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Patel KI, Saha N, Dhameliya TM, Chakraborti AK. Recent advancements in the quest of benzazoles as anti-Mycobacterium tuberculosis agents. Bioorg Chem 2025; 155:108093. [PMID: 39764919 DOI: 10.1016/j.bioorg.2024.108093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 12/14/2024] [Accepted: 12/22/2024] [Indexed: 01/24/2025]
Abstract
Tuberculosis (TB) remains a global health challenge, claiming numerous lives each year, despite recent advancements in drug discovery and treatment strategies. Current TB treatment typically involves long-duration chemotherapy regimens that are often accompanied by adverse effects. The introduction of new anti-TB drugs, such as Bedaquiline, Delamanid, and Pretomanid, offers hope for more effective treatment, although challenges persist keeping the quest to find new anti-TB chemotypes an incessant exercise of medicinal chemists. Towards this initiative, the benzazoles continue to draw attention and have been recognised as new anti-TB scaffolds. Benzazole-containing compounds emerged as new chemotypes with potential to offer a versatile platform for new anti-TB drug design to generate new leads for further optimization. The elucidation of their chemical properties, biological effects, and potential mechanisms of action, would lead to identify innovative candidates for TB therapy. As medicinal chemists delve deeper into the SARs and mechanisms of action of benzazole derivatives, new opportunities for creating effective and safe anti-TB medications arise. This review highlights the potential impact of benzazole-based compounds on the search for new therapeutic agents against tuberculosis, emphasizing the importance of continued research and innovation in the field.
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Affiliation(s)
- Kshitij I Patel
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, Punjab 160 062, India
| | - Nirjhar Saha
- School of Chemical Sciences, Indian Association for the Cultivation of Science, Jadavpur, Kolkata, West Bengal 700 032, India
| | - Tejas M Dhameliya
- Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382 481, India
| | - Asit K Chakraborti
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, Punjab 160 062, India; School of Chemical Sciences, Indian Association for the Cultivation of Science, Jadavpur, Kolkata, West Bengal 700 032, India.
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Oon CE, Subramaniam AV, Ooi LY, Yehya AHS, Lee YT, Kaur G, Sasidharan S, Qiu B, Wang X. BZD9L1 benzimidazole analogue hampers colorectal tumor progression by impeding angiogenesis. World J Gastrointest Oncol 2023; 15:810-827. [PMID: 37275453 PMCID: PMC10237024 DOI: 10.4251/wjgo.v15.i5.810] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/17/2023] [Accepted: 04/21/2023] [Indexed: 05/12/2023] Open
Abstract
BACKGROUND The development of new vasculatures (angiogenesis) is indispensable in supplying oxygen and nutrients to fuel tumor growth. Epigenetic dysregulation in the tumor vasculature is critical to colorectal cancer (CRC) progression. Sirtuin (SIRT) enzymes are highly expressed in blood vessels. BZD9L1 benzimidazole analogue is a SIRT 1 and 2 inhibitor with reported anticancer activities in CRC. However, its role has yet to be explored in CRC tumor angiogenesis.
AIM To investigate the anti-angiogenic potential of BZD9L1 on endothelial cells (EC) in vitro, ex vivo and in HCT116 CRC xenograft in vivo models.
METHODS EA.hy926 EC were treated with half inhibitory concentration (IC50) (2.5 μM), IC50 (5.0 μM), and double IC50 (10.0 μM) of BZD9L1 and assessed for cell proliferation, adhesion and SIRT 1 and 2 protein expression. Next, 2.5 μM and 5.0 μM of BZD9L1 were employed in downstream in vitro assays, including cell cycle, cell death and sprouting in EC. The effect of BZD9L1 on cell adhesion molecules and SIRT 1 and 2 were assessed via real-time quantitative polymerase chain reaction (qPCR). The growth factors secreted by EC post-treatment were evaluated using the Quantibody Human Angiogenesis Array. Indirect co-culture with HCT116 CRC cells was performed to investigate the impact of growth factors modulated by BZD9L1-treated EC on CRC. The effect of BZD9L1 on sprouting impediment and vessel regression was determined using mouse choroids. HCT116 cells were also injected subcutaneously into nude mice and analyzed for the outcome of BZD9L1 on tumor necrosis, Ki67 protein expression indicative of proliferation, cluster of differentiation 31 (CD31) and CD34 EC markers, and SIRT 1 and 2 genes via hematoxylin and eosin, immunohistochemistry and qPCR, respectively.
RESULTS BZD9L1 impeded EC proliferation, adhesion, and spheroid sprouting through the downregulation of intercellular adhesion molecule 1, vascular endothelial cadherin, integrin-alpha V, SIRT1 and SIRT2 genes. The compound also arrested the cells at G1 phase and induced apoptosis in the EC. In mouse choroids, BZD9L1 inhibited sprouting and regressed sprouting vessels compared to the negative control. Compared to the negative control, the compound also reduced the protein levels of angiogenin, basic fibroblast growth factor, platelet-derived growth factor and placental growth factor, which then inhibited HCT116 CRC spheroid invasion in co-culture. In addition, a significant reduction in CRC tumor growth was noted alongside the downregulation of human SIRT1 (hSIRT1), hSIRT2, CD31, and CD34 EC markers and murine SIRT2 gene, while the murine SIRT1 gene remained unaffected, compared to vehicle control. Histology analyses revealed that BZD9L1 at low (50 mg/kg) and high (250 mg/kg) doses reduced Ki-67 protein expression, while BZD9L1 at the high dose diminished tumor necrosis compared to vehicle control.
CONCLUSION These results highlighted the anti-angiogenic potential of BZD9L1 to reduce CRC tumor progression. Furthermore, together with previous anticancer findings, this study provides valuable insights into the potential of BZD9L1 to co-target CRC tumor vasculatures and cancer cells via SIRT1 and/or SIRT2 down-regulation to improve the therapeutic outcome.
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Affiliation(s)
- Chern Ein Oon
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Penang 11800, Malaysia
| | - Ayappa V Subramaniam
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Penang 11800, Malaysia
| | - Lik Yang Ooi
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Penang 11800, Malaysia
| | - Ashwaq Hamid Salem Yehya
- Cancer Research, Eman Biodiscoveries, Kedah 08000, Malaysia
- Vatche and Tamar Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, United States
| | - Yeuan Ting Lee
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Penang 11800, Malaysia
| | - Gurjeet Kaur
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Penang 11800, Malaysia
| | - Sreenivasan Sasidharan
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Penang 11800, Malaysia
| | - Beiying Qiu
- Academic Clinical Program, Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore
- Singapore National Eye Centre, Singapore Eye Research Institute, Singapore 168751, Singapore
| | - Xiaomeng Wang
- Academic Clinical Program, Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore
- Singapore National Eye Centre, Singapore Eye Research Institute, Singapore 169857, Singapore
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Kuppuswamy U, Rajan RK, Kumar A, Ramanathan M. In-silico and in-vitro analysis of novel substituted benzimidazolyl derivatives for antimycobacterial potentials targeting enoyl acyl carrier protein reductase (InhA). FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2022. [DOI: 10.1186/s43094-022-00449-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Abstract
Background
The emergence of mutated drug-resistant strains of Mycobacterium tuberculosis has reinvigorated the development of effective chemotherapy for MDR-TB (multidrug-resistant resistance tuberculosis). Enoyl acyl carrier protein reductase (InhA) involved in the mycobacterial fatty acid elongation system has been chosen as a potential target.
Result
All of the lead compounds had a definite Rf value and a sharp melting point, confirming that no tautomeric forms exist and that the keto (CO) group is apparent in the IR and 13C NMR spectrum data. Structure-based drug design revealed the presence of amino acid residues like TYR 158, ILE 194, and PHE 149 which are crucial for InhA inhibitory activity and were considered favorable interactions. Among all, compounds 4, 5a, and 5c showed better docking and binding free energy owing to favorable interactions. Interestingly, there was a strong correlation between the binding free energy and the antimycobacterial susceptibility assay, where compounds 4, 5a, and 5c had greater activity. All the lead compounds also had good oral absorption and gut permeability. The presence of a carboxylic linker (–COOH–) between benzimidazole and the rest of the structure of the lead compounds was found to be crucial for activity as the oxygen atom and hydroxyl group of the linker formed most of the favorable interactions. The presence of chlorophenyl showed a favorable effect on InhA inhibition which might be owing to its hydrophobic interaction with PHE 149.
Conclusion
Three of the seven lead compounds synthesized had an IC value of approximately 0.5 μg/ml in the in-vitro Alamar blue assay against the Mycobacterium tuberculosis H37Rv strain, which is roughly comparable to the standard marketed drug, Isoniazid (INH). This manifestation of promising activity that resulted from combining in-silico and wet lab experimentation could be a great starting point for developing potent antimycobacterial agents to combat multidrug-resistant tuberculosis.
Graphical abstract
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Begunov RS, Zaitseva YV, Sokolov AA, Egorov DO, Filimonov SI. Synthesis and Antibacterial Activity of 1,2,3,4-Tetrahydro- and Pyrido[1,2-a]Benzimidazoles. Pharm Chem J 2022. [DOI: 10.1007/s11094-022-02596-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Leshabane M, Dziwornu GA, Coertzen D, Reader J, Moyo P, van der Watt M, Chisanga K, Nsanzubuhoro C, Ferger R, Erlank E, Venter N, Koekemoer L, Chibale K, Birkholtz LM. Benzimidazole Derivatives Are Potent against Multiple Life Cycle Stages of Plasmodium falciparum Malaria Parasites. ACS Infect Dis 2021; 7:1945-1955. [PMID: 33673735 DOI: 10.1021/acsinfecdis.0c00910] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The continued emergence of resistance to front-line antimalarial treatments is of great concern. Therefore, new compounds that potentially have a novel target in various developmental stages of Plasmodium parasites are needed to treat patients and halt the spread of malaria. Here, several benzimidazole derivatives were screened for activity against the symptom-causing intraerythrocytic asexual blood stages and the transmissible gametocyte stages of P. falciparum. Submicromolar activity was obtained for 54 compounds against asexual blood stage parasites with 6 potent at IC50 < 100 nM while not displaying any marked toxicity against mammalian cells. Nanomolar potency was also observed against gametocytes with two compounds active against early stage gametocytes and two compounds active against late-stage gametocytes. The transmission-blocking potential of the latter was confirmed as they could prevent male gamete exflagellation and the lead compound reduced transmission by 72% in an in vivo mosquito feeding model. These compounds therefore have activity against multiple stages of Plasmodium parasites with potential for differential targets.
