DESIGN, MOLECULAR DOCKING STUDIES, IN SILICO DRUG LIKELINESS PREDICTION AND SYNTHESIS OF SOME BENZIMIDAZOLE DERIVATIVES AS ANTIHYPERTENSIVE AGENTS

Hypertension is a major public problem in the Kingdom of Saudi Arabia. Many ACE inhibitors are in clinical use as antihypertensive agents. However, theses ACE inhibitors possess many undesirable side effects. Recently, benzimidazole derivatives have been reported to possess ACE inhibitory activity. Therefore, it was aimed to provide some benzimidazole derivatives as ACE inhibitors with high potency and low toxicity. A series of some benzimidazole derivatives was designed as ACE inhibitor based on the literature. Molecular docking studies were carried out by using AutoDock vina software to identify the potent compounds. The compounds with predicted high potency were subjected for their toxicity prediction by osiris property calculator and the drug likeliness studies were carried out using available online softwares. The selected compounds were synthesized and evaluated for their ACE inhibitory activity using lisinopril as a standard drug. The compound 2-(2- (butylthio)-5-methoxy-1H-indol-1-yl)-1-(2-nitrophenyl)ethan-1-one (17) was identified as an equipotent ACE inhibitor with respect to lisinopril. The in silico toxicity studies revealed that this compound was safe with respect to tumorogenecity, irritation effect, and reproductive effect. The application of the Lipinski's Rule of 5 and drug likeliness studies also revealed that this compound had an acceptable level of drug likeliness property with a potential to become a good orally active candidate. The in vitro ACE inhibitory assay of this compound also revealed that it was almost equipotent with respect to lisinopril. The compound (17) has required attributes to become a potential candidate as an ACE inhibitor. However, further studies are recommended to ensure its efficacy and safety in different animal models. Keywords: Molecular modelling, benzimidazole derivatives, ACE inhibitor, drug likeliness, toxicity.