AccScience Publishing / GTM / Online First / DOI: 10.36922/gtm.8147
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Platelet aggregation inhibition by fluorophenyl-substituted 2-isoxazoline-5-carboxylic acids and their derivatives

Mikalai M. Kauhanka1* Marharita E. Parkhach1 Svetlana N. Borisevich1 Stanislava V. Glinnik1 Elena N. Haluk1
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1 Department of General Chemistry, Career Guidance and Pre-University Training Faculty, Belarusian State Medical University, Minsk, Belarus
Global Translational Medicine, 8147 https://doi.org/10.36922/gtm.8147
Submitted: 23 December 2024 | Revised: 26 February 2025 | Accepted: 20 March 2025 | Published: 4 April 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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.
References
  1. Jennings LK. Mechanisms of platelet activation: Need for new strategies to protect against platelet-mediated atherothrombosis. Thromb Haemost. 2009;102(2):248-257. doi: 10.1160/TH09-03-0192

 

  1. Angiolillo DJ, Capodanno D, Goto, S. Platelet thrombin receptor antagonism and atherothrombosis. Eur Heart J. 2010;31(1):17-28. doi: 10.1093/eurheartj/ehp504

 

  1. Fuentes QE, Fuentes QF, Andrés V, Pello OM, Font de Mora J, Palomo GI. Role of platelets as mediators that link inflammation and thrombosis in atherosclerosis. Platelets. 2013;24(4):255-262. doi: 10.3109/09537104.2012.690113

 

  1. Viallard JF, Solanilla A, Gauthier B, et al. Increased soluble and platelet-associated CD40 ligand in essential thrombocythemia and reactive thrombocytosis. Blood. 2002;99(7):2612-2614. doi: 10.1182/blood.v99.7.2612

 

  1. Ruggeri ZM. Mechanisms initiating platelet thrombus formation. Thromb Haemost. 1997;78(1):611-616. doi: 10.1055/s-0038-1657598

 

  1. Gutiérrez M, Amigo J, Fuentes E, Palomo I, Astudillo L. Synthetic isoxazole as antiplatelet agent. Platelets. 2014;25(4):234-238. doi: 10.3109/09537104.2013.807335

 

  1. Xue CB, Roderick J, Mousa S, Olson RE, DeGrado WF. Synthesis and antiplatelet effects of an isoxazole series of glycoprotein IIb/IIIa antagonists. Bioorg Med Chem Lett. 1998;8(24):3499-3504. doi: 10.1016/s0960-894x(98)00637-4

 

  1. Yogesh W, Pravin M, Pramod K. Application, reactivity and synthesis of isoxazole derivatives. Mini-Rev Org Chem. 2021;18(1):55-77. doi: 10.2174/1570193x17999200511131621

 

  1. Shanshan L, Yiou M, Luchen J, Xueyan Y, Wei Z, Yunfei D. Oxazole and isoxazole-containing pharmaceuticals: Targets, pharmacological activities, and their SAR studies. RSC Med Chem. 2025;16(4):1461-1469. doi: 10.1039/D4MD00777H

 

  1. Mohan K, Vikul K, Meenakshi S. A review of isoxazole biological activity and present synthetic techniques. Int J Pharm Chem Anal. 2024;11(4):307-317. doi: 10.18231/j.ijpca.2024.045

 

  1. Vinholt PJ, Frederiksen H, Hvas AM, Sprogøe U, Nielsen, C. Measurement of platelet aggregation, independently of patient platelet count: A flow-cytometric approach. J Thromb Haemost. 2017;15(6):1191-1202. doi: 10.1111/jth.13675
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