust efficiency. None of the compounds showed selectivity to Cyclooxygenase-2 (COX-2). However, regulation of COX and lipoxygenase (LOX) cascade by PA can reduce non-steroidal analgesic drugs (NSAIDs)-related side effects, including asthma. RU showed robust regulation of cytokine-mediated pathways like RAS/MAPK and PI3K/NF-kB by inhibition of EGFR and IKBα (IKK), which may prevent multi-organ failure due to cytokine storm in several microbial infections, for example, SARS-CoV-2. Further investigation, using in vivo and in vitro experiments, can be conducted to develop multi-target anti-inflammatory drugs using the isolated compounds from the extract.
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Rai SK, Ganeshan S, Mariappan R, Rajendran AP, Balasubramaniem A, Pugazhendhi A, Varalakshmi P. Mesoporous nanoparticles for the delivery of (9S,E)-8-ethyl-9-methylnonadec-6-en-3-one (EME): A study of anti-inflammatory and tumor suppressing potential in RAW 264.7, He La and HepG2 cell lines. Process Biochem 2021. [DOI: 10.1016/j.procbio.2021.10.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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26
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Topical Administration of 15-Deoxy- Δ 12,14-Prostaglandin J 2 Using a Nonionic Cream: Effect on UVB-Induced Skin Oxidative, Inflammatory, and Histopathological Modifications in Mice. Mediators Inflamm 2021; 2021:9330596. [PMID: 34764817 PMCID: PMC8577928 DOI: 10.1155/2021/9330596] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 10/23/2021] [Indexed: 12/20/2022] Open
Abstract
UVB radiation is certainly one of the most important environmental threats to which we are subjected to. This fact highlights the crucial protective role of the skin. However, the skin itself may not be capable of protecting against UVB depending on irradiation intensity and time of exposition. Sun blockers are used to protect our skin, but they fail to fully protect it against oxidative and inflammatory injuries initiated by UVB. To solve this issue, topical administration of active molecules is an option. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is an arachidonic acid-derived lipid with proresolution and anti-inflammatory actions. However, as far as we are aware, there is no evidence of its therapeutic use in a topical formulation to treat the deleterious events initiated by UVB, which was the aim of the present study. We used a nonionic cream to vehiculate 15d-PGJ2 (30, 90, and 300 ng/mouse) (TFcPGJ2) in the skin of hairless mice. UVB increased skin edema, myeloperoxidase activity, metalloproteinase-9 activity, lipid peroxidation, superoxide anion production, gp91phox and COX-2 mRNA expression, cytokine production, sunburn and mast cells, thickening of the epidermis, and collagen degradation. UVB also diminished skin ability to reduce iron and scavenge free radicals, reduced glutathione (GSH), sulfhydryl proteins, and catalase activity. TFcPGJ2 inhibited all these pathological alterations in the skin caused by UVB. No activity was observed with the unloaded topical formulation. The protective outcome of TFcPGJ2 indicates it is a promising therapeutic approach against cutaneous inflammatory and oxidative pathological alterations.
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Quitian-Useche YF, Sánchez-Ortiz BL, Borges SF, Ramos B, de Souza GC, Batista MA, da Silva Hage Melim LI, Ferreira IM, Carvalho JCT, Borges RS. Fatty ethanolamide of Bertholletia excelsa triglycerides (Brazil nuts): anti-inflammatory action and acute toxicity evaluation in Zebrafish (Danio rerio). Inflammopharmacology 2021; 29:1519-1537. [PMID: 34498144 DOI: 10.1007/s10787-021-00867-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 08/13/2021] [Indexed: 11/28/2022]
Abstract
Fatty amides (N-alkylamides) are bioactive lipids that are widely distributed in microorganisms, animals, and plants. The low yield in the extraction process of spilantol, a fatty amide, which is mainly related to its diverse biological effects, compromises its application on a large scale. Thus, this study proposes an alternative method to synthesise fatty amides from Bertholletia excelsa (AGBe) oil, with a chemical structure similar to that of spilantol. Carrageenan-induced abdominal oedema in vivo models were used in zebrafish (Danio rerio). In in vivo studies, oral AGBe produced no signs of toxicity. In the histopathological study, AGBe did not cause significant changes in the main metabolising organs (liver, kidneys, and intestines). All doses of AGBe (100 mg/kg, 500 mg/kg, and 750 mg/kg) were effective in reducing oedema by 65%, 69%, and 95%, respectively, producing a dose-response effect compared to the control group, and spilantol-inhibited oedema by 48%. In the in silico study, with the use of molecular docking, it was observed that among the AGBe, the molecules 18:1, ω-7-ethanolamine, and 18:1, ω-9-ethanolamine stood out, with 21 interactions for COX-2 and 20 interactions for PLA2, respectively, surpassing the spilantol standard with 15 interactions for COX-2 and PLA2. The anti-inflammatory action hypothesis was confirmed in the in silico study, demonstrating the involvement of AGBe in the process of inhibiting the enzymes COX-2 and PLA2. Therefore, based on all the results obtained and the fact that until the dose of 1000 mg/kg was administered orally in zebrafish, it was not possible to determine the LD50; it can be said that AGBe is effective and safe for anti-inflammatory activity.
