Platelet aggregation inhibition by fluorophenyl-substituted 2-isoxazoline-5-carboxylic acids and their derivatives

Abstract

Platelets perform many important bodily functions, with their primary task being the prevention of bleeding by facilitating hemostasis. While platelets protect the body from blood loss, they also contribute to the development of serious diseases, such as atherosclerosis and its complications. Understanding the dual role of platelets is crucial for developing new treatments aimed at reducing thrombotic risk while improving the prognosis for patients with cardiovascular diseases. Specifically, elucidating the mechanisms underlying platelet activation may facilitate the development of selective agents that inhibit pathological platelet activity without compromising their protective function. In this context, the present study evaluated the antiplatelet activity of newly synthesized fluorophenyl-substituted 2-isoxazoline-5-carboxylic acids and their derivatives. Results showed that all compounds demonstrated the ability to suppress platelet aggregation. Increasing the concentration of the active substance from 1 to 25 mmol/L enhanced the inhibitory effect of the compounds. Methyl esters, compared to derivatives with a free carboxyl group, exhibited a stronger ability to suppress the activation of platelet receptors glycoprotein (GP) IIa/IIIb, thereby inhibiting their binding to fibrinogen and subsequent aggregation. The half-maximal inhibitory concentration values for two of the studied compounds were 7.5 mmol/L (methyl ester of 3-[3-fluorophenyl]-2-isoxazoline carboxylic acid) and 12.5 mmol/L (methyl ester of 3-[2-fluorophenyl]-2-isoxazoline carboxylic acid), respectively. In conclusion, the findings of this study indicate that 3-aryl-2-isoxazoline-5-carboxylic acids and their methyl esters, containing a single fluorine atom in the aryl group, effectively suppress the activation of platelet receptors GPIIa/IIIb.

Keywords

Antiplatelet agent / Heterocycle / 2-isoxazoline / Platelet / Flow cytometry

Funding

The work was carried out with financial support from the Ministry of Health of the Republic of Belarus, grant 2.2.2/20240516.

Conflict of interest

The authors declare that they have no competing interests.

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