N‑(Arylcarbamothioyl)benzamide Derivatives as Selective Antimycobacterial Agents and Their Supramolecular Structural Features

Mycobacterium tuberculosis (Mtb) remains a major global health threat, intensified by multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. We synthesized a series of N-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 (N-benzoyl-arylthiourea possessing p-(N-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 N-benzoyl-arylthioureas with promising anti-TB activity, supported by structure–activity relationships, docking, and crystallographic insights.