Design and in silico screening of novel isoniazid-based Schiff base derivatives followed by synthesis and biological evaluation of the lead compound against Mycobacterium tuberculosis H37Rv

The development of new antitubercular agents is critically needed due to the rising incidence of drug-resistant Mycobacterium tuberculosis . In the present study, a series of isoniazid-based Schiff base derivatives was designed and evaluated using an integrated in silico approach. A virtual library comprising 30 compounds was designed and systematically screened. Based on an integrated computational screening strategy involving drug-likeness evaluation, absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling, Prediction of Activity Spectra for Substances (PASS) analysis, and molecular docking, the highest-ranked lead compound (SLB-5) was selected for synthesis, structural characterization, and biological evaluation. Molecular docking was performed against enoyl-acyl carrier protein reductase (InhA) of M. tuberculosis (PDB ID: 6EP8), identifying compounds with favorable predicted binding affinities ranging from − 8.7 to − 9.5 kcal/mol, which were more favorable than the docking score of isoniazid (− 5.8 kcal/mol). The selected lead compound, SLB-5, was synthesized via Schiff base condensation and characterized using Fourier-transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance (¹H NMR), and high-resolution mass spectrometry (HRMS), confirming the formation of the azomethine (–C=N–) linkage. The antitubercular activity of SLB-5 was evaluated against M. tuberculosis H37Rv using the Alamar Blue assay, demonstrating concentration-dependent growth inhibition. Overall, the findings suggest that isoniazid-based Schiff base derivatives represent a promising scaffold for the development of new antitubercular agents. The study demonstrates the utility of an integrated computational screening workflow for prioritizing lead compounds for synthesis and biological evaluation, with SLB-5 emerging as a promising candidate for further investigation.