<i>N</i> -(Arylcarbamothioyl)benzamide Derivatives as Selective Antimycobacterial Agents and Their Supramolecular Structural Features

<i>Mycobacterium tuberculosis</i> (Mtb) remains a major global health threat, intensified by multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. We synthesized a series of <i>N</i>-benzoyl-arylthiourea derivatives (IITKDA1-20) as hybrids of isoniazid/pyrazinamide and ethionamide to explore their antimycobacterial potential. Our evaluation of synthesized library members for antimycobacterial activity has identified IITKDA10 (<i>N</i>-benzoyl-arylthiourea possessing <i>p</i>-(<i>N</i>-Boc)-thionamide) as the maximally effective inhibitor of Mtb (1 μg/mL MIC). Further, the physicochemical properties indicated a trend of high topological polar surface area (tPSA) and partition coefficient (ClogP) in the range of 3-4 was optimal for the compounds to be active against Mtb. Molecular docking of IITKDA10 into the InhA (enoyl-[acyl-carrier-protein] reductase) active site revealed strong binding (-9.63 kcal/mol), stabilized by hydrogen bonds and π-alkyl interactions. Further, crystal packing analysis indicated that hydrogen bonding networks guided supramolecular architecture, and structural planarity (e.g., IITKDA4, IITKDA8) correlated with higher activity. In contrast, twisted or L-shaped conformations (IITKDA2, IITKDA5) showed reduced potency. This study presents a structurally and functionally diverse set of <i>N</i>-benzoyl-arylthioureas with promising anti-TB activity, supported by structure-activity relationships, docking, and crystallographic insights.