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Affiliation(s)
- Meta Leshabane
- Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Private Bag X20, Hatfield 0028, South Africa
| | | | - Dina Coertzen
- Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Private Bag X20, Hatfield 0028, South Africa
| | - Janette Reader
- Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Private Bag X20, Hatfield 0028, South Africa
| | - Phanankosi Moyo
- Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Private Bag X20, Hatfield 0028, South Africa
| | - Mariëtte van der Watt
- Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Private Bag X20, Hatfield 0028, South Africa
| | - Kelly Chisanga
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
| | | | - Richard Ferger
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
| | - Erica Erlank
- Wits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, and Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, 2193, South Africa
| | - Nelius Venter
- Wits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, and Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, 2193, South Africa
| | - Lizette Koekemoer
- Wits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, and Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, 2193, South Africa
| | - Kelly Chibale
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa
- South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa
| | - Lyn-Marie Birkholtz
- Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Private Bag X20, Hatfield 0028, South Africa
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Alsayed SSR, Lun S, Payne A, Bishai WR, Gunosewoyo H. Facile synthesis and antimycobacterial activity of isoniazid, pyrazinamide and ciprofloxacin derivatives. Chem Biol Drug Des 2021; 97:1137-1150. [PMID: 33638304 PMCID: PMC8113106 DOI: 10.1111/cbdd.13836] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 01/12/2021] [Accepted: 01/28/2021] [Indexed: 12/14/2022]
Abstract
Several rationally designed isoniazid (INH), pyrazinamide (PZA) and ciprofloxacin (CPF) derivatives were conveniently synthesized and evaluated in vitro against H37Rv Mycobacterium tuberculosis (M. tb) strain. CPF derivative 16 displayed a modest activity (MIC = 16 µg/ml) and was docked into the M. tb DNA gyrase. Isoniazid-pyrazinoic acid (INH-POA) hybrid 21a showed the highest potency in our study (MIC = 2 µg/ml). It also retained its high activity against the other tested M. tb drug-sensitive strain (DS) V4207 (MIC = 4 µg/ml) and demonstrated negligible cytotoxicity against Vero cells (IC50 ≥ 64 µg/ml). Four tested drug-resistant (DR) M. tb strains were refractory to 21a, similar to INH, whilst being sensitive to CPF. Compound 21a was also inactive against two non-tuberculous mycobacterial (NTM) strains, suggesting its selective activity against M. tb. The noteworthy activity of 21a against DS strains and its low cytotoxicity highlight its potential to treat DS M. tb.
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Affiliation(s)
- Shahinda S. R. Alsayed
- School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, Perth, WA 6102, Australia
| | - Shichun Lun
- Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, 1550, Orleans Street, Baltimore, Maryland, 21231-1044, United States
| | - Alan Payne
- School of Molecular and Life Sciences, Curtin University, Perth, WA 6102, Australia
| | - William R. Bishai
- Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, 1550, Orleans Street, Baltimore, Maryland, 21231-1044, United States
- Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland, 20815-6789, United States
| | - Hendra Gunosewoyo
- School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, Perth, WA 6102, Australia
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Rakib EM, Boga C, Calvaresi M, Chigr M, Franchi P, Gualandi I, Ihammi A, Lucarini M, Micheletti G, Spinelli D, Tonelli D. A multidisciplinary study of chemico-physical properties of different classes of 2-aryl-5(or 6)-nitrobenzimidazoles: NMR, electrochemical behavior, ESR, and DFT calculations. ARAB J CHEM 2021. [DOI: 10.1016/j.arabjc.2021.103179] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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8
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Fedotov VV, Rusinov VL, Ulomsky EN, Mukhin EM, Gorbunov EB, Chupakhin ON. Pyrimido[1,2- a]benzimidazoles: synthesis and perspective of their pharmacological use. Chem Heterocycl Compd (N Y) 2021; 57:383-409. [PMID: 34024913 PMCID: PMC8121645 DOI: 10.1007/s10593-021-02916-4] [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: 11/13/2020] [Accepted: 01/12/2021] [Indexed: 01/26/2023]
Abstract
The review presents data on the synthesis as well as studies of biological activity of new derivatives of pyrimido[1,2-a]benzimidazoles published over the last decade. The bibliography of the review includes 136 sources.
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Affiliation(s)
- Victor V. Fedotov
- Ural Federal University named after the first President of Russia B. N. Yeltsin, 19 Mira St, Yekaterinburg, 620002 Russia
| | - Vladimir L. Rusinov
- Ural Federal University named after the first President of Russia B. N. Yeltsin, 19 Mira St, Yekaterinburg, 620002 Russia
- Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 22/20 Sofyi Kovalevskoi St, Yekaterinburg, 620108 Russia
| | - Evgeny N. Ulomsky
- Ural Federal University named after the first President of Russia B. N. Yeltsin, 19 Mira St, Yekaterinburg, 620002 Russia
- Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 22/20 Sofyi Kovalevskoi St, Yekaterinburg, 620108 Russia
| | - Evgeny M. Mukhin
- Ural Federal University named after the first President of Russia B. N. Yeltsin, 19 Mira St, Yekaterinburg, 620002 Russia
| | - Evgeny B. Gorbunov
- Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 22/20 Sofyi Kovalevskoi St, Yekaterinburg, 620108 Russia
| | - Oleg N. Chupakhin
- Ural Federal University named after the first President of Russia B. N. Yeltsin, 19 Mira St, Yekaterinburg, 620002 Russia
- Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 22/20 Sofyi Kovalevskoi St, Yekaterinburg, 620108 Russia
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Probst A, Chisanga K, Dziwornu GA, Haeberli C, Keiser J, Chibale K. Expanding the Activity Profile of Pyrido[1,2- a]benzimidazoles: Synthesis and Evaluation of Novel N1-1-Phenylethanamine Derivatives against Schistosoma mansoni. ACS Infect Dis 2021; 7:1032-1043. [PMID: 32786285 DOI: 10.1021/acsinfecdis.0c00278] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Praziquantel is the only widely available drug to treat schistosomiasis. With very few candidates currently in the drug development pipeline, there is an urgent need to discover and develop novel antischistosomal drugs. In this regard, the pyrido[1,2-a]benzimidazole (PBI) scaffold has emerged as a promising chemotype in hit-to-lead efforts. Here, we report a novel series of antischistosomal PBIs with potent in vitro activity (IC50 values of 0.08-1.43 μM) against Schistosoma mansoni newly transformed schistosomula and adult worms. Moreover, the current PBIs demonstrated good hepatic microsomal stability (>70% of drug remaining after 30 min) and were nontoxic to the Chinese hamster ovarian and human liver HepG2 cells, though toxicity (selectivity index, SI < 10) against the rat L6 myoblast cell line was observed. The compounds showed a small therapeutic window but were efficacious in vivo, exhibiting moderate to high worm burden reductions of 35.8-89.6% in S. mansoni-infected mice.
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Affiliation(s)
- Alexandra Probst
- Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland
- University of Basel, P.O. Box CH-4003, Basel, Switzerland
| | - Kelly Chisanga
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
| | | | - Cécile Haeberli
- Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland
- University of Basel, P.O. Box CH-4003, Basel, Switzerland
| | - Jennifer Keiser
- Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland
- University of Basel, P.O. Box CH-4003, Basel, Switzerland
| | - Kelly Chibale
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
- Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa
- South African Medical Research Council Drug Discovery Unit, University of Cape Town, Rondebosch 7701, South Africa
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Alsayed SSR, Lun S, Bailey AW, Suri A, Huang CC, Mocerino M, Payne A, Sredni ST, Bishai WR, Gunosewoyo H. Design, synthesis and evaluation of novel indole-2-carboxamides for growth inhibition of Mycobacterium tuberculosis and paediatric brain tumour cells. RSC Adv 2021; 11:15497-15511. [PMID: 35481189 PMCID: PMC9029315 DOI: 10.1039/d0ra10728j] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 04/10/2021] [Indexed: 12/17/2022] Open
Abstract
The omnipresent threat of tuberculosis (TB) and the scant treatment options thereof necessitate the development of new antitubercular agents, preferably working via a novel mechanism of action distinct from the current drugs. Various studies identified the mycobacterial membrane protein large 3 transporter (MmpL3) as the target of several classes of compounds, including the indole-2-caboxamides. Herein, several indoleamide analogues were rationally designed, synthesised, and evaluated for their antitubercular and antitumour activities. Compound 8g displayed the highest activity (MIC = 0.32 μM) against the drug-sensitive (DS) Mycobacterium tuberculosis (M. tb) H37Rv strain. This compound also exhibited high selective activity towards M. tb over mammalian cells [IC50 (Vero cells) = 40.9 μM, SI = 128], suggesting its minimal cytotoxicity. In addition, when docked into the MmpL3 active site, 8g adopted a binding profile similar to the indoleamide ligand ICA38. A related compound 8f showed dual antitubercular (MIC = 0.62 μM) and cytotoxic activities against paediatric glioblastoma multiforme (GBM) cell line KNS42 [IC50 (viability) = 0.84 μM]. Compound 8f also showed poor cytotoxic activity against healthy Vero cells (IC50 = 39.9 μM). Compounds 9a and 15, which were inactive against M. tb, showed potent cytotoxic (IC50 = 8.25 and 5.04 μM, respectively) and antiproliferative activities (IC50 = 9.85 and 6.62 μM, respectively) against KNS42 cells. Transcriptional analysis of KNS42 cells treated with compound 15 revealed a significant downregulation in the expression of the carbonic anhydrase 9 (CA9) and the spleen tyrosine kinase (SYK) genes. The expression levels of these genes in GBM tumours were previously shown to contribute to tumour progression, suggesting their involvement in our observed antitumour activities. Compounds 9a and 15 were selected for further evaluations against three different paediatric brain tumour cell lines (BT12, BT16 and DAOY) and non-neoplastic human fibroblast cells HFF1. Compound 9a showed remarkable cytotoxic (IC50 = 0.89 and 1.81 μM, respectively) and antiproliferative activities (IC50 = 7.44 and 6.06 μM, respectively) against the two tested atypical teratoid/rhabdoid tumour (AT/RT) cells BT12 and BT16. Interestingly, compound 9a was not cytotoxic when tested against non-neoplastic HFF1 cells [IC50 (viability) = 119 μM]. This suggests that an indoleamide scaffold can be fine-tuned to confer a set of derivatives with selective antitubercular and/or antitumour activities. In this study, we demonstrated that an indoleamide scaffold can be fine-tuned to confer a set of derivatives with selective antitubercular and/or antitumour activities.![]()