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Affiliation(s)
- Yesica Fernanda Quitian-Useche
- Programa de Pós-Graduação em Ciências Farmacêuticas, Departamento de Ciências Biológicas e da Saúde, Curso de Farmácia, Universidade Federal do Amapá, Rod. JK, km 02, Macapá, Amapá, 68902-280, Brazil.,Laboratório de Pesquisa em Fármacos, Departamento de Ciências Biológicas e da Saúde, Universidade Federal do Amapá, Rod. JK, km 02, Macapá, Amapá, 68902-280, Brazil
| | - Brenda Lorena Sánchez-Ortiz
- Laboratório de Pesquisa em Fármacos, Departamento de Ciências Biológicas e da Saúde, Universidade Federal do Amapá, Rod. JK, km 02, Macapá, Amapá, 68902-280, Brazil
| | - Swanny Ferreira Borges
- Programa de Pós-Graduação em Ciências Farmacêuticas, Departamento de Ciências Biológicas e da Saúde, Curso de Farmácia, Universidade Federal do Amapá, Rod. JK, km 02, Macapá, Amapá, 68902-280, Brazil.,Laboratório de Pesquisa em Fármacos, Departamento de Ciências Biológicas e da Saúde, Universidade Federal do Amapá, Rod. JK, km 02, Macapá, Amapá, 68902-280, Brazil
| | - Benilson Ramos
- Laboratório de Biocatálise e Síntese Orgânica Aplicada, Departamento de Ciências Exatas, Curso de Química, Universidade Federal do Amapá, Rod. JK, km 02, Macapá, Amapá, 68902-280, Brazil
| | - Gisele Custódio de Souza
- Laboratório de Pesquisa em Fármacos, Departamento de Ciências Biológicas e da Saúde, Universidade Federal do Amapá, Rod. JK, km 02, Macapá, Amapá, 68902-280, Brazil
| | - Mateus Alves Batista
- Laboratório de Química Farmacêutica e Medicinal (PharMedChem), Departamento de Ciências Biológicas e da Saúde, Curso de Farmácia, Universidade Federal do Amapá, Rod. JK, km 02, Macapá, Amapá, 68902-280, Brazil
| | - Lorane Izabel da Silva Hage Melim
- Programa de Pós-Graduação em Ciências Farmacêuticas, Departamento de Ciências Biológicas e da Saúde, Curso de Farmácia, Universidade Federal do Amapá, Rod. JK, km 02, Macapá, Amapá, 68902-280, Brazil.,Laboratório de Química Farmacêutica e Medicinal (PharMedChem), Departamento de Ciências Biológicas e da Saúde, Curso de Farmácia, Universidade Federal do Amapá, Rod. JK, km 02, Macapá, Amapá, 68902-280, Brazil
| | - Irlon Maciel Ferreira
- Programa de Pós-Graduação em Ciências Farmacêuticas, Departamento de Ciências Biológicas e da Saúde, Curso de Farmácia, Universidade Federal do Amapá, Rod. JK, km 02, Macapá, Amapá, 68902-280, Brazil.,Laboratório de Biocatálise e Síntese Orgânica Aplicada, Departamento de Ciências Exatas, Curso de Química, Universidade Federal do Amapá, Rod. JK, km 02, Macapá, Amapá, 68902-280, Brazil
| | - José Carlos Tavares Carvalho
- Programa de Pós-Graduação em Ciências Farmacêuticas, Departamento de Ciências Biológicas e da Saúde, Curso de Farmácia, Universidade Federal do Amapá, Rod. JK, km 02, Macapá, Amapá, 68902-280, Brazil.,Laboratório de Pesquisa em Fármacos, Departamento de Ciências Biológicas e da Saúde, Universidade Federal do Amapá, Rod. JK, km 02, Macapá, Amapá, 68902-280, Brazil
| | - Raphaelle Sousa Borges
- Programa de Pós-Graduação em Ciências Farmacêuticas, Departamento de Ciências Biológicas e da Saúde, Curso de Farmácia, Universidade Federal do Amapá, Rod. JK, km 02, Macapá, Amapá, 68902-280, Brazil. .,Laboratório de Pesquisa em Fármacos, Departamento de Ciências Biológicas e da Saúde, Universidade Federal do Amapá, Rod. JK, km 02, Macapá, Amapá, 68902-280, Brazil.
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Cistobislactones A-B, two sixteen-membered spiro-linked macrocylic bislactones from marine octopus Cistopus indicus: new anti-inflammatory agents attenuate arachidonate 5-lipoxygenase. Med Chem Res 2021. [DOI: 10.1007/s00044-021-02790-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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29
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Paulose SK, Chakraborty K. Antioxidant spiropharanone, an undescribed variant of trans-decalin spiro-γ-lactone, from pharaoh cuttlefish Sepia pharaonis: Twin inhibitors of inflammatory 5-lipoxygenase and serine protease dipeptidyl peptidase-4. J Food Biochem 2021; 45:e13919. [PMID: 34486135 DOI: 10.1111/jfbc.13919] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 08/18/2021] [Accepted: 08/23/2021] [Indexed: 12/16/2022]
Abstract
Marine pharaoh cuttlefish Sepia pharaonis (family Sepiidae) is regarded as an economically important class of cephalopod in the coastal Mediterranean and Asian regions. Bioassay-guided chromatographic purification of solvent extract of S. pharaonis led to the identification of a trans-decalin based spirolactone, spiropharanone, which was characterized as 1-hydroxy-7-(4'-methoxy-3-methylbut-2-enyl)-3,9,15-trimethyl-8-oxo-octahydro-5H-spiro[furan-8,9-naphtho]-8-yl-acetate by spectroscopic techniques. Spiropharanone exhibited significantly greater anti-inflammatory activity by attenuating pro-inflammatory 5-lipoxygenase (IC50 1.02 mM) than the non-steroidal drug ibuprofen (IC50 4.61 mM, p ≤ .05). Superior antioxidant properties of spiropharanone against free radicals (EC50 ~1.20 mM) and other oxidants (hydroxyl [EC50 0.97 mM] and superoxide [EC50 1.47 mM] scavenging) also reinforced its promising anti-inflammatory activity. The studied spiropharanone also exhibited significant attenuation toward insulin secretion regulating enzyme dipeptidyl peptidase-4 (IC50 0.92 mM) recognizing its anti-hyperglycemic potential. Significantly higher electronic properties (topological polar surface area ~100) combined with balanced hydrophilic-lipophilic properties (partition coefficient of logarithmic octanol-water ~3) and lesser docking parameters of spiropharanone demonstrated that the compound could be utilized as an important bioactive lead against oxidative stress, inflammation, and hyperglycemic-related ailments. PRACTICAL APPLICATIONS: Nutritionally rich edible marine pharaoh cuttlefish Sepia pharaonis occupies a prominent place among seafood fisheries owing to the presence of bioactive nutrients and functional food ingredients. These marine cuttlefish are widely distributed along the Asian and Mediterranean coasts, and consumed as culinary delicacy for decades. An undescribed trans-decalin spirolactone, spiropharanone was isolated from the organic extract of S. pharaonis based on bioactivity-assisted sequential chromatographic fractionation. Spiropharanone displayed promising antioxidant potential along with attenuation properties against inducible pro-inflammatory 5-lipoxygenase and insulin secretion regulating enzyme dipeptidyl peptidase-4. This study established the ameliorating potential of a naturally derived marine food constituent against inflammatory and diabetic ailments, and thus anticipated as functional food lead in pharmaceutical formulations towards inflammation and maintaining glucose homeostasis.
