Novel Coumarin–Hydrazone Hybrids as Potential Antiplatelet Agents: Microwave-Assisted Synthesis, Characterization, In Vitro and In Silico Biological Evaluations and Toxicity Assessment

Abstract

This work focuses on the synthesis and characterization of a new series of coumarin–hydrazone derivatives, as well as the evaluation of their inhibitory effects on platelet aggregation induced by adenosine diphosphate (ADP), arachidonic acid (AA), and collagen. Compounds 10 and 11 exhibit a significant inhibition of ADP-induced platelet aggregation. The AA-induced aggregation pathway was inhibited by compound 11 (45%), while none showed an inhibitory effect against collagen-induced aggregation. In addition, both compounds inhibited platelet binding to fibrinogen, CD62-P expression, and glycoprotein IIb/IIIa activation. The interaction of these compounds with their potential targets, P2Y12 and COX-1, was studied using a molecular docking approach. Furthermore, the ADMET properties of the compounds selected were evaluated in silico using Swiss ADME and ProTox-II tools. Selected active compounds demonstrated interesting pharmacokinetic and drug properties, indicating a favorable ADMET profile. In vitro and in silico results are in accordance. Toxicity on lymphocytes, erythrocytes, and platelets was evaluated for the two selected molecules and found to be safe. In summary, this study proposes two novel coumarin–hydrazone derivatives as new potential treatments to prevent cardiovascular events by acting on platelet adhesion, activation, and aggregation.