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Affiliation(s)
- Shahinda S R Alsayed
- Curtin Medical School, Faculty of Health Sciences, Curtin University Bentley Perth WA 6102 Australia
| | - Shichun Lun
- Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine 1550, Orleans Street Baltimore Maryland 21231-1044 USA
| | - Anders W Bailey
- Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital of Chicago Chicago IL 60611 USA
| | - Amreena Suri
- Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital of Chicago Chicago IL 60611 USA
| | - Chiang-Ching Huang
- Department of Biostatistics, Zilber School of Public Health, University of Wisconsin Milwaukee WI 53205 USA
| | - Mauro Mocerino
- School of Molecular and Life Sciences, Curtin University Perth WA 6102 Australia
| | - Alan Payne
- School of Molecular and Life Sciences, Curtin University Perth WA 6102 Australia
| | - Simone Treiger Sredni
- Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital of Chicago Chicago IL 60611 USA.,Department of Surgery, Northwestern University, Feinberg School of Medicine Chicago IL 60611 USA
| | - William R Bishai
- Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine 1550, Orleans Street Baltimore Maryland 21231-1044 USA .,Howard Hughes Medical Institute 4000 Jones Bridge Road Chevy Chase Maryland 20815-6789 USA
| | - Hendra Gunosewoyo
- Curtin Medical School, Faculty of Health Sciences, Curtin University Bentley Perth WA 6102 Australia
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Zhang W, Liu LL, Lun S, Wang SS, Xiao S, Gunosewoyo H, Yang F, Tang J, Bishai WR, Yu LF. Design and synthesis of mycobacterial pks13 inhibitors: Conformationally rigid tetracyclic molecules. Eur J Med Chem 2021; 213:113202. [PMID: 33516983 DOI: 10.1016/j.ejmech.2021.113202] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 11/03/2020] [Accepted: 01/12/2021] [Indexed: 10/22/2022]
Abstract
We previously reported a series of coumestans-a naturally occurring tetracyclic scaffold containing a δ-lactone-that effectively target the thioesterase domain of polyketide synthase 13 (Pks13) in Mycobacterium tuberculosis (Mtb), resulting in superior anti-tuberculosis (TB) activity. Compared to the corresponding 'open-form' ethyl benzofuran-3-carboxylates, the enhanced anti-TB effects seen with the conformationally restricted coumestan series could be attributed to the extra π-π stacking interactions between the benzene ring of coumestans and the phenyl ring of F1670 residue located in the Pks13-TE binding domain. To further probe this binding feature, novel tetracyclic analogues were synthesized and evaluated for their anti-TB activity against the Mtb strain H37Rv. Initial comparison of the 'open-form' analogueues against the tetracyclic counterparts again showed that the latter is superior in terms of anti-TB activity. In particular, the δ-lactam-containing 5H-benzofuro [3,2-c]quinolin-6-ones gave the most promising results. Compound 65 demonstrated potent activity against Mtb H37Rv with MIC value between 0.0313 and 0.0625 μg/mL, with high selectivity to Vero cells (64-128 fold). The thermal stability analysis supports the notion that the tetracyclic compounds bind to the Pks13-TE domain as measured by nano DSF, consistent with the observed SAR trends. Compound 65 also showed excellent selectivity against actinobacteria and therefore unlikely to develop potential drug resistance to nonpathogenic bacteria.
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Affiliation(s)
- Wei Zhang
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China
| | - Ling-Ling Liu
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China
| | - Shichun Lun
- Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, Baltimore, MD, 21231-1044, United States
| | - Shuang-Shuang Wang
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China
| | - Shiqi Xiao
- Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, Baltimore, MD, 21231-1044, United States
| | - Hendra Gunosewoyo
- School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, Perth, WA, 6102, Australia
| | - Fan Yang
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China
| | - Jie Tang
- Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China
| | - William R Bishai
- Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, Baltimore, MD, 21231-1044, United States.
| | - Li-Fang Yu
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China.
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12
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Dhameliya TM, Patel KI, Tiwari R, Vagolu SK, Panda D, Sriram D, Chakraborti AK. Design, synthesis, and biological evaluation of benzo[d]imidazole-2-carboxamides as new anti-TB agents. Bioorg Chem 2020; 107:104538. [PMID: 33349456 DOI: 10.1016/j.bioorg.2020.104538] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 10/17/2020] [Accepted: 12/04/2020] [Indexed: 01/25/2023]
Abstract
Tuberculosis is the leading cause of death globally among infectious diseases. Due to the development of resistance of Mycobacterium tuberculosis to currently used anti-TB medicines and the TB-HIV synergism the urgent need to develop novel anti-mycobacterial agents has been realized. The drug-to-target path has been the successful strategy for new anti-TB drug development. All the six drug candidates that have shown promise during the clinical trials and some of these being approved for treatment against MDR TB are the results of phenotype screening of small molecule compound libraries. In search of compounds belonging to novel pharmacophoric class that could be subjected to whole cell assay to generate new anti-TB leads the benzo[d]imidazole-2-carboxamide moiety has been designed as a novel anti-TB scaffold. The design was based on the identification of the benzimidazole ring as a prominent substructure of the FDA approved drugs, the structural analysis of reported anti-TB benzimidazoles, and the presence of the C-2 carboxamido functionality in novel bioisoteric anti-TB benzothiazoles. Twenty seven final compounds have been prepared via NH4Cl-catalyzed amidation of ethyl benzo[d]imidazole-2-carboxylates, as the required intermediates, obtained through a green "all water" one-pot synthetic route following a tandem N-arylation-reduction-cyclocondensation procedure. All of the synthesised target compounds were assessed for anti-TB potential using H37Rv ATCC27294 strain. Thirteen compounds were found with better MIC (0.78-6.25 µg/mL) than the standard drugs and being non-cytotoxic nature (<50% inhibition against RAW 264.7 cell lines at 50 µg/mL). The compound 8e exhibited best anti-TB activity (MIC: 2.15 µM and selectivity index: > 60) and a few others e.g., 8a, 8f, 8k and 8o are the next best anti-TB hits (MIC: 1.56 µg/mL). The determination and analysis of various physiochemical parameters revealed favorable druglike properties of the active compounds. The compounds 8a-l and 8o, with MIC values of ≤ 6.25 μg/mL, have high LipE values (10.66-11.77) that are higher than that of the suggested value of > 6 derived from empirical evidence for quality drug candidates and highlight their therapeutic potential. The highest LipE value of 11.77 of the best active compound 8e with the MIC of 0.78 μg/mL indicates its better absorption and clearance as a probable clinical candidate for anti-TB drug discovery. These findings highlight the discovery of benzimidazole-2-carboxamides for further development as new anti-TB agents.
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Affiliation(s)
- Tejas M Dhameliya
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, 160 062 Punjab, India
| | - Kshitij I Patel
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, 160 062 Punjab, India
| | - Rishu Tiwari
- Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Mumbai 400 076, India
| | - Siva Krishna Vagolu
- Department of Pharmacy, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, India
| | - Dulal Panda
- Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Mumbai 400 076, India
| | - Dharmarajan Sriram
- Department of Pharmacy, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, India
| | - Asit K Chakraborti
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, 160 062 Punjab, India; Department of Chemistry, Indian Institute of Technology - Ropar, Rupnagar, Punjab 140 001, India.
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13
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Alsayed SSR, Lun S, Payne A, Bishai WR, Gunosewoyo H. Design, synthesis and antimycobacterial evaluation of novel adamantane and adamantanol analogues effective against drug-resistant tuberculosis. Bioorg Chem 2020; 106:104486. [PMID: 33276981 DOI: 10.1016/j.bioorg.2020.104486] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 11/11/2020] [Accepted: 11/16/2020] [Indexed: 12/14/2022]
Abstract
The treacherous nature of tuberculosis (TB) combined with the ubiquitous presence of the drug-resistant (DR) forms pose this disease as a growing public health menace. Therefore, it is imperative to develop new chemotherapeutic agents with a novel mechanism of action to circumvent the cross-resistance problems. The unique architecture of the Mycobacterium tuberculosis (M. tb) outer envelope plays a predominant role in its pathogenesis, contributing to its intrinsic resistance against available therapeutic agents. The mycobacterial membrane protein large 3 (MmpL3), which is a key player in forging the M. tb rigid cell wall, represents an emerging target for TB drug development. Several indole-2-carboxamides were previously identified in our group as potent anti-TB agents that act as inhibitor of MmpL3 transporter protein. Despite their highly potent in vitro activities, the lingering Achilles heel of these indoleamides can be ascribed to their high lipophilicity as well as low water solubility. In this study, we report our attempt to improve the aqueous solubility of these indole-2-carboxamides while maintaining an adequate lipophilicity to allow effective M. tb cell wall penetration. A more polar adamantanol moiety was incorporated into the framework of several indole-2-carboxamides, whereupon the corresponding analogues were tested for their anti-TB activity against drug-sensitive (DS) M. tb H37Rv strain. Three adamantanol derivatives 8i, 8j and 8l showed nearly 2- and 4-fold higher activity (MIC = 1.32 - 2.89 µM) than ethambutol (MIC = 4.89 µM). Remarkably, the most potent adamantanol analogue 8j demonstrated high selectivity towards DS and DR M. tb strains over mammalian cells [IC50 (Vero cells) ≥ 169 µM], evincing its lack of cytotoxicity. The top eight active compounds 8b, 8d, 8f, 8i, 8j, 8k, 8l and 10a retained their in vitro potency against DR M. tb strains and were docked into the MmpL3 active site. The most potent adamantanol/adamantane-based indoleamides 8j/8k displayed a two-fold surge in potency against extensively DR (XDR) M. tb strains with MIC values of 0.66 and 0.012 µM, respectively. The adamantanol-containing indole-2-carboxamides exhibited improved water solubility both in silico and experimentally, relative to the adamantane counterparts. Overall, the observed antimycobacterial and physicochemical profiles support the notion that adamantanol moiety is a suitable replacement to the adamantane scaffold within the series of indole-2-carboxamide-based MmpL3 inhibitors.