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Affiliation(s)
- Silpa Kunnappilly Paulose
- Marine Bioprospecting Section of Marine Biotechnology Division, Central Marine Fisheries Research Institute, Cochin, India.,Department of Chemistry, Mangalore University, Mangalagangothri, India
| | - Kajal Chakraborty
- Marine Bioprospecting Section of Marine Biotechnology Division, Central Marine Fisheries Research Institute, Cochin, India
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Singh VP, Dowarah J, Marak BN, Sran BS, Tewari AK. Study of the structure-bioactivity of fleximers: synthesis, crystal structure, Hirshfeld surface analysis, and anti-inflammatory assays. J Mol Struct 2021. [DOI: 10.1016/j.molstruc.2021.130513] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Anti-Inflammatory, Antipyretic, and Analgesic Properties of Potamogeton perfoliatus Extract: In Vitro and In Vivo Study. Molecules 2021; 26:molecules26164826. [PMID: 34443414 PMCID: PMC8400542 DOI: 10.3390/molecules26164826] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 07/25/2021] [Accepted: 08/07/2021] [Indexed: 12/11/2022] Open
Abstract
Natural antioxidants, especially those of plant origins, have shown a plethora of biological activities with substantial economic value, as they can be extracted from agro-wastes and/or under exploited plant species. The perennial hydrophyte, Potamogeton perfoliatus, has been used traditionally to treat several health disorders; however, little is known about its biological and its medicinal effects. Here, we used an integrated in vitro and in vivo framework to examine the potential effect of P. perfoliatus on oxidative stress, nociception, inflammatory models, and brewer’s yeast-induced pyrexia in mice. Our results suggested a consistent in vitro inhibition of three enzymes, namely 5-lipoxygenase, cyclooxygenases 1 and 2 (COX-1 and COX-2), as well as a potent antioxidant effect. These results were confirmed in vivo where the studied extract attenuated carrageenan-induced paw edema, carrageenan-induced leukocyte migration into the peritoneal cavity by 25, 44 and 64% at 200, 400 and 600 mg/kg, p.o., respectively. Moreover, the extract decreased acetic acid-induced vascular permeability by 45% at 600 mg/kg, p.o., and chemical hyperalgesia in mice by 86% by 400 mg/kg, p.o., in acetic acid-induced writhing assay. The extract (400 mg/kg) showed a longer response latency at the 3 h time point (2.5 fold of the control) similar to the nalbuphine, the standard opioid analgesic. Additionally, pronounced antipyretic effects were observed at 600 mg/kg, comparable to paracetamol. Using LC-MS/MS, we identified 15 secondary metabolites that most likely contributed to the obtained biological activities. Altogether, our findings indicate that P. perfoliatus has anti-inflammatory, antioxidant, analgesic and antipyretic effects, thus supporting its traditional use and promoting its valorization as a potential candidate in treating oxidative stress-associated diseases.
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Elzahhar PA, Alaaeddine RA, Nassra R, Ismail A, Labib HF, Temraz MG, Belal ASF, El-Yazbi AF. Challenging inflammatory process at molecular, cellular and in vivo levels via some new pyrazolyl thiazolones. J Enzyme Inhib Med Chem 2021; 36:669-684. [PMID: 33618602 PMCID: PMC7901699 DOI: 10.1080/14756366.2021.1887169] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The work reported herein describes the synthesis of a new series of anti-inflammatory pyrazolyl thiazolones. In addition to COX-2/15-LOX inhibition, these hybrids exerted their anti-inflammatory actions through novel mechanisms. The most active compounds possessed COX-2 inhibitory activities comparable to celecoxib (IC50 values of 0.09-0.14 µM) with significant 15-LOX inhibitory activities (IC50s 1.96 to 3.52 µM). Upon investigation of their in vivo anti-inflammatory activities and ulcerogenic profiles, these compounds showed activity patterns equivalent or more superior to diclofenac and/or celecoxib. Intriguingly, the most active compounds were more effective than diclofenac in suppressing monocyte-to-macrophage differentiation and inflammatory cytokine production by activated macrophages, as well as their ability to induce macrophage apoptosis. The latter finding potentially adds a new dimension to the previously reported anti-inflammatory mechanisms of similar compounds. These compounds were effectively docked into COX-2 and 15-LOX active sites. Also, in silico predictions confirmed the appropriateness of these compounds as drug-like candidates.
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Affiliation(s)
- Perihan A Elzahhar
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Rana A Alaaeddine
- Department of Pharmacology and Toxicology, Faculty of Medicine and Medical Centre, American University of Beirut, Beirut, Lebanon
| | - Rasha Nassra
- Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Azza Ismail
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Hala F Labib
- Department of Pharmaceutical Chemistry, College of Pharmacy, Arab Academy of Science Technology and Maritime Transport, Alexandria, Egypt
| | | | - Ahmed S F Belal
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Ahmed F El-Yazbi
- Department of Pharmacology and Toxicology, Faculty of Medicine and Medical Centre, American University of Beirut, Beirut, Lebanon.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, E gypt
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Said MF, Georgey HH, Mohammed ER. Synthesis and computational studies of novel fused pyrimidinones as a promising scaffold with analgesic, anti-inflammatory and COX inhibitory potential. Eur J Med Chem 2021; 224:113682. [PMID: 34245948 DOI: 10.1016/j.ejmech.2021.113682] [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: 04/19/2021] [Revised: 06/29/2021] [Accepted: 06/30/2021] [Indexed: 01/30/2023]
Abstract
Addressing the global need for the development of safe and potent NSAIDs, new series of oxadiazolo and thiadiazolo fused pyrmidinones were synthesized and initially tested for their analgesic activity. All tested compounds showed promising analgesic activity compared with the reference standard indomethacin. Moreover, anti-inflammatory activity evaluation, ulcerogenic liability, and in vitro COX-1, COX-2 enzyme inhibition assays were also performed for the most active derivatives. The methoxyphenyl piperazinyl derivative 3d showed analgesic activity surpassing indomethacin with protection of 100%, and 83%; respectively. Also 3d showed good anti-inflammatory activity with relatively lower ulcer index compared with other tested compounds, and potent COX-1 and COX-2 inhibitory activity with IC50 = 0.140, 0.007 μm, respectively, and with a selectivity index of 20.00 which was better than the reference standards and the other tested congeners. Additionally, compounds 3b, 3g and 3h revealed moderate selectivity (SI = 3.53, 3.70 and 5.87, respectively). Moreover, in silico physicochemical parameters revealed that the new fused pyrimidinones demonstrated promising pharmacokinetic properties. Furthermore, computational studies in form of 2D-quantitative structure-activity relationship (2D-QSAR) and 3D-pharmacophore confirmed the potential analgesic properties of the new target compounds.
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Affiliation(s)
- Mona F Said
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt.
| | - Hanan H Georgey
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, 11777, Egypt.
| | - Eman R Mohammed
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt
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Cuesta SA, Meneses L. The Role of Organic Small Molecules in Pain Management. Molecules 2021; 26:4029. [PMID: 34279369 PMCID: PMC8271912 DOI: 10.3390/molecules26134029] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/25/2021] [Accepted: 06/27/2021] [Indexed: 12/28/2022] Open
Abstract
In this review, a timeline starting at the willow bark and ending in the latest discoveries of analgesic and anti-inflammatory drugs will be discussed. Furthermore, the chemical features of the different small organic molecules that have been used in pain management will be studied. Then, the mechanism of different types of pain will be assessed, including neuropathic pain, inflammatory pain, and the relationship found between oxidative stress and pain. This will include obtaining insights into the cyclooxygenase action mechanism of nonsteroidal anti-inflammatory drugs (NSAID) such as ibuprofen and etoricoxib and the structural difference between the two cyclooxygenase isoforms leading to a selective inhibition, the action mechanism of pregabalin and its use in chronic neuropathic pain, new theories and studies on the analgesic action mechanism of paracetamol and how changes in its structure can lead to better characteristics of this drug, and cannabinoid action mechanism in managing pain through a cannabinoid receptor mechanism. Finally, an overview of the different approaches science is taking to develop more efficient molecules for pain treatment will be presented.
