In silico design, synthesis and antitubercular activity of novel 2-acylhydrazono-5-arylmethylene-4-thiazolidinones as enoyl-acyl carrier protein reductase inhibitors

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

Keywords:

• Mycobacterium tuberculosis
• MtInhA inhibitors
• thiazolidin-4-one
• molecular modeling
• molecular dynamics

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. (2023) (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.

Additional information

Funding

This study was carried out without any funding.