Design, in silico simulation, and pharmacological evaluation of novel eugenol-vanillin hybrids as potential vasorelaxant and antihypertensive agents

Regarding the fight against arterial hypertension one of the major causes of cardiovascular morbidity at the global level, our study is intended a contribution for the rational elaboration of a new antihypertensive drug. With this purpose, we synthesized a set of hybrids compounds, which spans from the union of two natural compounds eugenol and vanillin already fed for its potent biological properties. The adopted synthetic pathway was based on a hemisynthesis fashion that allowed obtaining three isoxazoline derivatives, named 5a, 5b, and 5c. The synthesized compounds were characterized by using standard spectroscopic techniques such as FT-IR, ¹H NMR and ¹³C NMR for their structure identification. Vasorelaxants effect was tested in vitro using isolated rat aortic ring segments that were precontracted with epinephrine (10 µM). Results showed a concentration-dependent vasorelaxant effect for all three compounds. Compounds 5a and 5c exhibited similar effects with verapamil, which has been marketed as a calcium channel antagonist and an antihypertensive agent. These results underline the excellent pharmacological potential of the compounds prepared. To investigate the possible molecular mechanism of action, compound 5a was selected for a molecular docking study. It exhibited a high binding affinity toward several target receptors associated with vascular regulation, specifically the crystallographic structures 6JP5, 5CXV, 7UQW, 1M9M, and 8HBF. Furthermore, compound 5a established a stable hydrogen bond network, particularly with receptors 5CXV and 7UQW, which may contribute to the stabilization of its conformation within the active binding sites.