UNUIGBE ISONAH

Hypertension affects approximately 1.3 billion people globally and remains a leading cause of cardiovascular morbidity and mortality. Despite available treatments, challenges including resistant hypertension, poor adherence, and adverse effects persist. This study employed integrated computational and experimental approaches to design and synthesize novel imidazole-based antihypertensive compounds. Molecular docking using AutoDock Vina evaluated four imidazole derivatives against key hypertension-related targets: 6L88, 7BVQ, 5XPR, and 1O86. The compound 2-hexyl-4-phenyl-1H-imidazole exhibited superior binding with affinities of -6.3 to -7.9 (kcal/mol) to all the targets used. SwissADME analysis predicted favorable pharmacokinetics: high gastrointestinal absorption, optimal lipophilicity, and full Lipinski compliance. ProTox-3.0 toxicity profiling also showed acceptable safety with no predicted mutagenicity, carcinogenicity, immunotoxicity, or cytotoxicity. Based on these results, 2-hexyl-4-phenyl-1H-imidazole was synthesized via Debus-Radziszewski condensation with 77.3% yield and melting point of 184-186°C. Structure-activity analysis confirmed both hexyl and phenyl substituents are essential for optimal binding. This work demonstrates rational drug design principles in identifying promising antihypertensive leads and establishes a foundation for developing imidazolebased cardiovascular agents

Hypertension remains a leading cause of cardiovascular morbidity, necessitating novel multitarget inhibitors. Imidazole derivatives exhibit diverse pharmacological activities, including potential modulation of vasoconstrictive pathways, yet few studies integrate computational
screening with synthetic validation for antihypertensive lead discovery. Four imidazole compounds were subjected to molecular docking using AutoDock Vina against
ACE (7bvq), AT1R (7ej8), ETAR (6ke5), and renin (5xpr) to predict binding affinities. The lead compound, 2-methyl-4,5-diphenyl-1H-imidazole, was synthesized via one-pot condensation of benzil, acetaldehyde, and ammonium acetate under reflux, followed by recrystallization. Physicochemical properties, ADMET parameters, and toxicity profiles were evaluated using SwissADME and Pro Tox 3 platforms. Docking revealed 2-methyl-4,5-diphenyl-1H-imidazole as the most potent ligand, with binding energies of -8.9 to -6.9 kcal/mol across all targets, driven by hydrophobic. It displayed high gastrointestinal absorption, blood-brain barrier permeability, balanced lipophilicity, and no
cardiotoxicity or nephrotoxicity. Synthesis yielded 57.36 % of pure yellowish crystals (m.p. 69- 71 °C). Other derivatives showed weaker binding, restricted distribution, or higher genotoxic risks. 2-Methyl-4,5-diphenyl-1H-imidazole is identified as a promising multitarget antihypertensive
lead with favorable drug-like properties and synthetic accessibility. It warrants further biological evaluation in enzyme inhibition, vasorelaxation, and in vivo models to advance toward clinical development.