Structure-guided hydrophobic modulation at the 3-position of Senecio nutans-derived chalcones Drives divergent...

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 Senecio nutans modulates vascular reactivity and RAS-related pathways.

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 in vitro ACE inhibition assays were conducted to support functional findings.

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 in vitro. Docking studies supported productive accommodation of chalcones within the ACE catalytic pocket, and CHAL 13 showed moderate but significant ACE inhibition in vitro (IC₅₀ = 20.25 µM), whereas CHAL A was markedly less active.

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 Ca²⁺-dependent contraction and partial modulation of the ACE/Ang II axis. These findings identify CHAL 13 as a promising lead-like scaffold for the development of multifunctional vascular-active agents and support further optimization of prenylated chalcones for antihypertensive drug discovery.