Page 112 - GTM-4-2

Global Translational Medicine Platelet aggregation inhibition by 2-isoxazolines

such as acute coronary syndromes, unstable angina, diseases. Thus, platelets are multifunctional cells that play a
myocardial infarction, ischemic attack, and peripheral key role in maintaining hemostasis and the development of
arterial disease. Platelet activation occurs under the multiple pathologies. They can protect the body from blood
1
influence of various agonists, such as arachidonic acid, loss and contribute to serious diseases like atherosclerosis
adenosine diphosphate (ADP), thrombin, thromboxane and its complications. Understanding the mechanisms of
A2, and collagen. These substances activate platelets, platelet activation and their interactions with other cells
leading to their aggregation and thrombus formation, and molecules is important for developing new therapeutic
which are necessary to stop bleeding. However, in strategies to reduce the risk of thrombosis and improve the
atherosclerotic conditions, platelets begin to aggressively prognosis for patients with cardiovascular diseases.
interact with the vascular wall when an atheromatous This work aimed to study the ability of synthesized
plaque ruptures, leading to the formation of pathogenic fluorophenyl-substituted 2-isoxazoline-5-carboxylic acids
thrombi that block blood flow and cause ischemic tissue and their derivatives in inhibiting ADP-dependent platelet
damage. In recent years, researchers have discovered that aggregation. The preparation of platelet aggregation
2
platelets are not only involved in thrombus formation but inhibitors based on compounds containing an isoxazole
also play a role in the inflammatory processes associated ring with aromatic substituents in positions 3 and 5 of
with atherogenesis. For example, molecules such as 6
soluble CD40 ligand, C-C chemokine ligand 5, and soluble the heterocyclic fragment has been previously described.
P-selectin mediate platelet interactions with other cells, Among the compounds obtained, some were found to
contributing to the progression of atherosclerotic disease. slow down platelet aggregation. However, a limitation
3
of the previously described compounds is the absence
These interactions highlight the versatility of platelet of functional groups in the aromatic substituents, which
functions, which can both protect and harm the vascular could increase the affinity of the inhibitor molecules to
wall. Following an atheromatous plaque rupture, platelets
adhere to the damaged vessel area, releasing granule platelet receptors. Therefore, the present work investigated
contents that activate platelets and form thrombi. This the activity of compounds containing only one aromatic
process can cause intermittent or persistent obstruction of fragment in positions 3 and 5, a carboxyl group either in
blood flow, resulting in ischemic tissue injury and organ a free state or in the form of its methyl ester. Compounds
dysfunction with serious clinical consequences. 4 containing an aromatic fragment linked by bridging
7
groups to the isoxazole ring have also been studied. It was
Acetylsalicylic acid (aspirin) has traditionally been assumed that the absence of conjugation in the heterocyclic
used to combat platelet hyperactivity and reduce the fragment of 2-isoxazoline and the rigidity imparted to the
risk of serious ischemic events, such as stroke and molecule by the second aromatic fragment would increase
myocardial infarction. This drug has become the standard the inhibitory ability of the compounds under study. It
of care for many patients with cardiovascular disease, should be noted that work is currently ongoing to obtain
including those who have undergone coronary artery new isoxazole- and 2-isoxazoline-containing substances
bypass grafting. Acetylsalicylic acid acts by inhibiting the to assess their potential for medical use. 8-10 The novelty of
enzyme cyclooxygenase, which leads to a decrease in the the compounds studied in this work lies in their fluorine-
synthesis of thromboxane A2, a potent agonist of platelet substituted nature conjugated with the 2-isoxazoline cycle,
aggregation. However, despite its effectiveness, the use of which has not been explored as substances that promote
aspirin is associated with some limitations and risks. For the inhibition of platelet aggregation.
example, some patients may develop resistance to aspirin,
which reduces its effectiveness. In addition, long-term use 2. Materials and methods
may lead to an increased risk of gastrointestinal bleeding. 2.1. Compounds of study
In this regard, new antiplatelet drugs, such as clopidogrel
and ticlopidine, are being studied, which can be combined Infrared (IR) spectra were recorded using a Specord 75 IR
with aspirin to increase the effectiveness of treatment instrument (Carl Zeiss Jena, Germany). Ultraviolet (UV)
and reduce the risk of thrombosis. In recent years, there spectra of the solutions were obtained using a Specord M40
5
has also been interest in studying the role of platelets in instrument (Carl Zeiss Jena, Germany). Nuclear magnetic
other pathological aspects, including their role in immune resonance (NMR) spectra of solutions were recorded on
responses. Platelets can interact with immune cells, such a Bruker NMR spectrometer, Avance 400 (400 MHz)
as neutrophils and monocytes, promoting inflammation (Bruker, USA) in deuterochloroform, with chemical shifts
and modulating the immune response. This opens new (δ) reported relative to tetramethylsilane as the internal
horizons for understanding their role in the pathogenesis standard. Reaction progress and the characteristics of
of various diseases, including infectious and autoimmune the obtained compounds were monitored using thin-

Volume 4 Issue 2 (2025) 104 doi: 10.36922/gtm.8147