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Affiliation(s)
| | - Lorena Meneses
- Laboratorio de Química Computacional, Facultad de Ciencias Exactas y Naturales, Escuela de Ciencias Químicas, Pontificia Universidad Católica del Ecuador, Av. 12 de Octubre 1076 Apartado, Quito 17-01-2184, Ecuador;
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Kaduševičius E. Novel Applications of NSAIDs: Insight and Future Perspectives in Cardiovascular, Neurodegenerative, Diabetes and Cancer Disease Therapy. Int J Mol Sci 2021; 22:6637. [PMID: 34205719 PMCID: PMC8235426 DOI: 10.3390/ijms22126637] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 05/28/2021] [Accepted: 06/01/2021] [Indexed: 01/22/2023] Open
Abstract
Once it became clear that inflammation takes place in the modulation of different degenerative disease including neurodegenerative, cardiovascular, diabetes and cancer the researchers has started intensive programs evaluating potential role of non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention or therapy of these diseases. This review discusses the novel mechanism of action of NSAIDs and its potential use in the pharmacotherapy of neurodegenerative, cardiovascular, diabetes and cancer diseases. Many different molecular and cellular factors which are not yet fully understood play an important role in the pathogenesis of inflammation, axonal damage, demyelination, atherosclerosis, carcinogenesis thus further NSAID studies for a new potential indications based on precise pharmacotherapy model are warranted since NSAIDs are a heterogeneous group of medicines with relative different pharmacokinetics and pharmacodynamics profiles. Hopefully the new data from studies will fill in the gap between experimental and clinical results and translate our knowledge into successful disease therapy.
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Affiliation(s)
- Edmundas Kaduševičius
- Institute of Physiology and Pharmacology, Medical Academy, Lithuanian University of Health Sciences, 9 A. Mickeviciaus Street, LT-44307 Kaunas, Lithuania
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36
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Wang B, Wu L, Chen J, Dong L, Chen C, Wen Z, Hu J, Fleming I, Wang DW. Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets. Signal Transduct Target Ther 2021; 6:94. [PMID: 33637672 PMCID: PMC7910446 DOI: 10.1038/s41392-020-00443-w] [Citation(s) in RCA: 616] [Impact Index Per Article: 154.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/04/2020] [Accepted: 10/15/2020] [Indexed: 01/31/2023] Open
Abstract
The arachidonic acid (AA) pathway plays a key role in cardiovascular biology, carcinogenesis, and many inflammatory diseases, such as asthma, arthritis, etc. Esterified AA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2), which is in turn further metabolized by cyclooxygenases (COXs) and lipoxygenases (LOXs) and cytochrome P450 (CYP) enzymes to a spectrum of bioactive mediators that includes prostanoids, leukotrienes (LTs), epoxyeicosatrienoic acids (EETs), dihydroxyeicosatetraenoic acid (diHETEs), eicosatetraenoic acids (ETEs), and lipoxins (LXs). Many of the latter mediators are considered to be novel preventive and therapeutic targets for cardiovascular diseases (CVD), cancers, and inflammatory diseases. This review sets out to summarize the physiological and pathophysiological importance of the AA metabolizing pathways and outline the molecular mechanisms underlying the actions of AA related to its three main metabolic pathways in CVD and cancer progression will provide valuable insight for developing new therapeutic drugs for CVD and anti-cancer agents such as inhibitors of EETs or 2J2. Thus, we herein present a synopsis of AA metabolism in human health, cardiovascular and cancer biology, and the signaling pathways involved in these processes. To explore the role of the AA metabolism and potential therapies, we also introduce the current newly clinical studies targeting AA metabolisms in the different disease conditions.
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Affiliation(s)
- Bei Wang
- Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Hubei Province, Wuhan, China
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, Wuhan, China
| | - Lujin Wu
- Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Hubei Province, Wuhan, China
| | - Jing Chen
- Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Hubei Province, Wuhan, China
| | - Lingli Dong
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, Wuhan, China
| | - Chen Chen
- Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Hubei Province, Wuhan, China
| | - Zheng Wen
- Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Hubei Province, Wuhan, China
| | - Jiong Hu
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany
| | - Ingrid Fleming
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Hubei Province, Wuhan, China.
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Jamalan M, Barzegari E, Gholami-Borujeni F. Structure-Based Screening to Discover New Inhibitors for Papain-like Proteinase of SARS-CoV-2: An In Silico Study. J Proteome Res 2021; 20:1015-1026. [PMID: 33350309 PMCID: PMC7770893 DOI: 10.1021/acs.jproteome.0c00836] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Indexed: 12/23/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) expresses a multifunctional papain-like proteinase (PLpro), which mediates the processing of the viral replicase polyprotein. Inhibition of PLpro has been shown to suppress the viral replication. This study aimed to explore new anti-PLpro candidates by applying virtual screening based on GRL0617, a known PLpro inhibitor of SARS coronavirus (SARS-CoV). The three-dimensional (3D) structure of SARS-CoV-2 PLpro was built by homology modeling, using SARS-CoV PLpro as the template. The model was refined and studied through molecular dynamic simulation. AutoDock Vina was then used to perform virtual screening where 50 chemicals with at least 65% similarity to GRL0617 were docked with the optimized SARS-CoV-2 PLpro. In this screening, 5-(aminomethyl)-2-methyl-N-[(1R)-1-naphthalen-1-ylethyl]benzamide outperformed GRL0617 in terms of binding affinity (-9.7 kcal/mol). Furthermore, 2-(4-fluorobenzyl)-5-nitro-1H-isoindole-1,3(2H)-dione (previously introduced as an inhibitor of cyclooxygenase-2), 3-nitro-N-[(1r)-1-phenylethyl]-5-(trifluoromethyl)benzamide (inhibitor against Mycobacterium tuberculosis), as well as the recently introduced SARS-CoV-2 PLpro inhibitor 5-acetamido-2-methyl-N-[(1S)-1-naphthalen-1-ylethyl]benzamide showed promising affinity for the viral proteinase. All of the identified compounds demonstrated an acceptable pharmacokinetic profile. In conclusion, our findings represent rediscovery of analgesic, anti-inflammatory, antibacterial, or antiviral drugs as promising pharmaceutical candidates against the ongoing coronavirus.
