Design, synthesis and in silico evaluation of newer 1,4-dihydropyridine based amlodipine bio-isosteres as promising antihypertensive agents

Abstract

Hypertension remains a major global health concern, prompting ongoing research into innovative therapeutic approaches. This research encompasses the strategic design, synthesis, and computational assessment of a novel series of 1,4-dihydropyridine based scaffolds with the objective of developing promising antihypertensive agents as viable alternatives to the well-established dihydropyridine based drugs such as amlodipine, felodipine, nicardipine, etc. The crystal structure of the lead compound determined using X-ray crystallography offers crucial insights into its 3D-conformation and intermolecular interactions. In silico molecular docking experiments conducted against the calcium channel responsible for blood pressure regulation revealed superior docking scores for all the bioisosteres P1–P14 than the standard amlodipine, indicating their potential for enhanced therapeutic efficacy. Extensive ADMET profiling and structure–activity relationship (SAR) elucidated favourable pharmacokinetic properties and essential structural modifications influencing antihypertensive effectiveness. Specifically, P6–P10, P12 and P14 hybrids were found in accordance with Lipinski rules and exhibited druglikeliness attributes, involving high GI absorption and no BBB permeance. In particular, P7 was found to be crystalline in nature having the highest binding affinity with the concerned calcium channels with excellent ADMET profile. The findings highlight the significance of the presence of triazole tethered aryl/heteroaryl ring in the synthesized hybrids, providing a foundation for further preclinical and clinical translation as antihypertensive medications.