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Affiliation(s)
- Shahinda S R Alsayed
- School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, Perth, WA 6102, Australia
| | - Shichun Lun
- Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, 1550, Orleans Street, Baltimore, MD 21231-1044, United States
| | - Alan Payne
- School of Molecular and Life Sciences, Curtin University, Perth, WA 6102, Australia
| | - William R Bishai
- Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, 1550, Orleans Street, Baltimore, MD 21231-1044, United States; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland 20815-6789, United States.
| | - Hendra Gunosewoyo
- School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, Perth, WA 6102, Australia.
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14
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Onajole OK, Lun S, Yun YJ, Langue DY, Jaskula-Dybka M, Flores A, Frazier E, Scurry AC, Zavala A, Arreola KR, Pierzchalski B, Ayitou AJL, Bishai WR. Design, synthesis, and biological evaluation of novel imidazo[1,2-a]pyridinecarboxamides as potent anti-tuberculosis agents. Chem Biol Drug Des 2020; 96:1362-1371. [PMID: 32515129 DOI: 10.1111/cbdd.13739] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 05/13/2020] [Accepted: 05/31/2020] [Indexed: 12/14/2022]
Abstract
Tuberculosis (TB) is a highly infectious disease that has been plaguing the human race for centuries. The emergence of multidrug-resistant strains of TB has been detrimental to the fight against tuberculosis with very few safe therapeutic options available. As part of an ongoing effort to identify potent anti-tuberculosis agents, we synthesized and screened a series of novel imidazo[1,2-a]pyridinecarboxamide derivatives for their anti-tuberculosis properties. These compounds were designed based on reported anti-tuberculosis properties of the indolecarboxamides (I2Cs) and imidazo[1,2-a]pyridinecarboxamides (IPAs). In this series, we identified compounds 15 and 16 with excellent anti-TB activity against H37Rv strain of tuberculosis (MIC = 0.10-0.19 μM); these compounds were further screened against selected clinical isolates of Mtb. Compounds 15 and 16 showed excellent activities against multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of TB (MIC range: 0.05-1.5 μM) with excellent selectivity indices. In addition, preliminary ADME studies on compound 16 showed favorable pharmacokinetic properties.
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Affiliation(s)
- Oluseye K Onajole
- Department of Biological, Physical and Health Sciences, Roosevelt University, Chicago, IL, USA
| | - Shichun Lun
- Division of Infectious Disease, Department of Medicine, Center for Tuberculosis Research, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Young Ju Yun
- Department of Chemistry, Illinois Institute of Technology, Chicago, IL, USA
| | - Damkam Y Langue
- Department of Biological, Physical and Health Sciences, Roosevelt University, Chicago, IL, USA
| | - Michelle Jaskula-Dybka
- Department of Biological, Physical and Health Sciences, Roosevelt University, Chicago, IL, USA
| | - Adrian Flores
- Department of Biological, Physical and Health Sciences, Roosevelt University, Chicago, IL, USA
| | - Eriel Frazier
- Department of Biological, Physical and Health Sciences, Roosevelt University, Chicago, IL, USA
| | - Ashle C Scurry
- Department of Biological, Physical and Health Sciences, Roosevelt University, Chicago, IL, USA
| | - Ambernice Zavala
- Department of Biological, Physical and Health Sciences, Roosevelt University, Chicago, IL, USA
| | - Karen R Arreola
- Department of Biological, Physical and Health Sciences, Roosevelt University, Chicago, IL, USA
| | - Bryce Pierzchalski
- Department of Biological, Physical and Health Sciences, Roosevelt University, Chicago, IL, USA
| | - A Jean-Luc Ayitou
- Department of Chemistry, Illinois Institute of Technology, Chicago, IL, USA
| | - William R Bishai
- Division of Infectious Disease, Department of Medicine, Center for Tuberculosis Research, Johns Hopkins School of Medicine, Baltimore, MD, USA.,Howard Hughes Medical Institute, Chevy Chase, MD, USA
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15
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Alsayed SSR, Lun S, Luna G, Beh CC, Payne AD, Foster N, Bishai WR, Gunosewoyo H. Design, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents. RSC Adv 2020; 10:7523-7540. [PMID: 33014349 PMCID: PMC7497412 DOI: 10.1039/c9ra10663d] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 02/10/2020] [Indexed: 12/19/2022] Open
Abstract
Our group has previously reported several indolecarboxamides exhibiting potent antitubercular activity. Herein, we rationally designed several arylcarboxamides based on our previously reported homology model and the recently published crystal structure of the mycobacterial membrane protein large 3 (MmpL3). Many analogues showed considerable anti-TB activity against drug-sensitive (DS) Mycobacterium tuberculosis (M. tb) strain. Naphthamide derivatives 13c and 13d were the most active compounds in our study (MIC: 6.55, 7.11 μM, respectively), showing comparable potency to the first line anti-tuberculosis (anti-TB) drug ethambutol (MIC: 4.89 μM). In addition to the naphthamide derivatives, we also identified the quinolone-2-carboxamides and 4-arylthiazole-2-carboxamides as potential MmpL3 inhibitors in which compounds 8i and 18b had MIC values of 9.97 and 9.82 μM, respectively. All four compounds retained their high activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) M. tb strains. It is worth noting that the two most active compounds 13c and 13d also exhibited the highest selective activity towards DS, MDR and XDR M. tb strains over mammalian cells [IC50 (Vero cells) ≥ 227 μM], indicating their potential lack of cytotoxicity. The four compounds were docked into the MmpL3 active site and were studied for their drug-likeness using Lipinski's rule of five. Synthesis and pharmacological evaluation of arylcarboxamide derivatives based on an antimycobacterial indole-2-carboxamide scaffold. The most active compounds demonstrated activities against MDR and XDR M. tb strains.![]()
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Affiliation(s)
- Shahinda S R Alsayed
- School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, Perth, WA 6102, Australia.
| | - Shichun Lun
- Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, 1550, Orleans Street, Baltimore, Maryland 21231-1044, USA.
| | - Giuseppe Luna
- School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, Perth, WA 6102, Australia.
| | - Chau Chun Beh
- Western Australia School of Mines: Minerals, Energy and Chemical Engineering, Curtin University, Bentley 6102, WA, Australia
| | - Alan D Payne
- School of Molecular and Life Sciences, Curtin University, Perth, WA 6102, Australia
| | - Neil Foster
- Western Australia School of Mines: Minerals, Energy and Chemical Engineering, Curtin University, Bentley 6102, WA, Australia
| | - William R Bishai
- Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, 1550, Orleans Street, Baltimore, Maryland 21231-1044, USA. .,Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland 20815-6789, USA
| | - Hendra Gunosewoyo
- School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, Perth, WA 6102, Australia.
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16
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Zhang W, Lun S, Liu LL, Xiao S, Duan G, Gunosewoyo H, Yang F, Tang J, Bishai WR, Yu LF. Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis. Part II. J Med Chem 2019; 62:3575-3589. [DOI: 10.1021/acs.jmedchem.9b00010] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
| | - Shichun Lun
- Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, Baltimore, Maryland 21231-1044, United States
| | | | - Shiqi Xiao
- Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, Baltimore, Maryland 21231-1044, United States
| | | | - Hendra Gunosewoyo
- School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, Perth, Western Australia 6102, Australia
| | | | | | - William R. Bishai
- Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, Baltimore, Maryland 21231-1044, United States
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17
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Veale CGL. Unpacking the Pathogen Box-An Open Source Tool for Fighting Neglected Tropical Disease. ChemMedChem 2019; 14:386-453. [PMID: 30614200 DOI: 10.1002/cmdc.201800755] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Indexed: 12/13/2022]
Abstract
The Pathogen Box is a 400-strong collection of drug-like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in-depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure-activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.
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Affiliation(s)
- Clinton G L Veale
- School of Chemistry and Physics, Pietermaritzburg Campus, University of KwaZulu-Natal, Private Bag X01, Scottsville, 3209, South Africa
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18
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Machado D, Girardini M, Viveiros M, Pieroni M. Challenging the Drug-Likeness Dogma for New Drug Discovery in Tuberculosis. Front Microbiol 2018; 9:1367. [PMID: 30018597 PMCID: PMC6037898 DOI: 10.3389/fmicb.2018.01367] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 06/06/2018] [Indexed: 01/28/2023] Open
Abstract
The emergence of multi- and extensively drug resistant tuberculosis worldwide poses a great threat to human health and highlight the need to discover and develop new, effective and inexpensive antituberculosis agents. High-throughput screening assays against well-validated drug targets and structure based drug design have been employed to discover new lead compounds. However, the great majority fail to demonstrate any antimycobacterial activity when tested against Mycobacterium tuberculosis in whole-cell screening assays. This is mainly due to some of the intrinsic properties of the bacilli, such as the extremely low permeability of its cell wall, slow growth, drug resistance, drug tolerance, and persistence. In this sense, understanding the pathways involved in M. tuberculosis drug tolerance, persistence, and pathogenesis, may reveal new approaches for drug development. Moreover, the need for compounds presenting a novel mode of action is of utmost importance due to the emergence of resistance not only to the currently used antituberculosis agents, but also to those in the pipeline. Cheminformatics studies have shown that drugs endowed with antituberculosis activity have the peculiarity of being more lipophilic than many other antibacterials, likely because this leads to improved cell penetration through the extremely waxy mycobacterial cell wall. Moreover, the interaction of the lipophilic moiety with the membrane alters its stability and functional integrity due to the disruption of the proton motive force, resulting in cell death. When a ligand-based medicinal chemistry campaign is ongoing, it is always difficult to predict whether a chemical modification or a functional group would be suitable for improving the activity. Nevertheless, in the “instruction manual” of medicinal chemists, certain functional groups or certain physicochemical characteristics (i.e., high lipophilicity) are considered red flags to look out for in order to safeguard drug-likeness and avoid attritions in the drug discovery process. In this review, we describe how antituberculosis compounds challenge established rules such as the Lipinski's “rule of five” and how medicinal chemistry for antituberculosis compounds must be thought beyond such dogmatic schemes.