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Affiliation(s)
- Mostafa Jamalan
- Department
of Biochemistry, Abadan Faculty of Medical
Sciences, Abadan 6313833177, Iran
| | - Ebrahim Barzegari
- Medical
Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah 6715847141, Iran
| | - Fathollah Gholami-Borujeni
- Department
of Environmental Health, Mazandaran University
of Medical Sciences, Mazandaran 4815733971, Iran
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Abdel-Aziz AAM, El-Azab AS, AlSaif NA, Alanazi MM, El-Gendy MA, Obaidullah AJ, Alkahtani HM, Almehizia AA, Al-Suwaidan IA. Synthesis, anti-inflammatory, cytotoxic, and COX-1/2 inhibitory activities of cyclic imides bearing 3-benzenesulfonamide, oxime, and β-phenylalanine scaffolds: a molecular docking study. J Enzyme Inhib Med Chem 2020; 35:610-621. [PMID: 32013633 PMCID: PMC7034070 DOI: 10.1080/14756366.2020.1722120] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 01/14/2020] [Accepted: 01/19/2020] [Indexed: 12/26/2022] Open
Abstract
Cyclic imides containing 3-benzenesulfonamide, oxime, and β-phenylalanine derivatives were synthesised and evaluated to elucidate their in vivo anti-inflammatory and ulcerogenic activity and in vitro cytotoxic effects. Most active anti-inflammatory agents were subjected to in vitro COX-1/2 inhibition assay. 3-Benzenesulfonamides (2-4, and 9), oximes (11-13), and β-phenylalanine derivative (18) showed potential anti-inflammatory activities with 71.2-82.9% oedema inhibition relative to celecoxib and diclofenac (85.6 and 83.4%, respectively). Most active cyclic imides 4, 9, 12, 13, and 18 possessed ED50 of 35.4-45.3 mg kg-1 relative to that of celecoxib (34.1 mg kg-1). For the cytotoxic evaluation, the selected derivatives 2-6 and 8 exhibited weak positive cytotoxic effects (PCE = 2/59-5/59) at 10 μM compared to the standard drug, imatinib (PCE = 20/59). Cyclic imides bearing 3-benzenesulfonamide (2-5, and 9), acetophenone oxime (11-14, 18, and 19) exhibited high selectivity against COX-2 with SI > 55.6-333.3 relative to that for celecoxib [SI > 387.6]. β-Phenylalanine derivatives 21-24 and 28 were non-selective towards COX-1/2 isozymes as indicated by their SI of 0.46-0.68.
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Affiliation(s)
- Alaa A.-M. Abdel-Aziz
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Adel S. El-Azab
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Nawaf A. AlSaif
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed M. Alanazi
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Manal A. El-Gendy
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Ahmad J. Obaidullah
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Hamad M. Alkahtani
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Abdulrahman A. Almehizia
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Ibrahim A. Al-Suwaidan
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
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Silva LP, Santos EC, Borges BA, Veloso MP, Chagas-Paula DA, Gonçalves RV, Novaes RD. Tagitinin F has anti-inflammatory, anti-nociceptive and anti-matrix metalloproteinase properties: An in silico, in vitro and in vivo study. Pharmacol Res 2020; 164:105303. [PMID: 33212290 DOI: 10.1016/j.phrs.2020.105303] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 10/18/2020] [Accepted: 11/09/2020] [Indexed: 01/13/2023]
Abstract
Sesquiterpene lactones (SL) are natural bioactive molecules indicated as potential scaffolds for anti-inflammatory and analgesic drug design. However, their anti-inflammatory applicability remains underestimated since the impact of SL on inflammatory nociception and tissue repair are overlooked. Thus, we used an integrated in silico, in vitro and in vivo framework to investigate the impact of tagitinin F (TAG-F) on lipopolysaccharide (LPS)-challenged macrophages, excisional skin wounds, and carrageenan-induced paw edema and mechanical hyperalgesia in mice. RAW 264.7 macrophages in culture were challenged with LPS and treated with TAG-F (5, 10, 50 and 100 μM). The paw of BALB/c mice was injected with carrageenan and treated with 0.5% and 1% TAG-F. Excisional wounds were also produced in BALB/c mice and treated with 0.5% and 1% TAG-F. Our results indicated a consistent concentration-dependent downregulation in 5-lipoxygenase, cyclooxygenase 1 and 2 (COX-1 and COX-2), matrix metalloproteinase 1 and 2 (MMP-1 and MMP-2) activities; as well as attenuation in prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and tumor necrosis factor-α (TNF-α) production in both in vitro and in vivo models. In vivo, TAG-F also attenuated carrageenan-induced paw edema and mechanical hyperalgesia in mice. From the excisional skin wound, TAG-F was still effective in reducing neutrophils and macrophages infiltration and stimulating collagen deposition in the scar tissue, accelerating tissue maturation. Together, our findings indicate that the anti-inflammatory effect of TAG-F is more comprehensive than previously suggested, exerting a significant impact on the control of edema, inflammatory pain and modulating central metabolic processes linked to skin wound healing.
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Affiliation(s)
- Laíla Pereira Silva
- Institute of Biomedical Sciences, Department of Structural Biology, Federal University of Alfenas, Alfenas, Minas Gerais, 37130-001, Brazil; Center of Heath Sciences, University Jose do Rosario Vellano, Minas Gerais, Brazil
| | - Eliziária Cardoso Santos
- School of Medicine, Federal University of Jequitinhonha and Mucuri Valleys, Diamantina, Minas Gerais, 39100-000, Brazil
| | - Bruno Arantes Borges
- Institute of Chemistry, Federal University of Alfenas, Alfenas, Minas Gerais, 37130-001, Brazil
| | - Marcia Paranho Veloso
- Faculty of Pharmaceutical Sciences, Federal University of Alfenas, Alfenas, Minas Gerais, 37130-001, Brazil
| | | | | | - Rômulo Dias Novaes
- Institute of Biomedical Sciences, Department of Structural Biology, Federal University of Alfenas, Alfenas, Minas Gerais, 37130-001, Brazil.
