Structure-guided hydrophobic modulation at the 3-position of

Background: Hypertension is a major global health challenge driven by sustained alterations in vascular tone and dysregulation of the renin-angiotensin system (RAS). Although natural products provide valuable scaffolds for vascular drug discovery, systematic structure-function studies linking defined hydrophobic modifications to vascular mechanisms remain limited. This study aimed to evaluate how hydrophobic substitution at the three-position of chalcones derived from Methods: A focused series of chalcones bearing either an allyl or a prenyl substituent at the three-position was synthesized and evaluated. Vasorelaxant effects were assessed in isolated aortic rings from spontaneously hypertensive rats under receptor-mediated (phenylephrine), depolarization-induced (KCl), and angiotensin I-induced contractile conditions. Molecular docking studies were performed to explore interactions with the angiotensin-converting enzyme (ACE) catalytic site, and Results: All chalcones induced concentration-dependent relaxation in precontracted aortic rings; however, their pharmacological profiles depended on the nature of the 3-substituent. The prenylated derivative CHAL 13 showed the most consistent activity across complementary vascular models, retaining inhibitory effects under depolarizing conditions and significantly attenuating angiotensin I-induced contraction. In contrast, the allylated derivative CHAL A showed a more limited mechanistic profile: although retaining activity in phenylephrine-precontracted rings, it exhibited weaker inhibition under depolarizing conditions and markedly lower ACE inhibitory potency Conclusion: Hydrophobic substitution at the three-position is a relevant determinant of the vascular behavior of S. nutans-derived chalcones. Prenylation favors a broader vasoactive profile associated with interference in Ca