ABSTRACT Over the past decade, tetrazole derivatives have emerged as essential pharmacophores for mechanism‐based antihypertensive therapies, owing to their unique bioisosteric and electronic features. This review highlights progress from 2010 to 2025, focusing on tetrazole‐based agents as bioisosteric alternatives to carboxylic acids, which enhance metabolic stability, lipophilicity, and receptor affinity. Major angiotensin II receptor blockers—losartan, candesartan, and irbesartan—illustrate their clinical impact on efficacy and tolerability. Advancements in classical 1,3‐dipolar cycloaddition, green synthetic methodologies (including nano‐catalysis), and scaffold modification have broadened chemical diversity and access to novel compounds. Recent innovations feature tetrazole hybrids that target complex cardiovascular pathways, validated by molecular docking and pharmacological studies. Novel structures like benzothiazole, thiazolo4,5‐bpyridine, oxadiazole‐tetrazole linkers, and carbazole hybrids represent promising directions. Furthermore, artificial intelligence and machine learning are accelerating lead optimization and sustainable synthesis. Collectively, tetrazole substitution enhances angiotensin receptor affinity through bioisosteric mimicry of carboxylates; however, permeability–ionization trade‐offs remain a recurrent limitation. While ARBs demonstrate established clinical success, most tetrazole‐based hybrids remain at preclinical proof‐of‐concept stages with limited PK/PD validation. Future progress requires addressing selectivity, safety liabilities, and scalable synthetic considerations.
Umarani et al. (Fri,) studied this question.