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Sisa M, Dvorakova M, Temml V, Jarosova V, Vanek T, Landa P. Synthesis, inhibitory activity and in silico docking of dual COX/5-LOX inhibitors with quinone and resorcinol core. Eur J Med Chem 2020; 204:112620. [PMID: 32738413 DOI: 10.1016/j.ejmech.2020.112620] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 06/22/2020] [Accepted: 06/22/2020] [Indexed: 12/12/2022]
Abstract
Based on the significant anti-inflammatory activity of natural quinone primin (5a), series of 1,4-benzoquinones, hydroquinones, and related resorcinols were designed, synthesized, characterized and tested for their ability to inhibit the activity of cyclooxygenase (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) enzymes. Structural modifications resulted in the identification of two compounds 5b (2-methoxy-6-undecyl-1,4-benzoquinone) and 6b (2-methoxy-6-undecyl-1,4-hydroquinone) as potent dual COX/5-LOX inhibitors. The IC50 values evaluated in vitro using enzymatic assay were for compound 5b IC50 = 1.07, 0.57, and 0.34 μM and for compound 6b IC50 = 1.07, 0.55, and 0.28 μM for COX-1, COX-2, and 5-LOX enzyme, respectively. In addition, compound 6d was identified as the most potent 5-LOX inhibitor (IC50 = 0.14 μM; reference inhibitor zileuton IC50 = 0.66 μM) from the tested compounds while its inhibitory potential against COX enzymes (IC50 = 2.65 and 2.71 μM for COX-1 and COX-2, respectively) was comparable with the reference inhibitor ibuprofen (IC50 = 4.50 and 2.46 μM, respectively). The most important structural modification leading to increased inhibitory activity towards both COXs and 5-LOX was the elongation of alkyl chain in position 6 from 5 to 11 carbons. Moreover, the monoacetylation in ortho position of bromo-hydroquinone 13 led to the discovery of potent (IC50 = 0.17 μM) 5-LOX inhibitor 17 (2-bromo-6-methoxy-1,4-benzoquinone) while bromination stabilized the hydroquinone form. Docking analysis revealed the interaction of compounds with Tyr355 and Arg120 in the catalytic site of COX enzymes, while the hydrophobic parts of the molecules filled the hydrophobic substrate channel leading up to Tyr385. In the allosteric catalytic site of 5-LOX, compounds bound to Tyr142 and formed aromatic interactions with Arg138. Taken together, we identified optimal alkyl chain length for dual COX/5-LOX inhibition and investigated other structural modifications influencing COX and 5-LOX inhibitory activity.
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Affiliation(s)
- Miroslav Sisa
- Laboratory of Plant Biotechnologies, Institute of Experimental Botany of the Czech Academy of Sciences, Rozvojova 263, 165 02 Prague 6, Lysolaje, Czech Republic
| | - Marcela Dvorakova
- Laboratory of Plant Biotechnologies, Institute of Experimental Botany of the Czech Academy of Sciences, Rozvojova 263, 165 02 Prague 6, Lysolaje, Czech Republic
| | - Veronika Temml
- Department of Pharmacy/Pharmacognosy and Center of Molecular Biosciences (CMBI), University of Innsbruck, Innrain 80-82, 6020, Innsbruck, Austria
| | - Veronika Jarosova
- Laboratory of Plant Biotechnologies, Institute of Experimental Botany of the Czech Academy of Sciences, Rozvojova 263, 165 02 Prague 6, Lysolaje, Czech Republic; Department of Food Science, Faculty of Agrobiology, Food and Natural Resources, The Czech University of Life Sciences Prague, Kamycka 129, 165 21 Prague 6, Suchdol, Czech Republic
| | - Tomas Vanek
- Laboratory of Plant Biotechnologies, Institute of Experimental Botany of the Czech Academy of Sciences, Rozvojova 263, 165 02 Prague 6, Lysolaje, Czech Republic
| | - Premysl Landa
- Laboratory of Plant Biotechnologies, Institute of Experimental Botany of the Czech Academy of Sciences, Rozvojova 263, 165 02 Prague 6, Lysolaje, Czech Republic.
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Chaudhary N, Aparoy P. Application of per-residue energy decomposition to identify the set of amino acids critical for in silico prediction of COX-2 inhibitory activity. Heliyon 2020; 6:e04944. [PMID: 33083581 PMCID: PMC7550918 DOI: 10.1016/j.heliyon.2020.e04944] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/31/2020] [Accepted: 09/11/2020] [Indexed: 12/29/2022] Open
Abstract
The enormous magnitude of scientific research carried out in the field of NSAIDs and cyclooxygenases (COXs) is known. They are crucial in pain management. COX-2 inhibitors have evolved over the years; from traditional NSAIDs to isoform-specific. The present study is aimed to identify a cluster of amino acids in the catalytic site whose energy contribution can better explain COX-2 inhibitory activity accurately than the binding energy of the whole protein. Initially, MD simulations (25 ns) and MM-PBSA calculations were performed for 8 diarylheterocyclic inhibitors. Per-residue energy decomposition studies were carried out to elucidate the energy contribution of each amino acid, and their correlation with COX-2 inhibitory activity was enumerated. A cluster of catalytic amino acids whose free energy sum has a high correlation with biological data was identified. The cluster of Gln178, Ser339, Tyr341, Arg499, Phe504, Val509 and Ala513 showed the correlation of -0.60. Further, the study was extended to a total of 26 COX-2 inhibitors belonging to different classes to validate the applicability of the cluster of amino acids identified. Results clearly suggest that the cluster of amino acids identified provide accurate screening method, and can be applied to predict COX-2 inhibitory activity of small molecules.