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Affiliation(s)
- Diana Machado
- Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Lisbon, Portugal
| | - Miriam Girardini
- P4T Group, Department of Food and Drug, University of Parma, Parma, Italy
| | - Miguel Viveiros
- Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Lisbon, Portugal
| | - Marco Pieroni
- P4T Group, Department of Food and Drug, University of Parma, Parma, Italy
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19
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Campaniço A, Moreira R, Lopes F. Drug discovery in tuberculosis. New drug targets and antimycobacterial agents. Eur J Med Chem 2018; 150:525-545. [DOI: 10.1016/j.ejmech.2018.03.020] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 03/05/2018] [Accepted: 03/06/2018] [Indexed: 01/24/2023]
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20
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A simple and efficient synthesis of benzimidazoles containing piperazine or morpholine skeleton at C-6 position as glucosidase inhibitors with antioxidant activity. Bioorg Chem 2018; 76:468-477. [DOI: 10.1016/j.bioorg.2017.12.019] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Revised: 12/15/2017] [Accepted: 12/15/2017] [Indexed: 01/10/2023]
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21
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Anguru MR, Taduri AK, Bhoomireddy RD, Jojula M, Gunda SK. Novel drug targets for Mycobacterium tuberculosis: 2-heterostyrylbenzimidazoles as inhibitors of cell wall protein synthesis. Chem Cent J 2017; 11:68. [PMID: 29086847 PMCID: PMC5524660 DOI: 10.1186/s13065-017-0295-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Accepted: 07/11/2017] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND Multi drug-resistant and mycobacterial infections are a major public health challenge, leading to high mortality and socioeconomic burdens through worldwide. Novel therapeutics are necessary to treat the drug resistant strains, since no new chemical entities are emerged in the last four decades for the treatment of TB. FINDINGS A series of novel 2-heterostyrylbenzimidazole derivatives were synthesised by cyclisation of (3,4-diaminophenyl)(phenyl)methanone, cinnamic acid using glycerol in high yield. The molecular structures of target compounds (5a-5n) were confirmed by 1H and 13C NMR spectroscopy and mass spectrometry. Newly synthesized compounds were screened for anti-tubercular activity and the MIC was determined against Mycobacterium tuberculosis H37Rv by broth microdilution method using Lowenstein Jensen medium (LJ). These compounds docked into the active site of "Crystal structure of pantothenate synthetase in complex with 2-(2-(benzofuran-2-ylsulfonylcarbamoyl)-5-methoxy-1H-indol-1-yl)acetic acid" (PDB code, 3IVX). Auto dock 4.2 software was used for docking studies. RESULTS 5d, 5e, 5f, 5g, 5i, and 5l show better activity and the most active inhibitor of tuberculosis 5f showed a promising inhibition of M. tuberculosis with MIC value of 16 μg/mL. The molecules functionalized with electron-donating groups (Cl, O, S, etc.) on different aromatic aldehydes (5a-5n) were found to be more active in inhibiting M. tuberculosis. CONCLUSIONS On the basis of docking studies, 5f has shown good affinity for the enzyme. Comparison was made with the binding energies of the standard drugs amoxicillin (-34.28 kcal/mol) and ciprofloxacin (-28.20 kcal/mol). Among all the designed compounds, the compound 5f shows highest binding energy with two amino acid interactions Lys160, Val187 (-9.80 kcal/mol).
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Affiliation(s)
- Mohana Rao Anguru
- Department of Chemistry, College of Engineering, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad, 500 085 India
| | - Ashok Kumar Taduri
- Department of Chemistry, College of Engineering, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad, 500 085 India
| | - Rama Devi Bhoomireddy
- Department of Chemistry, College of Engineering, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad, 500 085 India
| | - Malathi Jojula
- Department of Microbiology, Sri Shivani College of Pharmacy, Warangal, 506002 India
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22
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Okombo J, Singh K, Mayoka G, Ndubi F, Barnard L, Njogu PM, Njoroge M, Gibhard L, Brunschwig C, Vargas M, Keiser J, Egan TJ, Chibale K. Antischistosomal Activity of Pyrido[1,2-a]benzimidazole Derivatives and Correlation with Inhibition of β-Hematin Formation. ACS Infect Dis 2017; 3:411-420. [PMID: 28440625 DOI: 10.1021/acsinfecdis.6b00205] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
The extensive use of praziquantel against schistosomiasis raises concerns about drug resistance. New therapeutic alternatives targeting critical pathways within the parasite are therefore urgently needed. Hemozoin formation in Schistosoma presents one such target. We assessed the in vitro antischistosomal activity of pyrido[1,2-a]benzimidazoles (PBIs) and investigated correlations with their ability to inhibit β-hematin formation. We further evaluated the in vivo efficacy of representative compounds in experimental mice and conducted pharmacokinetic analysis on the most potent. At 10 μM, 48/57 compounds resulted in >70% mortality of newly transformed schistosomula, whereas 37 of these maintained >60% mortality of adult S. mansoni. No correlations were observed between β-hematin inhibitory and antischistosomal activities against both larval and adult parasites, suggesting possible presence of other target(s) or a mode of inhibition of crystal formation that is not adequately modeled by the assay. The most active compound in vivo showed 58.7 and 61.3% total and female worm burden reduction, respectively. Pharmacokinetic analysis suggested solubility-limited absorption and high hepatic clearance as possible contributors to the modest efficacy despite good in vitro activity. The PBIs evaluated in this report thus merit further optimization to improve their efficacy and to elucidate their possible mode of action.
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Affiliation(s)
- John Okombo
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
| | - Kawaljit Singh
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
| | - Godfrey Mayoka
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
| | - Ferdinand Ndubi
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
| | - Linley Barnard
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
| | - Peter M. Njogu
- Department of Pharmaceutical Chemistry, University of Nairobi, P.O. Box 19676, Nairobi 00202, Kenya
| | - Mathew Njoroge
- Drug Discovery and Development Centre (H3D),
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa
| | - Liezl Gibhard
- Drug Discovery and Development Centre (H3D),
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa
| | - Christel Brunschwig
- Drug Discovery and Development Centre (H3D),
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa
| | - Mireille Vargas
- Department of Medical Parasitology and
Infection Biology, Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland
- University of Basel, 4003 Basel, Switzerland
| | - Jennifer Keiser
- Department of Medical Parasitology and
Infection Biology, Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland
- University of Basel, 4003 Basel, Switzerland
| | - Timothy J. Egan
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
| | - Kelly Chibale
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
- South African Medical Research Council,
Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa
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23
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Pieroni M, Azzali E, Basilico N, Parapini S, Zolkiewski M, Beato C, Annunziato G, Bruno A, Vacondio F, Costantino G. Accepting the Invitation to Open Innovation in Malaria Drug Discovery: Synthesis, Biological Evaluation, and Investigation on the Structure–Activity Relationships of Benzo[b]thiophene-2-carboxamides as Antimalarial Agents. J Med Chem 2017; 60:1959-1970. [DOI: 10.1021/acs.jmedchem.6b01685] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
| | | | - Nicoletta Basilico
- Dipartimento
di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università di Milano, via Pascal 36, Milano 20133, Italy
| | - Silvia Parapini
- Dipartimento
di Scienze Farmacologiche e Biomolecolari, Università di Milano, via Pascal 36, Milano 20133, Italy
| | - Michal Zolkiewski
- Department
of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, Kansas 66506, United States
| | | | | | | | | | - Gabriele Costantino
- Centro
Interdipartimentale Misure (CIM) ’G. Casnati’, University of Parma, Parco Area delle Scienze 23/A, 43124 Parma, Italy
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24
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25
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Borges da Silva R, Teixeira RI, Wardell JL, Wardell SMSV, Garden SJ. Copper(ii) catalyzed synthesis of novel helical luminescent benzo[4,5]imidazo[1,2-a][1,10]phenanthrolines via an intramolecular C–H amination reaction. Org Biomol Chem 2017; 15:812-826. [DOI: 10.1039/c6ob02508k] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Novel helical luminescent benzoimidazophenanthrolines were prepared using a Cu(ii) catalyzed C–H amination reaction.
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Affiliation(s)
- Ramon Borges da Silva
- Instituto de Química
- Universidade Federal do Rio de Janeiro
- Centro Tecnológica
- Bloco A
- Cidade Universitária
| | - Rodolfo Inêz Teixeira
- Instituto de Química
- Universidade Federal do Rio de Janeiro
- Centro Tecnológica
- Bloco A
- Cidade Universitária
| | - James L. Wardell
- Instituto de Tecnologia em Fármacos – Farmanguinhos
- Fiocruz. R. Sizenando Nabuco
- Rio de Janeiro
- Brazil
- Department of Chemistry
| | | | - Simon J. Garden
- Instituto de Química
- Universidade Federal do Rio de Janeiro
- Centro Tecnológica
- Bloco A
- Cidade Universitária
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26
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Benzimidazole-core as an antimycobacterial agent. Pharmacol Rep 2016; 68:1254-1265. [DOI: 10.1016/j.pharep.2016.08.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 07/27/2016] [Accepted: 08/04/2016] [Indexed: 12/18/2022]
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27
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Antibiotic Methylation: A New Mechanism of Antimicrobial Resistance. Trends Microbiol 2016; 24:771-772. [PMID: 27593675 DOI: 10.1016/j.tim.2016.08.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 08/16/2016] [Indexed: 11/23/2022]
Abstract
In new research on Mycobacterium tuberculosis, the causative agent of tuberculosis, Warrier and colleagues have discovered a novel mode of bacterial drug resistance, namely antibiotic inactivation via N-methylation.
