Design, Synthesis, and Molecular Docking Studies of Novel Solanidine-Benzoyl Hydrazone Hybrids as Potential InhA Inhibitors

Abstract

Tuberculosis (TB) remains a major global health concern due to increasing drug resistance, poor bioavailability of first-line drugs, and associated hepatotoxicity. This study reports the design, synthesis, and molecular docking evaluation of novel solanidine–benzoyl hydrazone hybrid derivatives (MK-1 to MK-12) as potential inhibitors of the enoyl-acyl carrier protein reductase (InhA) enzyme of Mycobacterium tuberculosis. The compounds were synthesized via a multi-step process involving Vilsmeier–Haack formylation, Schiff base formation, and cyclization, and were characterized using FTIR, TLC, and mass spectrometry. Molecular docking studies using AutoDock Vina against the InhA enzyme (PDB ID: 5JFO) revealed strong binding affinities (−9.3 to −7.8 kcal/mol), exceeding that of the standard drug isoniazid (−7.5 kcal/mol). ADMET prediction using SwissADME demonstrated favorable drug-likeness, good oral bioavailability, and compliance with Lipinski’s rule of five for most compounds. Toxicity profiling indicated moderate hepatotoxicity, neurotoxicity, and nephrotoxicity risks, while cardiotoxicity remained negligible. Phytochemical screening of Solanum virginianum confirmed the presence of bioactive constituents such as alkaloids, flavonoids, saponins, and glycosides, supporting its pharmacological relevance. The findings suggest that these hybrid derivatives exhibit promising anti-tubercular potential and may serve as effective adjuncts to existing therapies with improved efficacy and reduced toxicity.