DISCOVERING POTENT INHIBITORS AGAINST THE ENOYL-ACYL CARRIER PROTEIN REDUCTASE (InhA) OF MYCOBACTERIUM TUBERCULOSIS: STRUCTURE- BASED DESIGN, SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF QUINOLINE HYDRAZONES

Article history Enoyl-ACP reductases catalyze the final step in the elongation cycle of the bacterial fatty acid biosynthesis (FAS-II) pathway, has been recognized as a promising target for the development of new drugs for TB. Here we present the discovery of a quinoline class of compounds as inhibitors of this enzyme using a combined approach of rational selection of compounds for screening, analogue search and docking studies. Various arylhydrazides were added to 3 rd position of the 2-chloro/2-methoxy-quinoline nucleus to evaluate their influence on the activity toward Mycobacterium tuberculosis H37Rv (MTB) and Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Vibrio cholera. Structures of these compounds were established by FTIR, 1 H NMR, 13 C NMR and mass spectroscopy. The synthesized compounds showed a MIC range of antitubercular activity, extending from 0.2 to 3.125 µg/ml against M. tuberculosis H37Rv. Among the Schiff bases, compound 6b, 6c and 6e exhibited highest activity against the tested mycobacteria at a MIC of 0.2 µg/mL. Hydrogen bonding pattern and Cscore for compounds 4a-e, 6a-6e, 7a and 8a found satisfactory on enoyl ACP- reductase enzyme. Compounds showed promising inhibitory potency because of replacement of 2 nd position chlorine atom with electron-donating methoxy group which can cause a compound to become less acidic. Analysis of the docking study provided details on the fine relationship linking structure and activity, and offer clues for structural modifications that can improve the activity.