Design, Synthesis, and Molecular Docking of Benzimidazole Derivatives as Angiotensin II AT1-Receptor Antagonists in a...

High blood pressure is a major risk factor of cardiovascular disorders. Experimental models of hypertension play a critical role in elucidating its pathophysiological mechanisms and in evaluating novel therapeutic agents. In this study, a series of benzimidazole-based derivatives (I- XIIIa-d) were designed and synthesized. The structural elucidation of the resulting pyrazoles, pyrimidines, diazepines, and isoxazoles were confirmed and examined against L-NAME induced hypertension in rats via targeting angiotensin II AT1 receptor comparing with Telmisartan as a reference drug. Significant reduction in systolic and diastolic blood pressure were observed upon treatment with VI, XIIIa, and XIIId compounds. Additionally, these compounds modulated the key signaling pathways involved in vascular remodeling, oxidative stress, and apoptosis by restoration of survival kinase signaling (Akt/GSK3β), enhancement of anti-apoptotic and anti-inflammatory regulators (BCL2, PPARγ), modulation of angiotensin receptor balance (AT1/ AT2), and attenuation of myocardial damage markers (CPK, LDH). The molecular docking showed that compounds VI, XIIIa, and XIIId had the strongest binding affinity against Ang II AT1 receptor. In conclusion, these findings suggest that the structural modifications of benzimidazole core can yield potent antihypertensive agents via a multi-mechanistic mode of action. They also emerge as promising candidates for further pharmacological development in hypertension treatment and cardiovascular complications.