A series of benzimidazole-oxadiazole-based Schiff base derivatives (1-10) was synthesized and evaluated as potential angiotensin-converting enzyme (ACE) inhibitors. The compounds were characterized using standard spectroscopic techniques and assessed for ACE inhibitory activity through in vitro enzyme assays, with ramipril used as the reference inhibitor. Several derivatives demonstrated significant inhibition, with analogue 8, bearing a trifluoromethyl (CF₃) substituent, exhibiting superior potency compared to ramipril. Molecular docking studies revealed favorable hydrogen bonding and hydrophobic interactions of the active compounds within the ACE catalytic pocket, supporting the observed inhibitory trends. Density functional theory (DFT) calculations provided insight into electronic features associated with enhanced activity, while in silico ADMET analysis suggested acceptable drug-likeness profiles. Furthermore, in vivo toxicity evaluation in rats indicated no observable adverse effects at the tested doses. Overall, the study identifies these benzimidazole-oxadiazole Schiff bases as promising ACE inhibitory scaffolds for further pharmacological optimization.
