Benzenesulfonohydrazide-tethered non-fused and fused heterocycles as potential anti-mycobacterial agents targeting enoyl acyl carrier protein reductase (InhA) with antibiofilm activity.

Because resistant variants of the disease are always emerging, tuberculosis is a global issue that affects economies. New antitubercular medications should be developed, and this can be done by inhibiting druggable targets. Enoyl acyl carrier protein (ACP) reductase (InhA) is a crucial enzyme for the survival of Mycobacterium tuberculosis (MTB). In this study, a series of small molecules based on non-fused and fused heterocycles (pyridine, coumarin, quinoline, and indole) tethered with benzenesulfonohydrazide were prepared via an aza-Michael reaction exploiting a one-pot synthesis approach. The synthesized molecules (2-7) were evaluated for their activity against tubercle bacilli. Three analogues showed efficacy against tuberculosis, with compound 7 demonstrating a MIC value as low as 8 μg mL-1. Consequently, compounds 3 and 7 successfully hindered the growth of mycobacteria in human monocyte-derived macrophages (MDMs), demonstrating their ability to penetrate human professional phagocytes. Furthermore, they restricted the ability of mycobacteria to produce biofilms. In addition, the inhibitory effects of compounds 3 and 7 against InhA were assessed. Compound 7 exhibited the best efficacy, with an IC50 value of 0.91 μM. The findings showed that the sulfonamide and methyl ester's carbonyl functionalities were engaged in hydrogen bonding with the essential Ile194 and Tyr158 residues, respectively.