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Affiliation(s)
- Neha Chaudhary
- Centre for Computational Biology and Bioinformatics, School of Life Sciences, Central University of Himachal Pradesh, Dharamshala, Himachal Pradesh, 176215, India
| | - Polamarasetty Aparoy
- Centre for Computational Biology and Bioinformatics, School of Life Sciences, Central University of Himachal Pradesh, Dharamshala, Himachal Pradesh, 176215, India.,Faculty of Biology, Indian Institute of Petroleum & Energy, Visakhapatnam, Andhra Pradesh, India
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42
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Hawash M, Jaradat N, Hameedi S, Mousa A. Design, synthesis and biological evaluation of novel benzodioxole derivatives as COX inhibitors and cytotoxic agents. BMC Chem 2020; 14:54. [PMID: 32944715 PMCID: PMC7487730 DOI: 10.1186/s13065-020-00706-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 09/02/2020] [Indexed: 02/06/2023] Open
Abstract
Non-steroidal anti-inflammatory drugs are among the most used drugs. They are competitive inhibitors of cyclooxygenase (COX). Twelve novel compounds (aryl acetate and aryl acetic acid groups) were synthesized in this work in order to identify which one was the most potent and which group was most selective towards COX1 and COX2 by using an in vitro COX inhibition assay kit. The cytotoxicity was evaluated for these compounds utilizing MTS assay against cervical carcinoma cells line (HeLa). The synthesized compounds were identified using FTIR, HRMS, 1H-NMR, and 13C-NMR techniques. The results showed that the most potent compound against the COX1 enzyme was 4f with IC50 = 0.725 µM. The compound 3b showed potent activity against both COX1 and COX2 with IC50 = 1.12 and 1.3 µM, respectively, and its selectivity ratio (0.862) was found to be better than Ketoprofen (0.196). In contrast, compound 4d was the most selective with a COX1/COX2 ratio value of 1.809 in comparison with the Ketoprofen ratio. All compounds showed cytotoxic activity against the HeLa Cervical cancer cell line at a higher concentration ranges (0.219–1.94 mM), and the most cytotoxic compound was 3e with a CC50 value of 219 µM. This was tenfold more than its IC50 values of 2.36 and 2.73 µM against COX1 and COX2, respectively. In general, the synthesized library has moderate activity against both enzymes (i.e., COX1 and COX2) and ortho halogenated compounds were more potent than the meta ones.![]()
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Affiliation(s)
- Mohammed Hawash
- Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, P.O. Box 7, Nablus, 00970 Palestine
| | - Nidal Jaradat
- Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, P.O. Box 7, Nablus, 00970 Palestine
| | - Saba Hameedi
- Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, P.O. Box 7, Nablus, 00970 Palestine
| | - Ahmed Mousa
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, 00970 Palestine
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43
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Beura S, Chetti P. Identification of potential human COX-2 inhibitors using computational modeling and molecular dynamics simulations. J Mol Struct 2020. [DOI: 10.1016/j.molstruc.2020.128271] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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44
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Elzahhar PA, Abd El Wahab SM, Elagawany M, Daabees H, Belal AS, EL-Yazbi AF, Eid AH, Alaaeddine R, Hegazy RR, Allam RM, Helmy MW, Bahaa Elgendy, Angeli A, El-Hawash SA, Supuran CT. Expanding the anticancer potential of 1,2,3-triazoles via simultaneously targeting Cyclooxygenase-2, 15-lipoxygenase and tumor-associated carbonic anhydrases. Eur J Med Chem 2020; 200:112439. [DOI: 10.1016/j.ejmech.2020.112439] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 05/05/2020] [Accepted: 05/06/2020] [Indexed: 12/21/2022]
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45
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Shaaban MA, Kamal AM, Faggal SI, Farag NA, Aborehab NM, Elsahar AE, Mohamed KO. Design, synthesis, and biological evaluation of new pyrazoloquinazoline derivatives as dual COX-2/5-LOX inhibitors. Arch Pharm (Weinheim) 2020; 353:e2000027. [PMID: 32696514 DOI: 10.1002/ardp.202000027] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 06/19/2020] [Accepted: 06/23/2020] [Indexed: 01/02/2023]
Abstract
A new series of pyrazoloquinazoline derivatives equipped with different chalcones was designed, synthesized, and identified through 1 H nuclear magnetic resonance (NMR), 13 C NMR, and infrared spectroscopic techniques. Our design strategy of the quinazolinone-privileged scaffold as a new scaffold was based on merging pharmacophores previously reported to exhibit cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LOX) inhibitory activity. All the newly synthesized derivatives were biologically evaluated for COX and 5-LOX inhibitory activity and COX-2 selectivity, using celecoxib and zileuton as reference drugs, as they exhibited promising anti-inflammatory activity. Compound 3j was found to be the most promising derivative, with IC50 values of 667 and 47 nM against COX-1 and COX-2, respectively, which are superior to that of celecoxib (IC50 value against COX-2 = 95 nM), showing an SI of 14.2 that was much better than celecoxib. Compounds 3f and 3h exhibited COX-1 inhibition, with IC50 values of 1,485 and 684 nM, respectively. The synthesized compounds showed a significant inhibitory activity against 5-LOX, with IC50 values ranging from 0.6 to 4.3 µM, where compounds 3f and 3h were found to be the most potent derivatives, with IC50 values of 0.6 and 1.0 µM, respectively, in comparison with that of zileuton (IC50 = 0.8 µM). These promising derivatives, 3f, 3h, and 3j, were further investigated in vivo for anti-inflammatory, gastric ulcerogenic effects, and prostaglandin production (PGE2) in rat serum. The molecular docking studies concerning the binding sites of COX-2 and 5-LOX revealed similar orientation, compared with reported inhibitors, which encouraged us to design new leads targeting COX-2 and 5-LOX as dual inhibitors, as a new avenue in anti-inflammatory therapy.
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Affiliation(s)
- Mohamed A Shaaban
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Aliaa M Kamal
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.,Department of Organic Chemistry, Faculty of Pharmacy, October University for Modern Science and Arts (MSA), Giza, Egypt
| | - Samar I Faggal
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Nahla A Farag
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Misr International University, Cairo, Egypt
| | - Nora M Aborehab
- Department of Biochemistry, Faculty of Pharmacy, October University for Modern Science and Arts (MSA), Giza, Egypt
| | - Ayman E Elsahar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Khaled O Mohamed
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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46
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Orafaie A, Mousavian M, Orafai H, Sadeghian H. An overview of lipoxygenase inhibitors with approach of in vivo studies. Prostaglandins Other Lipid Mediat 2020; 148:106411. [DOI: 10.1016/j.prostaglandins.2020.106411] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Revised: 12/27/2019] [Accepted: 01/07/2020] [Indexed: 12/30/2022]
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47
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1,4-Disubstituted 1 H-1,2,3-Triazoles for Renal Diseases: Studies of Viability, Anti-Inflammatory, and Antioxidant Activities. Int J Mol Sci 2020; 21:ijms21113823. [PMID: 32481556 PMCID: PMC7312092 DOI: 10.3390/ijms21113823] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 05/21/2020] [Accepted: 05/26/2020] [Indexed: 12/15/2022] Open
Abstract
Inflammation is a hallmark of many metabolic diseases. We previously showed that ferrocene-appended 1H-1,2,3-triazole hybrids inhibit nitric oxide (NO) production in in vitro models of lipopolysaccharide-induced inflammation in the BV-2 cell. In the present study, we explored the viability, anti-inflammatory, and antioxidant potential of ferrocene-1H-1,2,3-triazole hybrids using biochemical assays in rat mesangial cells (RMCs). We found that, among all the ferrocene-1H-1,2,3-triazole hybrids, X2-X4 exhibited an antioxidant effect on mitochondrial free radicals. Among all the studied compounds, X4 demonstrated the best anti-inflammatory effect on RMCs. These results were supplemented by in silico studies including molecular docking with human cytosolic phospholipase A2 (cPLA2) and cyclooxygenase 2 (COX-2) enzymes as well as absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling. Besides, two new crystal structures of the compounds have also been reported. In addition, combining the results from the inducible nitric oxide synthase (iNOS), cPLA2, COX-2, and matrix metalloproteinase-9 (MMP-9) enzymatic activity analysis and NO production also confirmed this argument. Overall, the results of this study will be a valuable addition to the growing body of work on biological activities of triazole-based compounds.
