Mechanochemical Synthesis, Characterization, and Biological Evaluation of N-Cyclohexyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxamide Derivatives

Objective: To address the global threat of multi-drug resistant tuberculosis (MDR-TB), which compromises roughly 20% of current clinical cases, we designed a structurally diverse library of N-cyclohexyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (THPM) derivatives targeting essential mycobacterial enzymes. Methods: A sustainable, solvent-free mechanochemical grindstone methodology was developed to assemble the target scaffolds, followed by comprehensive in silico docking and in vitro phenotypic screening against Mycobacterium tuberculosis (Mtb). Results and Discussion: The green synthetic approach afforded the target compounds with excellent yields (85–95%) and significantly reduced reaction times compared to conventional reflux protocols. Among the synthesized library, compounds 8 and 9 emerged as highly potent candidates, exhibiting exceptional binding affinities toward both DprE1 and InhA, optimal drug-like properties, and robust anti-TB activity (MIC down to 0.8 μg/mL). Conclusions: These findings demonstrate that mechanochemically synthesized THPM scaffolds represent highly promising lead structures for sustainable anti-TB drug discovery.