Expansion of a novel lead targeting M. tuberculosis DHFR as antitubercular agents

Kalicharan Sharma, Omprakash Tanwar, Girdhar Singh Deora, S. Ali, M. M. Alam, M. S. Zaman, Vagolu Siva Krishna, Dharmarajan Sriram, Mymoona Akhter

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Abstract

A series of 1-(1-benzyl-2-methyl-5-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)-1H-indol-3-yl)ethanone and ethyl 1-benzyl-2-methyl-5-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)-1H-indole-3-carboxylate derivatives were designed based on bioisosteric replacement of previously reported antitubercular agent (IND-07). Twenty ligands were successfully synthesized and some of them were found to have good in vitro activity (MIC < 10 μM) against the H 37 Rv strain of Mycobacterium tuberculosis. Among these compounds, KC-08 and KC-11 inhibited Mtb-DHFR with 4- and 18-fold selectivity for Mtb-DHFR over h-DHFR, respectively. Compound KC-11 display acceptable ADME, and better pharmacokinetic profiles than IND-07. Docking studies were performed to predict the binding mode of the compounds within the active site of Mtb-DHFR and h-DHFR. The results of our study suggest that compound KC-11 may serve as a valuable lead for the design and development of selective inhibitors of Mtb-DHFR with potential therapeutic application in tuberculosis.

Original languageEnglish
Pages (from-to)1421-1429
Number of pages9
JournalBioorganic & Medicinal Chemistry
Volume27
Issue number7
DOIs
Publication statusPublished - 1 Jan 2019

Cite this

Sharma, K., Tanwar, O., Deora, G. S., Ali, S., Alam, M. M., Zaman, M. S., Krishna, V. S., Sriram, D., & Akhter, M. (2019). Expansion of a novel lead targeting M. tuberculosis DHFR as antitubercular agents. Bioorganic & Medicinal Chemistry, 27(7), 1421-1429. https://doi.org/10.1016/j.bmc.2019.02.053