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48
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Identification of cysteinyl-leukotriene-receptor 1 antagonists as ligands for the bile acid receptor GPBAR1. Biochem Pharmacol 2020; 177:113987. [PMID: 32330496 DOI: 10.1016/j.bcp.2020.113987] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 04/17/2020] [Indexed: 01/06/2023]
Abstract
The cysteinyl leukotrienes (CysLTs), i.e. LTC4, LTD4 and LTE4, are a family of proinflammatory agents synthesized from the arachidonic acid. In target cells, these lipid mediators bind to the cysteinyl leukotriene receptors (CysLTR), a family of seven transmembrane G-protein coupled receptors. The CysLT1R is a validated target for treatment of pulmonary diseases and several selective antagonists for this receptor, including montelukast, zafirlukast and pranlukast, have shown effective in the management of asthma. Nevertheless, others CysLT1R antagonists, such as the alpha-pentyl-3-[2-quinolinylmethoxy] benzyl alcohol (REV5901), have been extensively characterized without reaching sufficient priority for clinical development. Since drug reposition is an efficient approach for maximizing investment in drug discovery, we have investigated whether CysLT1R antagonists might exert off-target effects. In the report we demonstrate that REV5901 interacts with GPBAR1, a well characterized cell membrane receptor for secondary bile acids. REV5901 transactivates GPBAR1 in GPBAR1-transfected cells with an EC50 of 2.5 µM and accommodates the GPBAR1 binding site as shown by in silico analysis. Exposure of macrophages to REV5901 abrogates the inflammatory response elicited by bacterial endotoxin in a GPBAR1-dependent manner. In vivo, in contrast to montelukast, REV5901 attenuates inflammation and immune dysfunction in rodent models of colitis. The beneficial effects exerted by REV5901 in these models were abrogated by GPBAR1 gene ablation, confirming that REV5901, a shelved CysLT1R antagonist, is a GPBAR1 ligand. These data ground the basis for the development of novel hybrid ligands designed for simultaneous modulation of CysTL1R and GPBAR1.
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49
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Izzotti A, Balansky R, Micale RT, Pulliero A, La Maestra S, De Flora S. Modulation of smoke-induced DNA and microRNA alterations in mouse lung by licofelone, a triple COX-1, COX-2 and 5-LOX inhibitor. Carcinogenesis 2020; 41:91-99. [PMID: 31562745 PMCID: PMC7456342 DOI: 10.1093/carcin/bgz158] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 07/29/2019] [Accepted: 09/19/2019] [Indexed: 02/06/2023] Open
Abstract
Chronic inflammation plays a crucial role in the carcinogenesis process and, in particular, in smoking-related carcinogenesis. Therefore, anti-inflammatory agents provide an interesting perspective in the prevention of smoking-associated cancers. Among nonsteroidal anti-inflammatory drugs (NSAIDs), licofelone is a triple inhibitor of both cyclooxygenases (COX-1 and COX-2) and of 5-lipooxygenase (5-LOX) that has shown some encouraging results in cancer prevention models. We previously showed that the dietary administration of licofelone, starting after weanling, to Swiss H mice exposed for 4 months to mainstream cigarette smoke since birth attenuated preneoplastic lesions of inflammatory nature in both lung and urinary tract, and had some effects on the yield of lung tumors at 7.5 months of age. The present study aimed at evaluating the early modulation by licofelone of pulmonary DNA and RNA alterations either in smoke-free or smoke-exposed H mice after 10 weeks of exposure. Licofelone protected the mice from the smoke-induced loss of body weight and significantly attenuated smoke-induced nucleotide alterations by decreasing the levels of bulky DNA adducts and 8-hydroxy-2'-deoxyguanosine in mouse lung. Moreover, the drug counteracted dysregulation by smoke of several pulmonary microRNAs involved in stress response, inflammation, apoptosis, and oncogene suppression. However, even in smoke-free mice administration of the drug had significant effects on a broad panel of microRNAs and, as assessed in a subset of mice used in a parallel cancer chemoprevention study, licofelone even enhanced the smoke-induced systemic genotoxic damage after 4 months of exposure. Therefore, caution should be paid when administering licofelone to smokers for long periods.
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Affiliation(s)
- Alberto Izzotti
- Department of Health Sciences, University of Genoa, Genoa, Italy
- IRCCS Policlinico San Martino, Genoa, Italy
| | | | - Rosanna T Micale
- Department of Health Sciences, University of Genoa, Genoa, Italy
| | | | | | - Silvio De Flora
- Department of Health Sciences, University of Genoa, Genoa, Italy
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50
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Gedawy EM, Kassab AE, El Kerdawy AM. Design, synthesis and biological evaluation of novel pyrazole sulfonamide derivatives as dual COX-2/5-LOX inhibitors. Eur J Med Chem 2020; 189:112066. [PMID: 31982653 DOI: 10.1016/j.ejmech.2020.112066] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 01/11/2020] [Accepted: 01/11/2020] [Indexed: 12/13/2022]
Abstract
The current therapeutic demand focuses more on the discovery of safer NSAIDs rather than exploring more potent alternatives. The dual COX-2/5-LOX inhibition is a promising strategy for designing compounds with an enhanced efficacy, reduced side-effects and a broader anti-inflammatory spectrum in comparison to classical NSAIDs. In the present study, a hybridization strategy was adopted to combine the binding features of the non-selective COX inhibitor "sulindac" and the selective COX-2 inhibitor "celecoxib" which show 5-LOX inhibitory activity with that of licofelone and a celecoxib pyridone analogue which show dual COX-2/5-LOX inhibitory activity to design new series of pyrazole sulfonamide derivatives which, by design, should possess dual COX-2/5-LOX inhibitory activity. All the newly synthesized compounds were initially tested for their potential analgesic activity, then candidates that showed potential analgesic activity, were selected for the subsequent anti-inflammatory activity evaluation, as well as, ulcerogenicity testing. Moreover, in vitro assessment of their COX-1, COX-2 and 5-LOX inhibitory activities were performed. The benzothiophen-2-yl pyrazole carboxylic acid derivative 5b showed the most potent analgesic and anti-inflammatory activities surpassing that of celecoxib and indomethacin. It showed potent COX-1, COX-2 and 5-LOX inhibitory activity with IC50 of 5.40, 0.01 and 1.78 μM, respectively, showing a selectivity index of 344.56 that was much better than the used reference standards and its parent compounds, confirming its selectivity towards COX-2 over COX-1. The prodrug ester derivatives 6c and 6d showed equipotent activity to their parent compound 5b with no gastric ulcerogenicity. Molecular docking simulations confirmed that the newly synthesized compounds possess the structural features required for binding to the target enzymes COX-2 and 5-LOX.
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Affiliation(s)
- Ehab M Gedawy
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Pharmaceutical Industries, Badr University in Cairo BUC, Cairo, Egypt
| | - Asmaa E Kassab
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt.
| | - Ahmed M El Kerdawy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt; Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, New Giza University, Newgiza, km 22 Cairo-Alexandria Desert Road, Cairo, Egypt
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