Antiplatelet Activity and Toxicity Profile of Novel Phosphonium Salts Derived from Michael Reaction.

In this work, five novel phosphonium salts derived from the Michael reaction were screened for their antiplatelet activity. Our findings revealed that compounds 2a, 2b, 2c, and 2d significantly inhibit platelet aggregation triggered by ADP or collagen (P < 0.001). Notably, compound 2c inhibited the arachidonic acid pathway (P < 0.001). Moreover, the selected compounds reduce CD62-P expression and inhibit GPIIb/IIIa activation. The interactions of the active compounds with their targets, ADP and collagen receptors, P2Y12 and GPVI respectively were investigated in silico using molecular docking studies. The results revealed a strong affinity of the active compounds for P2Y12 and GPVI. Additionally, cytotoxicity assays on platelets, erythrocytes, and human embryonic kidney HEK293 cells showed that compounds 2a, 2c and 2d were non-toxic even at high concentrations. In summary, our study shows that phosphonium salts can have strong antiplatelet power and suggests that compounds 2a, 2c and 2d could be promising antiplatelet agents for the management of cardiovascular diseases.

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Copyright © 2024. Published by Elsevier B.V.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors would like to disclose potential competing interests in the form of a granted patent titled "Nouveaux sels de phosphonium issus des accepteurs de MICHAEL en tant qu'agents antiagrégants plaquettaire." This patent is awarded to Haitham Elleuch, Asma Haffouz, Ikram Ben Amor, Amira Jerbi, Jalel Gargouri, Farhat Rezgui, Ali Gargouri, and Basma HadjKacem. It is important to note that this patent has been issued to the ”Institut National de la Normalisation et de la Propriété Industrielle (INNORPI)” in Tunisia, bearing the reference number TN2022/0155.