Abstract
Mycobacteria regulate the synthesis of mycolic acid through the fatty acid synthase system type 1 (FAS I) and the fatty acid synthase system type-2 (FAS-II). Because mammalian cells exclusively utilize the FAS-I enzyme system for fatty acid production, targeting the FAS-II enzyme system could serve as a specific approach for developing selective antimycobacterial drugs. Enoyl-acyl carrier protein reductase enzyme (MtInhA), part of the FAS-II enzyme system, contains the NADH cofactor in its active site and reduces the intermediate. Molecular docking studies were performed on an in-house database (∼2200 compounds). For this study, five different crystal structures of MtInhA (PDB Code: 4TZK, 4BQP, 4D0S, 4BGE, 4BII) were used due to rotamer difference, mutation and the presence of cofactors. Molecular dynamics simulations (250 ns) were performed for the novel 2-acylhydrazono-5-arylmethylene-4-thiazolidinones derivatives selected by molecular docking studies. Twenty-three compounds selected by in silico methods were synthesized. Antitubercular activity and MtInhA enzyme inhibition studies were performed for compounds whose structures were elucidated by IR,1H-NMR,13C-NMR, HSQC, HMBC, MS and elemental analysis.
Communicated by Ramaswamy H. Sarma
Acknowledgement
Serap İpek Dingiş Birgül was supported with scholarships by the Council of Higher Education (CoHE-YOK100/2000) and The Scientific and Technological Research Council of Turkey (TUBİTAK-BİDEB-2211-A). Figures 4, 5 and 8 presented in the supplemental material of this article have been partially reproduced from “Trawally et al. (Citation2023) (Figures S73, S74 and S75), Copyright (2023)", with permission from Elsevier (Licence number: 5730950160537).
Data availability statement
The data that supports the findings of this work are available in the supplemental material.
Disclosure statement
No potential conflict of interest was reported by the authors.