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28
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Stec J, Onajole OK, Lun S, Guo H, Merenbloom B, Vistoli G, Bishai WR, Kozikowski AP. Indole-2-carboxamide-based MmpL3 Inhibitors Show Exceptional Antitubercular Activity in an Animal Model of Tuberculosis Infection. J Med Chem 2016; 59:6232-47. [DOI: 10.1021/acs.jmedchem.6b00415] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Jozef Stec
- Department
of Pharmaceutical Sciences, College of Pharmacy, Chicago State University, 9501 South King Drive, Chicago, Illinois 60628, United States
- Department
of Pharmaceutical Sciences, College of Pharmacy, Marshall B. Ketchum University, 2575 Yorba Linda Boulevard, Fullerton, California 92831, United States
| | - Oluseye K. Onajole
- Drug
Discovery Program, Department of Medicinal Chemistry and Pharmacognosy,
College of Pharmacy, University of Illinois at Chicago, 833 South
Wood Street, Chicago, Illinois 60612, United States
- Department
of Biological, Chemical, and Physical Sciences, Roosevelt University, 425 S. Wabash Avenue, Chicago, Illinois 60605, United States
| | - Shichun Lun
- Center
for Tuberculosis Research, Department of Medicine, Division of Infectious
Disease, Johns Hopkins School of Medicine, 1550 Orleans Street, Baltimore, Maryland 21231-1044, United States
| | - Haidan Guo
- Center
for Tuberculosis Research, Department of Medicine, Division of Infectious
Disease, Johns Hopkins School of Medicine, 1550 Orleans Street, Baltimore, Maryland 21231-1044, United States
| | - Benjamin Merenbloom
- Center
for Tuberculosis Research, Department of Medicine, Division of Infectious
Disease, Johns Hopkins School of Medicine, 1550 Orleans Street, Baltimore, Maryland 21231-1044, United States
| | - Giulio Vistoli
- Department
of Pharmaceutical Sciences, Università degli Studi di Milano, via Mangiagalli 25, I-20133 Milan, Italy
| | - William R. Bishai
- Center
for Tuberculosis Research, Department of Medicine, Division of Infectious
Disease, Johns Hopkins School of Medicine, 1550 Orleans Street, Baltimore, Maryland 21231-1044, United States
- Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland 20815-6789, United States
| | - Alan P. Kozikowski
- Drug
Discovery Program, Department of Medicinal Chemistry and Pharmacognosy,
College of Pharmacy, University of Illinois at Chicago, 833 South
Wood Street, Chicago, Illinois 60612, United States
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29
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Gong JX, He Y, Cui ZL, Guo YW. Synthesis, spectral characterization, and antituberculosis activity of thiazino[3,2-A]benzimidazole derivatives. PHOSPHORUS SULFUR 2016. [DOI: 10.1080/10426507.2015.1135149] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
- Jing-Xu Gong
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Ya He
- Clinic and Research Center of Tuberculosis, Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Zhen-Lin Cui
- Clinic and Research Center of Tuberculosis, Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yue-Wei Guo
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
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30
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Ajani OO, Aderohunmu DV, Ikpo CO, Adedapo AE, Olanrewaju IO. Functionalized Benzimidazole Scaffolds: Privileged Heterocycle for Drug Design in Therapeutic Medicine. Arch Pharm (Weinheim) 2016; 349:475-506. [PMID: 27213292 DOI: 10.1002/ardp.201500464] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 04/14/2016] [Accepted: 04/22/2016] [Indexed: 01/09/2023]
Abstract
Benzimidazole derivatives are crucial structural scaffolds found in diverse libraries of biologically active compounds which are therapeutically useful agents in drug discovery and medicinal research. They are structural isosteres of naturally occurring nucleotides, which allows them to interact with the biopolymers of living systems. Hence, there is a need to couple the latest information with the earlier documentations to understand the current status of the benzimidazole nucleus in medicinal chemistry research. This present work unveils the benzimidazole core as a multifunctional nucleus that serves as a resourceful tool of information for synthetic modifications of old existing candidates in order to tackle drug resistance bottlenecks in therapeutic medicine. This manuscript deals with the recent advances in the synthesis of benzimidazole derivatives, the widespread biological activities as well as pharmacokinetic reports. These present them as a toolbox for fighting infectious diseases and also make them excellent candidates for future drug design.
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Affiliation(s)
- Olayinka O Ajani
- Department of Chemistry, Covenant University, CST, Canaanland, Ota, Ogun State, Nigeria
| | - Damilola V Aderohunmu
- Department of Chemistry, Covenant University, CST, Canaanland, Ota, Ogun State, Nigeria
| | - Chinwe O Ikpo
- Department of Chemistry, University of the Western Cape, Bellville, Cape Town, South Africa
| | - Adebusayo E Adedapo
- Department of Chemistry, Covenant University, CST, Canaanland, Ota, Ogun State, Nigeria
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31
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Shruthi N, Poojary B, Kumar V, Hussain MM, Rai VM, Pai VR, Bhat M, Revannasiddappa BC. Novel benzimidazole–oxadiazole hybrid molecules as promising antimicrobial agents. RSC Adv 2016. [DOI: 10.1039/c5ra23282a] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
In the present study, we describe the design and expeditious synthesis of novel 2-aryl-5-(3-aryl-[1,2,4]-oxadiazol-5-yl)-1-methyl-1H-benzo[d]imidazole hybrid molecules as promising antimicrobial agents.
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Affiliation(s)
- N. Shruthi
- Department of Chemistry
- Mangalore University
- Mangalagangothri-574199
- India
| | - Boja Poojary
- Department of Chemistry
- Mangalore University
- Mangalagangothri-574199
- India
| | - Vasantha Kumar
- Department of Chemistry
- Mangalore University
- Mangalagangothri-574199
- India
| | | | | | - Vinitha R. Pai
- Department of Biochemistry
- Yenepoya University
- Mangalore
- India
| | - Mahima Bhat
- Department of Chemistry
- Mangalore University
- Mangalagangothri-574199
- India
| | - B. C. Revannasiddappa
- Department of Pharmacology
- N.G.S.M. Institute of Pharmaceutical Sciences
- Mangalore-575 018
- India
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32
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Warrier T, Martinez-Hoyos M, Marin-Amieva M, Colmenarejo G, Porras-De Francisco E, Alvarez-Pedraglio AI, Fraile-Gabaldon MT, Torres-Gomez PA, Lopez-Quezada L, Gold B, Roberts J, Ling Y, Somersan-Karakaya S, Little D, Cammack N, Nathan C, Mendoza-Losana A. Identification of Novel Anti-mycobacterial Compounds by Screening a Pharmaceutical Small-Molecule Library against Nonreplicating Mycobacterium tuberculosis. ACS Infect Dis 2015; 1:580-5. [PMID: 27623055 DOI: 10.1021/acsinfecdis.5b00025] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Identification of compounds that target metabolically diverse subpopulations of Mycobacterium tuberculosis (Mtb) may contribute to shortening the course of treatment for tuberculosis. This study screened 270,000 compounds from GlaxoSmithKline's collection against Mtb in a nonreplicating (NR) state imposed in vitro by a combination of four host-relevant stresses. Evaluation of 166 confirmed hits led to detailed characterization of 19 compounds for potency, specificity, cytotoxicity, and stability. Compounds representing five scaffolds depended on reactive nitrogen species for selective activity against NR Mtb, and two were stable in the assay conditions. Four novel scaffolds with activity against replicating (R) Mtb were also identified. However, none of the 19 compounds was active against Mtb in both NR and R states. There was minimal overlap between compounds found active against NR Mtb and those previously identified as active against R Mtb, supporting the hypothesis that NR Mtb depends on distinct metabolic pathways for survival.
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Affiliation(s)
- Thulasi Warrier
- Department of Microbiology and Immunology, Weill Cornell Medical College, 413 East 69th Street, New
York, New York 10021, United States
| | | | | | - Gonzalo Colmenarejo
- Department of Computational Chemistry, CIB-GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain
| | | | | | | | | | - Landys Lopez-Quezada
- Department of Microbiology and Immunology, Weill Cornell Medical College, 413 East 69th Street, New
York, New York 10021, United States
| | - Ben Gold
- Department of Microbiology and Immunology, Weill Cornell Medical College, 413 East 69th Street, New
York, New York 10021, United States
| | - Julia Roberts
- Department of Microbiology and Immunology, Weill Cornell Medical College, 413 East 69th Street, New
York, New York 10021, United States
| | - Yan Ling
- Department of Microbiology and Immunology, Weill Cornell Medical College, 413 East 69th Street, New
York, New York 10021, United States
| | - Selin Somersan-Karakaya
- Department of Microbiology and Immunology, Weill Cornell Medical College, 413 East 69th Street, New
York, New York 10021, United States
| | - David Little
- Department of Microbiology and Immunology, Weill Cornell Medical College, 413 East 69th Street, New
York, New York 10021, United States
| | - Nicholas Cammack
- DDW-GlaxoSmithKline, Severo Ochoa 2, Tres Cantos,
Madrid 28760, Spain
| | - Carl Nathan
- Department of Microbiology and Immunology, Weill Cornell Medical College, 413 East 69th Street, New
York, New York 10021, United States
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33
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34
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Mutation of Rv2887, a marR-like gene, confers Mycobacterium tuberculosis resistance to an imidazopyridine-based agent. Antimicrob Agents Chemother 2015; 59:6873-81. [PMID: 26303802 DOI: 10.1128/aac.01341-15] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 08/14/2015] [Indexed: 02/05/2023] Open
Abstract
Drug resistance is a major problem in Mycobacterium tuberculosis control, and it is critical to identify novel drug targets and new antimycobacterial compounds. We have previously identified an imidazo[1,2-a]pyridine-4-carbonitrile-based agent, MP-III-71, with strong activity against M. tuberculosis. In this study, we evaluated mechanisms of resistance to MP-III-71. We derived three independent M. tuberculosis mutants resistant to MP-III-71 and conducted whole-genome sequencing of these mutants. Loss-of-function mutations in Rv2887 were common to all three MP-III-71-resistant mutants, and we confirmed the role of Rv2887 as a gene required for MP-III-71 susceptibility using complementation. The Rv2887 protein was previously unannotated, but domain and homology analyses suggested it to be a transcriptional regulator in the MarR (multiple antibiotic resistance repressor) family, a group of proteins first identified in Escherichia coli to negatively regulate efflux pumps and other mechanisms of multidrug resistance. We found that two efflux pump inhibitors, verapamil and chlorpromazine, potentiate the action of MP-III-71 and that mutation of Rv2887 abrogates their activity. We also used transcriptome sequencing (RNA-seq) to identify genes which are differentially expressed in the presence and absence of a functional Rv2887 protein. We found that genes involved in benzoquinone and menaquinone biosynthesis were repressed by functional Rv2887. Thus, inactivating mutations of Rv2887, encoding a putative MarR-like transcriptional regulator, confer resistance to MP-III-71, an effective antimycobacterial compound that shows no cross-resistance to existing antituberculosis drugs. The mechanism of resistance of M. tuberculosis Rv2887 mutants may involve efflux pump upregulation and also drug methylation.
