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

We report design of a series of 2,4-diamino triazines as Mycobacterium tuberculosis (Mtb) dihydrofolate reductase inhibitors. The synthesized compounds were evaluated against Mtb (H37Rv and Dormant stage H37Ra), their cytotoxicity was assessed (HepG2 and A549 cell lines), and selectivity toward Mtb...

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Published inACS medicinal chemistry letters Vol. 6; no. 11; pp. 1140 - 1144
Main Authors Lele, Arundhati C, Raju, Archana, Khambete, Mihir P, Ray, M. K, Rajan, M. G. R, Arkile, Manisha A, Jadhav, Nandadeep J, Sarkar, Dhiman, Degani, Mariam S
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 12.11.2015
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Letter
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
Diamino triazine
selectivity
synergy
Mycobacterium tuberculosis
molecular modeling
enzyme assay
dihydrofolate reductase
ASSAY
DRUGS
BIOLOGICAL EVALUATION
AGENTS
DERIVATIVES
OPPORTUNISTIC MICROORGANISMS
DIHYDROFOLATE-REDUCTASE INHIBITORS
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Summary:We report design of a series of 2,4-diamino triazines as Mycobacterium tuberculosis (Mtb) dihydrofolate reductase inhibitors. The synthesized compounds were evaluated against Mtb (H37Rv and Dormant stage H37Ra), their cytotoxicity was assessed (HepG2 and A549 cell lines), and selectivity toward Mtb was evaluated by testing against other bacterial strains. Some derivatives showed promising activity along with low cytotoxicity. The most potent compound in the whole cell assay (MIC 0.325 μM against H37Rv) showed selectivity in the enzyme assay and exhibited synergy with second line anti-TB agent p-amino salicylic acid. This study therefore provides promising molecules for further development as antituberculosis DHFR inhibitors.
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ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.5b00367