Structural and Biological Investigation of (E)-2-((2-Butyl-4-Chloro-1H-Imidazol-5-yl)methylene) Hydrazine-1-Carbothioamide: Synthesis, StructuralInsights, Antitubercular Screening, Molecular Docking, DFT, and ADME Studies

The emergence of multidrug-resistant (MDR) strains of Mycobacterium tuberculosis has necessitated the development of novel antitubercular agents with unique pharmacophores. The present study aims to design and evaluate a new imidazole-hydrazone-thiourea hybrid molecule, (E)-2-((2-butyl-4-chloro-1H-imidazol-5-yl) methylene)hydrazine-1-carbothioamide (BCIM-HCT), for its antitubercular potential. The novelty of this work lies in the strategic hybridization of imidazole and hydrazone-thiourea moieties, expected to offer synergistic pharmacological effects. BCIM-HCT was synthesized via a condensation method and characterized using FT-IR, NMR, and density functional theory (DFT) calculations. The compound exhibited moderate antitubercular activity against M. tuberculosis H37Rv with a minimum inhibitory concentration (MIC) of 6.25 mu g/mL, determined via the microplate Alamar Blue assay (MABA). Molecular docking studies with Cytochrome P450 14 alpha-sterol demethylase (CYP51) revealed a notable binding affinity (-7.6 kcal/mol), stabilized by hydrogen bonding and hydrophobic interactions, suggesting a stable and specific ligand-protein interaction. DFT-based analyses, including molecular electrostatic potential (MEP), Mulliken charges, electron localization function (ELF), and reduced density gradient (RDG), provided insights into electronic structure, reactive sites, and non-covalent interactions. ADME predictions indicated favorable drug-like properties, including high gastrointestinal absorption, moderate lipophilicity, and compliance with Lipinski's Rule of Five. Although BCIM-HCT demonstrates moderate biological activity compared to first-line drugs, its unique structure, promising binding affinity, and favorable pharmacokinetic profile establish it as a potential lead compound for future antitubercular drug development.