Expansion of a novel lead targeting M. tuberculosis DHFR as antitubercular agents |
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Authors: | Kalicharan Sharma Omprakash Tanwar Girdhar Singh Deora S Ali MM Alam MS Zaman Vagolu Siva Krishna Dharmarajan Sriram Mymoona Akhter |
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Institution: | 1. Department of Pharmaceutical Chemistry, SPER, Jamia Hamdard, New Delhi 110062, India;2. Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia;3. Department of Biochemistry, SCLS, Jamia Hamdard, New Delhi 110062, India;4. Bioinformatics Infrastructure Facility Lab, Jamia Hamdard, New Delhi 110062, India;5. Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Hyderabad 500078, India |
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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 H37Rv 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. |
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Keywords: | Corresponding author at: Dept of Pharmaceutical Chemistry School of Pharmaceutical Education & Research Jamia Hamdard New Delhi 110062 India |
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