In Vitro and In Silico Evaluation of Isatin-Derived Spirooxindoles as Antituberculosis Drug Candidates.

Tuberculosis (TB) remains a major global health threat, exacerbated by multidrug-resistant Mycobacterium tuberculosis (MTB) strains. The development of new anti-TB agents is crucial. In this study, 17 isatin derivatives synthesized by our research group were evaluated for their in vitro activity against MTB strains and the two most potent compounds were assessed for cytotoxicity. Additionally, molecular docking was performed against 22 MTB protein targets to explore possible mechanisms of action, and ADMET predictions were used to determine pharmacokinetic and pharmacodynamic suitability. Also, we investigated the activity of A15, A16, and A17 against two genetically characterized multidrug-resistant clinical isolates (PT-12 and PT-20). As a result, the compounds A16 and A17 exhibited the highest anti-TB activity (MIC = 10 μM for both). Inverse molecular docking indicated the enzyme enoyl-[acyl-carrier-protein] reductase as a potential biological target. Cytotoxicity assays confirmed that A16 and A17 were non-toxic, and ADMET predictions indicated suitable drug-like properties for anti-TB therapy. Notably, A16 and A17 showed inhibitory effects against drug-resistant MTB isolates, with minimum inhibitory concentrations (MICs) ranging from 10 to 20 μM, suggesting their potential to overcome resistance mechanisms linked to mutations in katG and rpoB. These findings highlight A16 and A17 as promising candidates for anti-TB agents, particularly against multidrug-resistant strains.