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35
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Pieroni M, Machado D, Azzali E, Santos Costa S, Couto I, Costantino G, Viveiros M. Rational Design and Synthesis of Thioridazine Analogues as Enhancers of the Antituberculosis Therapy. J Med Chem 2015. [PMID: 26197353 DOI: 10.1021/acs.jmedchem.5b00428] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Tuberculosis, caused by Mycobacterium tuberculosis, is still one of the leading infectious diseases globally. Therefore, novel approaches are needed to face this disease. Efflux pumps are known to contribute to the emergence of M. tuberculosis drug resistance. Thioridazine has shown good anti-TB properties both in vitro and in vivo, likely due to its capacity to inhibit efflux mechanisms. Here we report the design and synthesis of a number of putative efflux inhibitors inspired by the structure of thioridazine. Compounds were evaluated for their in vitro and ex vivo activity against M. tuberculosis H37Rv. Compared to the parent molecule, some of the compounds synthesized showed higher efflux inhibitory capacity, less cytotoxicity, and a remarkable synergistic effect with anti-TB drugs both in vitro and in human macrophages, demonstrating their potential to be used as coadjuvants for the treatment of tuberculosis.
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Affiliation(s)
- Marco Pieroni
- †P4T Group, Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/A, Parma, 43124, Italy
| | - Diana Machado
- ‡Grupo de Micobactérias, Unidade de Microbiologia Médica, Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa (IHMT, UNL), Rua da Junqueira, 100, 1349-008 Lisbon, Portugal
| | - Elisa Azzali
- †P4T Group, Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/A, Parma, 43124, Italy
| | - Sofia Santos Costa
- ‡Grupo de Micobactérias, Unidade de Microbiologia Médica, Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa (IHMT, UNL), Rua da Junqueira, 100, 1349-008 Lisbon, Portugal
| | - Isabel Couto
- ‡Grupo de Micobactérias, Unidade de Microbiologia Médica, Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa (IHMT, UNL), Rua da Junqueira, 100, 1349-008 Lisbon, Portugal
| | - Gabriele Costantino
- †P4T Group, Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/A, Parma, 43124, Italy
| | - Miguel Viveiros
- ‡Grupo de Micobactérias, Unidade de Microbiologia Médica, Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa (IHMT, UNL), Rua da Junqueira, 100, 1349-008 Lisbon, Portugal
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36
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Pieroni M, Wan B, Zuliani V, Franzblau SG, Costantino G, Rivara M. Discovery of antitubercular 2,4-diphenyl-1H-imidazoles from chemical library repositioning and rational design. Eur J Med Chem 2015; 100:44-9. [PMID: 26071857 DOI: 10.1016/j.ejmech.2015.05.048] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 05/25/2015] [Accepted: 05/31/2015] [Indexed: 12/18/2022]
Abstract
TB, caused by Mycobacterium tuberculosis, is one of the deadliest infections worldwide. The co-infection with HIV and the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) strains have further increased the burden for this disease. In the attempt to respond to the constant need of novel therapeutic options, we herein report the discovery of 2,4-diphenyl-1H-imidazoles as effective antitubercular agents, with MIC in the low micromolar range against actively replicating and persistent M. tuberculosis strains. The good activity, along with the lack of toxicity and the feasible synthesis, underscore their value as novel scaffolds for the development of new anti-TB drugs.
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Affiliation(s)
- Marco Pieroni
- Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/A, Parma, 43124, Italy.
| | - Baojie Wan
- Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St., Chicago, IL 60612, USA
| | - Valentina Zuliani
- Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/A, Parma, 43124, Italy
| | - Scott G Franzblau
- Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St., Chicago, IL 60612, USA
| | - Gabriele Costantino
- Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/A, Parma, 43124, Italy
| | - Mirko Rivara
- Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/A, Parma, 43124, Italy.
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37
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Ramprasad J, Nayak N, Dalimba U, Yogeeswari P, Sriram D, Peethambar SK, Achur R, Kumar HSS. Synthesis and biological evaluation of new imidazo[2,1-b][1,3,4]thiadiazole-benzimidazole derivatives. Eur J Med Chem 2015; 95:49-63. [PMID: 25794789 DOI: 10.1016/j.ejmech.2015.03.024] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Revised: 03/11/2015] [Accepted: 03/12/2015] [Indexed: 11/27/2022]
Abstract
In this report, we describe the synthesis and biological evaluation of a new series of 2-(imidazo[2,1-b][1,3,4]thiadiazol-5-yl)-1H-benzimidazole derivatives (5a-ac). The molecules were analyzed by (1)H NMR, (13)C NMR, mass spectral and elemental data. The structure of one of the pre-final compounds, 6-(4-methoxyphenyl)-2-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4d) and that of a target compound, 2-[2-methyl-6-(4-methyl phenyl) imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-1H-benzimidazole (5aa) were confirmed by single crystal XRD studies. All the target compounds were screened for in vitro anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv strain. Seven (5c, 5d, 5l, 5p, 5r, 5z and 5aa) out of twenty nine compounds showed potent anti-tubercular activity with a MIC of 3.125 μg/mL. A p-substituted phenyl group (p-tolyl or p-chlorophenyl) in the imidazo[2,1-b][1,3,4]thiadiazole ring and/or a chloro group in the benzimidazole ring enhance anti-tuberculosis activity whereas a nitro group in the benzimidazole ring reduces the activity. In the antibacterial screening, compounds 5i, 5w and 5ac showed promising activity against the tested bacterial strains. Further, antifungal and antioxidant activities of these molecules were also investigated. In the cytotoxicity study, the active antitubercular compounds exhibited very low toxicity against a normal cell line.
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Affiliation(s)
- Jurupula Ramprasad
- Organic Chemistry Laboratory, Department of Chemistry, National Institute of Technology Karnataka, Surathkal, Srinivasanagar, Mangalore 575025, India
| | - Nagabhushana Nayak
- Organic Chemistry Laboratory, Department of Chemistry, National Institute of Technology Karnataka, Surathkal, Srinivasanagar, Mangalore 575025, India
| | - Udayakumar Dalimba
- Organic Chemistry Laboratory, Department of Chemistry, National Institute of Technology Karnataka, Surathkal, Srinivasanagar, Mangalore 575025, India.
| | - Perumal Yogeeswari
- Medicinal Chemistry and Drug Discovery Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Jawahar Nagar, Telangana 500078, India
| | - Dharmarajan Sriram
- Medicinal Chemistry and Drug Discovery Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Jawahar Nagar, Telangana 500078, India
| | - S K Peethambar
- Department of Biochemistry, Kuvempu University, Jnanasahyadri, Shankaraghatta 577451, India
| | - Rajeshwara Achur
- Department of Biochemistry, Kuvempu University, Jnanasahyadri, Shankaraghatta 577451, India
| | - H S Santosh Kumar
- Department of Bioinformatics, Kuvempu University, Jnanasahyadri, Shankaraghatta 577451, India
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38
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Yoon YK, Ali MA, Wei AC, Choon TS, Ismail R. Synthesis and evaluation of antimycobacterial activity of new benzimidazole aminoesters. Eur J Med Chem 2015; 93:614-24. [DOI: 10.1016/j.ejmech.2013.06.025] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Revised: 05/22/2013] [Accepted: 06/04/2013] [Indexed: 11/25/2022]
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39
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Monastyrskyi A, Namelikonda NK, Manetsch R. Metal-free arylation of ethyl acetoacetate with hypervalent diaryliodonium salts: an immediate access to diverse 3-aryl-4(1H)-quinolones. J Org Chem 2015; 80:2513-2520. [PMID: 25558982 DOI: 10.1021/jo5023958] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
A clean arylation protocol of ethyl acetoacetate was developed using hypervalent diaryliodonium salts under mild and metal-free conditions. The scope of the reaction, using symmetric and unsymmetric iodonium salts with varying sterics and electronics, was examined. Further, this method has been applied for the synthesis of antimalarial compound ELQ-300, which is currently in preclinical development.
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Affiliation(s)
- Andrii Monastyrskyi
- Department of Chemistry, University of South Florida, 4202 E Fowler Ave., Tampa, FL 33620, United States
| | - Niranjan K Namelikonda
- Department of Chemistry, University of South Florida, 4202 E Fowler Ave., Tampa, FL 33620, United States
| | - Roman Manetsch
- Department of Chemistry, University of South Florida, 4202 E Fowler Ave., Tampa, FL 33620, United States
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Keri RS, Hiremathad A, Budagumpi S, Nagaraja BM. Comprehensive Review in Current Developments of Benzimidazole-Based Medicinal Chemistry. Chem Biol Drug Des 2014; 86:19-65. [PMID: 25352112 DOI: 10.1111/cbdd.12462] [Citation(s) in RCA: 214] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 10/12/2014] [Indexed: 12/13/2022]
Abstract
The properties of benzimidazole and its derivatives have been studied over more than one hundred years. Benzimidazole derivatives are useful intermediates/subunits for the development of molecules of pharmaceutical or biological interest. Substituted benzimidazole derivatives have found applications in diverse therapeutic areas such as antiulcer, anticancer agents, and anthelmintic species to name just a few. This work systematically gives a comprehensive review in current developments of benzimidazole-based compounds in the whole range of medicinal chemistry as anticancer, antibacterial, antifungal, anti-inflammatory, analgesic agents, anti-HIV, antioxidant, anticonvulsant, antitubercular, antidiabetic, antileishmanial, antihistaminic, antimalarial agents, and other medicinal agents. This review will further be helpful for the researcher on the basis of substitution pattern around the nucleus with an aim to help medicinal chemists for developing an SAR on benzimidazole drugs/compounds.
