Antiplatelet activity and toxicity profile of novel phosphonium salts derived from Michael reaction

• Published in: European journal of pharmaceutical sciences Vol. 194; p. 106692
• Main Authors: Haffouz, Asma, Elleuch, Haitham, Khemakhem, Bassem, Ben Amor, Ikram, Jerbi, Amira, Gargouri, Jalel, Sahli, Emna, Mhadhbi, Noureddine, Ghalla, Houcine, Rezgui, Farhat, Gargouri, Ali, HadjKacem, Basma
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-03-2024
• Subjects: Antiplatelet activity; Cytotoxicity; Molecular docking; Phosphonium salts; Cytotoxicity; Phosphonium salts; Antiplatelet activity; Molecular docking; molecular docking; phosphonium salts; cytotoxicity
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2024.106692

•Novel four phosphonium salts inhibit ADP and collagen-induced platelet aggregation.•The four molecules inhibit platelet secretion and GPIIb/IIIa activation.•Docking analysis shows a strong affinity of molecules to P2Y12 and GPVI receptors.•Our molecules are safe and non-cytotoxic on platelets, erythrocytes, and HEK293 cells.
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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