Discovery of InhA inhibitors with anti-mycobacterial activity through a matched molecular pair approach

European Journal of Medicinal Chemistry
Hironori KanetakaShunsuke Aoki

Abstract

The Mycobacterium tuberculosis (M. tuberculosis) enoyl-acyl carrier protein reductase (mtInhA) is an attractive enzyme and a thoroughly studied target for tuberculosis therapy. In this study, to identify novel structure-activity relationships (SARs) of mtInhA inhibitors, a series of diphenyl ether derivatives were designed based on the matched molecular pair (MMP) method, and the binding energies of these compounds were subsequently estimated by in silico structure-based drug screening (SBDS) to provide more useful data. Consequently, the 10 unique candidate compounds (KEM1-KEM10) were identified and assessed for the inhibition of mtInhA enzymatic activity, in vitro antibiotic effects against model mycobacteria and toxicity level on both intestinal bacteria and mammalian cells. Among the compounds tested, phenyl group (KEM4) and 2-fluorobenzyl group (KEM7) substitutions produced preferable inhibitory effects on mtInhA enzymatic activity relative to those provided by a furyl group (KES4: base compound) at the terminal of the compound, and KEM7 inhibited the growth of the mycobacteria strain with a lower IC50 value. Moreover, most of the candidate compounds exhibited neither inhibition of the growth of enterobacteria nor toxic ef...Continue Reading

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Citations

Jun 1, 2017·International Journal of Mycobacteriology·Junichi TairaShunsuke Aoki
Feb 24, 2018·Pharmacological Reports : PR·Manaf AlMatarFatih Köksal
Nov 3, 2016·Archiv der Pharmazie·Bharathkumar InturiMadhusudhan N Purohit
Nov 17, 2020·European Journal of Medicinal Chemistry·Pankaj S GiraseRajshekhar Karpoormath
Oct 3, 2017·Journal of Chemical Information and Modeling·Iva LukacAndrew G Leach

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