Chemical characterization and cardiovascular effects of an oxime derived from a metabolite of Senecio nutans

Abstract Senecio nutans Sch. Bip. (Asteraceae) is traditionally used in Andean medicine to alleviate symptoms associated with high-altitude exposure, such as headaches, fatigue, and nausea. Previous studies have identified the p -hydroxyacetophenone derivative 4-hydroxy-3-(isopenten-2-yl) acetophenone ( Sn-IV ) as a bioactive metabolite with vasodilatory properties. This study aimed to evaluate whether oxime derivatization of Sn-IV enhances its cardiovascular activity and to compare the pharmacological effects of the synthetic oxime derivative OxSn-IV with those of the parent metabolite. OxSn-IV and structurally related oxime derivatives were synthesized from acetophenone precursors. The vascular effects of Sn-IV and OxSn-IV were evaluated in normotensive rats by measuring arterial blood pressure in vivo. Cardiac effects were evaluated in intact hearts (Langendorff), atrial preparations (organ bath), and in isolated ventricular myocytes (photometry). OxSn-IV significantly reduced mean arterial pressure in normotensive rats, whereas the parent metabolite Sn-IV showed minimal effects. OxSn-IV also attenuated the pressor response induced by phenylephrine and reduced heart rate. In isolated hearts, the compound decreased left ventricular pressure, dP/dtmax, and coronary perfusion pressure, showing negative inotropic effects. In isolated atria, OxSn-IV produced a concentration-dependent reduction in beating rate. OxSn-IV produced a negative inotropic effect on systolic calcium levels, thus sarcomere shortening. Oxime derivatization of the natural metabolite Sn-IV markedly enhances its cardiovascular activity. The results provide experimental evidence supporting the traditional use of S. nutans and suggest that oxime derivatives of its metabolites may represent promising scaffolds for the development of new cardiovascular agents.