Oxadiazolone-Triazole Derivatives as a New Scaffold for Modulation of Angiotensin II-Induced Vascular Contraction.

摘要

In this study, a series of novel angiotensin II type 1 receptor (AT1R) antagonist candidates containing the 1,2,4-oxadiazol-5-one nucleus and a 1,2,3-triazole moiety was designed, synthesized, and evaluated. Compounds 7a-j were obtained via a semiconvergent synthetic route employing copper-catalyzed azide-alkyne cycloaddition (click chemistry), yielding the target molecules in moderate to good yields. Biological activity was assessed through vascular reactivity assays using rat aortic rings in the presence of angiotensin II. Most compounds reduced angiotensin II-induced contraction, consistent with a putative AT1 receptor antagonist profile. Among them, compound 7f, bearing a methylenedioxyphenyl substituent, exhibited the most favorable biological profile within the series. The results indicate that electron-donating groups favor activity, while strongly electron-withdrawing substituents, such as nitro, are detrimental. Molecular docking studies predicted consistent interactions with key residues, particularly Arg167 and Tyr87, providing a plausible structural rationale for the observed biological activity. In silico ADME predictions indicated acceptable drug-like properties, including compliance with drug-likeness filters and a predicted bioavailability score, and no blood-brain barrier permeation.