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Affiliation(s)
- Rangappa S Keri
- Centre for Nano and Material Sciences, Jain University, Jain Global Campus, Bangalore, Karnataka, 562112, India
| | - Asha Hiremathad
- Centre for Nano and Material Sciences, Jain University, Jain Global Campus, Bangalore, Karnataka, 562112, India
| | - Srinivasa Budagumpi
- Centre for Nano and Material Sciences, Jain University, Jain Global Campus, Bangalore, Karnataka, 562112, India
| | - Bhari Mallanna Nagaraja
- Centre for Nano and Material Sciences, Jain University, Jain Global Campus, Bangalore, Karnataka, 562112, India
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Stec J, Vilchèze C, Lun S, Perryman AL, Wang X, Freundlich JS, Bishai W, Jacobs WR, Kozikowski AP. Biological evaluation of potent triclosan-derived inhibitors of the enoyl-acyl carrier protein reductase InhA in drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis. ChemMedChem 2014; 9:2528-37. [PMID: 25165007 PMCID: PMC4213240 DOI: 10.1002/cmdc.201402255] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2014] [Indexed: 11/09/2022]
Abstract
New triclosan (TRC) analogues were evaluated for their activity against the enoyl-acyl carrier protein reductase InhA in Mycobacterium tuberculosis (Mtb). TRC is a well-known inhibitor of InhA, and specific modifications to its positions 5 and 4' afforded 27 derivatives; of these compounds, seven derivatives showed improved potency over that of TRC. These analogues were active against both drug-susceptible and drug-resistant Mtb strains. The most active compound in this series, 4-(n-butyl)-1,2,3-triazolyl TRC derivative 3, had an MIC value of 0.6 μg mL(-1) (1.5 μM) against wild-type Mtb. At a concentration equal to its MIC, this compound inhibited purified InhA by 98 %, and showed an IC50 value of 90 nM. Compound 3 and the 5-methylisoxazole-modified TRC 14 were able to inhibit the biosynthesis of mycolic acids. Furthermore, mc(2) 4914, an Mtb strain overexpressing inhA, was found to be less susceptible to compounds 3 and 14, supporting the notion that InhA is the likely molecular target of the TRC derivatives presented herein.
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Affiliation(s)
- Jozef Stec
- Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States, Fax: +1-312-996-7107
- Department of Pharmaceutical Sciences, College of Pharmacy, Chicago State University, 9501 S. King Drive, Chicago, Illinois 60628, United States
| | - Catherine Vilchèze
- Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, United States
| | - Shichun Lun
- Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, Baltimore, MD 21231-1044, United States
| | - Alexander L. Perryman
- Center for Emerging & Re-emerging Pathogens, Division of Infectious, Diseases, Department of Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, United States
| | - Xin Wang
- Center for Emerging & Re-emerging Pathogens, Division of Infectious, Diseases, Department of Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, United States
| | - Joel S. Freundlich
- Center for Emerging & Re-emerging Pathogens, Division of Infectious, Diseases, Department of Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, United States
- Department of Pharmacology and Physiology, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, United States
| | - William Bishai
- Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, Baltimore, MD 21231-1044, United States
| | - William R. Jacobs
- Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, United States
| | - Alan P. Kozikowski
- Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States, Fax: +1-312-996-7107
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Indoleamides are active against drug-resistant Mycobacterium tuberculosis. Nat Commun 2014; 4:2907. [PMID: 24352433 PMCID: PMC3909880 DOI: 10.1038/ncomms3907] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Accepted: 11/11/2013] [Indexed: 01/23/2023] Open
Abstract
Responsible for nearly two million deaths each year, the infectious disease tuberculosis remains a serious global health challenge. The emergence of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis confounds control efforts, and new drugs with novel molecular targets are desperately needed. Here we describe lead compounds, the indoleamides, with potent activity against both drug-susceptible and drug-resistant strains of M. tuberculosis by targeting the mycolic acid transporter MmpL3. We identify a single mutation in mmpL3, which confers high resistance to the indoleamide class while remaining susceptible to currently used first- and second-line tuberculosis drugs, indicating a lack of cross-resistance. Importantly, an indoleamide derivative exhibits dose-dependent antimycobacterial activity when orally administered to M. tuberculosis-infected mice. The bioavailability of the indoleamides, combined with their ability to kill tubercle bacilli, indicates great potential for translational developments of this structure class for the treatment of drug-resistant tuberculosis.
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Patel AB, Kumari P, Chikhalia KH. One-Pot Synthesis of Novel Quinoline-Fused Azeto[1,2-a]benzimidazole Analogs Via Intramolecular Pd-Catalyzed C–N Coupling. Catal Letters 2014. [DOI: 10.1007/s10562-014-1266-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Kalalbandi VKA, Seetharamappa J, Katrahalli U, Bhat KG. Synthesis, crystal studies, anti-tuberculosis and cytotoxic studies of 1-[(2E)-3-phenylprop-2-enoyl]-1H-benzimidazole derivatives. Eur J Med Chem 2014; 79:194-202. [DOI: 10.1016/j.ejmech.2014.04.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Revised: 04/01/2014] [Accepted: 04/04/2014] [Indexed: 10/25/2022]
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Zheng R, Zhu C, Guo Q, Qin L, Wang J, Lu J, Cui H, Cui Z, Ge B, Liu J, Hu Z. Pyrosequencing for rapid detection of tuberculosis resistance in clinical isolates and sputum samples from re-treatment pulmonary tuberculosis patients. BMC Infect Dis 2014; 14:200. [PMID: 24725975 PMCID: PMC4021344 DOI: 10.1186/1471-2334-14-200] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 04/09/2014] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Multidrug-resistant tuberculosis (MDR-TB) is a major public health problem. Early diagnosis of MDR-TB patients is essential for minimizing the risk of Mycobacterium tuberculosis (MTB) transmission. The conventional drug susceptibility testing (DST) methods for detection of drug-resistant M. tuberculosis are laborious and cannot provide the rapid detection for clinical practice. METHODS The aim of this study was to develop a pyrosequencing approach for the simultaneous detection of resistance to rifampin (RIF), isoniazid (INH), ethambutol (EMB), streptomycin (SM), ofloxacin (OFL) and amikacin (AMK) in M. tuberculosis clinical isolates and sputum samples from re-treatment pulmonary tuberculosis (PTB) patients. We identified the optimum conditions for detection mutation of rpoB, katG, rpsl, embB, gyrA and rrs gene by pyrosequencing. Then this approach was applied to detect 205 clinical isolates and 24 sputum samples of M. tuberculosis from re-treatment PTB patients. RESULTS The mutations of rpoB and gyrA gene were detected by pyrosequencig with the SQA mode, and the mutations of katG, rpsl, embB, gyrA and rrs gene were detected by pyrosequencing with SNP mode. Compared with the Bactec MGIT 960 mycobacterial detection system, the accuracy of pyrosequencing for the detection of RIF, INH, EMB, SM, AMK and OFL resistance in clinical isolates was 95.0%, 79.2%, 70.3%, 84.5%, 96.5% and 91.1%, respectively. In sputum samples the accuracy was 83.3%, 83.3%, 60.9%, 83.3%, 87.5% and 91.7%, respectively. CONCLUSIONS The newly established pyrosequencing assay is a rapid and high-throughput method for the detection of resistance to RIF, INH, SM, EMB, OFL and AMK in M. tuberculosis. Pyrosequencing can be used as a practical molecular diagnostic tool for screening and predicting the resistance of re-treatment pulmonary tuberculosis patients.
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Affiliation(s)
- Ruijuan Zheng
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Rd, Shanghai 200433, People's Republic of China
| | - Changtai Zhu
- Department of Laboratory Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yishan Rd, Shanghai 200233, China
| | - Qi Guo
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Rd, Shanghai 200433, People's Republic of China
| | - Lianhua Qin
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Rd, Shanghai 200433, People's Republic of China
| | - Jie Wang
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Rd, Shanghai 200433, People's Republic of China
| | - Junmei Lu
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Rd, Shanghai 200433, People's Republic of China
| | - Haiyan Cui
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Rd, Shanghai 200433, People's Republic of China
| | - Zhenling Cui
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Rd, Shanghai 200433, People's Republic of China
| | - Baoxue Ge
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Rd, Shanghai 200433, People's Republic of China
| | - Jinming Liu
- Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Rd, Shanghai 200433, People’s Republic of China
| | - Zhongyi Hu
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Rd, Shanghai 200433, People's Republic of China
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Spectinamides: a challenge, a proof, and a suggestion. Trends Microbiol 2014; 22:170-1. [DOI: 10.1016/j.tim.2014.02.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Accepted: 02/21/2014] [Indexed: 11/17/2022]
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Yokokawa F. Recent Progress on the Development of Novel Antitubercular Agents from Whole-Cell Screening Hits. J SYN ORG CHEM JPN 2014. [DOI: 10.5059/yukigoseikyokaishi.72.1239] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Design, synthesis and investigation on the structure–activity relationships of N-substituted 2-aminothiazole derivatives as antitubercular agents. Eur J Med Chem 2014; 72:26-34. [DOI: 10.1016/j.ejmech.2013.11.007] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2013] [Revised: 10/14/2013] [Accepted: 11/05/2013] [Indexed: 11/23/2022]
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Antituberculosis: synthesis and antimycobacterial activity of novel benzimidazole derivatives. BIOMED RESEARCH INTERNATIONAL 2013; 2013:926309. [PMID: 24381946 PMCID: PMC3870127 DOI: 10.1155/2013/926309] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2013] [Revised: 07/24/2013] [Accepted: 07/29/2013] [Indexed: 01/01/2023]
Abstract
A total of seven novel benzimidazoles were synthesized by a 4-step reaction starting from 4-fluoro-3-nitrobenzoic acid under relatively mild reaction conditions. The synthesized compounds were screened for their antimycobacterial activity against M. tuberculosis H₃₇Rv (MTB-H₃₇Rv) and INH-resistant M. tuberculosis (INHR-MTB) strains using agar dilution method. Three of them displayed good activity with MIC of less than 0.2 μM. Compound ethyl 1-(2-(4-(4-(ethoxycarbonyl)-2-aminophenyl)piperazin-1-yl)ethyl)-2-(4-(5-(4-fluorophenyl)pyridin-3-ylphenyl-1H-benzo[d]imidazole-5-carboxylate (5 g) was found to be the most active with MIC of 0.112 μM against MTB-H₃₇Rv and 6.12 μM against INHR-MTB, respectively.
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