Chroman-Schiff base derivatives as potential Anti-Tubercular Agents: In silico studies, Synthesis, and Biological evaluation

Abstract

Tuberculosis (TB) continues to pose a significant public health challenge worldwide. Hydrazide-containing compounds have demonstrated considerable potential as anti- tubercular agents. In this study, we designed, synthesized, and evaluated a series of chroman- Schiff base derivatives, integrating a chroman scaffold with substituted phenyl moieties, as potential therapeutic candidates against TB. In silico studies were conducted to assess the binding interactions of the synthesized derivatives, specifically their R- and S-isomers, with the tuberculosis target protein InhA (PDB ID: 1ZID). Molecular docking revealed that two R-isomer derivatives, SM-5A and SM-6A, exhibited superior binding affinities (-10.6 kcal/mol) compared to the reference ligand INH-NADH (-10.3 kcal/mol) and the natural substrate NADH (-7.5 kcal/mol). Molecular dynamics simulations confirmed the long-term stability of these compound-protein complexes over a 100 ns trajectory, further substantiating their potential as stable inhibitors. The structures of the synthesized derivatives were validated using spectroscopic techniques, including FTIR, ¹³C NMR, ¹H NMR, and HR-MS. Biological evaluation via in vitro anti-tubercular assays against Mycobacterium tuberculosis H₃₇Rv (using the Microplate Alamar Blue Assay) demonstrated that several RRR-isomers displayed notable activity. Among them, SM-2 and SM-5 showed the most potent effects, with minimum inhibitory concentrations (MIC) of 32 µg/mL, comparable to standard anti-tubercular drugs such as isoniazid, ethambutol, and rifampicin. These findings highlight the chroman-schiff base scaffold as a promising foundation for the development of novel anti-tubercular agents. The integration of computational and experimental approaches in this study underscores the potential of these derivatives for further optimization and development into effective anti-tubercular therapeutics.

Keywords: Anti-tubercular; Coumarin; Docking; Dynamics; SAR; Simulation.