Design and Synthesis of a Focused Library of Diamino Triazines as Potential <i>Mycobacterium tuberculosis</i> DHFR Inhibitors

Lele, Arundhati C.; Raju, Archana; Khambete, Mihir; Ray, Mukti Kanta; Rajan, M. G. R.; Arkile, Manisha; Jadhav, Nandadeep J.; Sarkar, Dhiman; Degani, Mariam S.

doi:10.1021/acsmedchemlett.5b00367

Cited by 19 publications

(17 citation statements)

References 25 publications

(39 reference statements)

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“…This concordance in enzyme inhibition results from the overall similarity between the structures of the enzymes and has been noted in other studies examining DHFR inhibition in M . tuberculosis [ 18 , 30 , 31 ]. In order to investigate potential human cell toxicity, we have examined whether these potent compounds have cytotoxic effects in human dermal fibroblasts, HepG2 and MCF-10 cells.…”

Section: Resultsmentioning

confidence: 99%

“…Using a high-throughput screen of 32,000 compounds, an antifolate with a quinazoline ring was identified as an MtbDHFR inhibitor with moderate potency (MIC 99 = 207 μM) against the H37Rv strain [ 34 ]. Another study [ 31 ] reports the design and synthesis of a series of 16 diaminotriazines; one of these exhibits an MIC value of 0.325 μM against H37Rv. A third study [ 30 ] used a virtual screen to select eight compounds for biological evaluation.…”

Section: Discussionmentioning

confidence: 99%

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Propargyl-Linked Antifolates Are Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis

et al. 2016

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Mycobacterium tuberculosis continues to cause widespread, life-threatening disease. In the last decade, this threat has grown dramatically as multi- and extensively-drug resistant (MDR and XDR) bacteria have spread globally and the number of agents that effectively treat these infections is significantly reduced. We have been developing the propargyl-linked antifolates (PLAs) as potent inhibitors of the essential enzyme dihydrofolate reductase (DHFR) from bacteria and recently found that charged PLAs with partial zwitterionic character showed improved mycobacterial cell permeability. Building on a hypothesis that these PLAs may penetrate the outer membrane of M. tuberculosis and inhibit the essential cytoplasmic DHFR, we screened a group of PLAs for antitubercular activity. In this work, we identified several PLAs as potent inhibitors of the growth of M. tuberculosis with several of the compounds exhibiting minimum inhibition concentrations equal to or less than 1 μg/mL. Furthermore, two of the compounds were very potent inhibitors of MDR and XDR strains. A high resolution crystal structure of one PLA bound to DHFR from M. tuberculosis reveals the interactions of the ligands with the target enzyme.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Propargyl-Linked Antifolates Are Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis

et al. 2016

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“…Compound 21 displayed IC 50s of 25.8 μM and 42 μM against M. tuberculosis and human DHFRs, confirming selectivity to pathogen. The very low cytotoxicity profile of 21 in liver and lungs cell lines confirmed its potential as promising anti‐TB agent …”

Section: Benzotriazines and Benzotriazolesmentioning

confidence: 92%

New structural classes of antituberculosis agents

Kumar

Patel

Jain

2017

Medicinal Research Reviews

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Tuberculosis (TB), one of the deadliest diseases is shattering the health and socioeconomic status of the society. The emergence of multidrug resistant (MDR) and extremely drug resistant (XDR) strains has provided unprecedented lethal character to TB. The development of MDR and XDR strains of TB results in more deaths, longer duration of therapy, and appearance of the disease in the immunocompromised patients. Because of the development of rapid resistance by Mycobacterium tuberculosis, researchers are confronted with serious challenges in combating TB. For instance, the need for potency and specificity in therapeutic agents approaching clinics, and the increasing demand of low toxicity due to long duration of treatment. Recently, it is proposed that such challenges could be addressed by a shift from contemporary or known classes of drugs to new scaffold-containing or entirely new structural classes of drugs that possibly act on the previously unknown targets, resulting in possibly less instances of resistance development. The exploitation of advances made in the biology of TB in the last and present decades have created opportunities to discover a large number of new structural classes that specifically targets TB by molecular mechanism of action(s) unknown earlier. We have earlier reviewed new structural classes of anti-TB agents up to year 2005. This review covers literature reports of the subsequent 10 years on the discovery of new structural classes of synthetic anti-TB agents. Due to the availability of large number of research reports, we have divided new compounds in 38 structural classes, 368 structures, and 307 references.

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“…DHFR may not be a novel target, but it cannot be ignored as there is ample enthusiasm for the development of DHFR inhibitors, particularly with regard to mycobacteria. [18][19][20][21][22][23][24] This distinctive feature of DHFR makes it an ideal target for rational and effective drug design for antitubercular agents.…”

Section: Tuberculosis (Tb) Is a Global Epidemic Caused By Pathogenic mentioning

confidence: 99%

Preparation, biological evaluation and molecular docking study of imidazolyl dihydropyrimidines as potential Mycobacterium tuberculosis dihydrofolate reductase inhibitors

Desai

Trivedi

Khedkar

2016

Bioorganic & Medicinal Chemistry Letters

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Design and Synthesis of a Focused Library of Diamino Triazines as Potential Mycobacterium tuberculosis DHFR Inhibitors

Cited by 19 publications

References 25 publications

Propargyl-Linked Antifolates Are Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis

Propargyl-Linked Antifolates Are Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis

New structural classes of antituberculosis agents

Preparation, biological evaluation and molecular docking study of imidazolyl dihydropyrimidines as potential Mycobacterium tuberculosis dihydrofolate reductase inhibitors

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