Design, Synthesis, Antimycobacterial Evaluation, and In Silico Investigation of Benzisothiazole-Based Hydrazide Derivatives as Potential Anti-Tuberculosis Agents.

A series of novel benzisothiazole-based hydrazide derivatives was rationally designed, synthesized, and evaluated for their antitubercular activity. Among the synthesized compounds, derivative 8k emerged as the most potent candidate, exhibiting a minimum inhibitory concentration (MIC) of 0.25 μg/mL, along with a high selectivity index (SI) of 42 and confirmed bactericidal activity. To gain preliminary insights into its possible mechanism of action, compound 8k was subjected to molecular docking and 100 ns molecular dynamics simulations, using enoyl-acyl carrier protein reductase (InhA) as the proposed molecular target. The computational studies revealed favorable binding interactions and a relatively stable protein-ligand complex, suggesting InhA as a potential molecular target. However, experimental target-validation studies are required to confirm direct InhA inhibition and establish the proposed mechanism of action. Furthermore, in silico ADMET predictions indicated favorable pharmacokinetic characteristics and drug-likeness properties for the lead compound. Collectively, these findings highlight the potential of benzisothiazole-based hydrazide derivatives as promising scaffolds for the development of new antitubercular agents.