Estudo da ação antitrombótica de um análogo isoxazólico derivado de neolignana tetrahidrofurânica

Abstract

Cardiovascular diseases stand as the leading global cause of mortality, being the tromboses associated with arterial diseases one of the main causes of morbidity and mortality Thrombosis can lead to arterial obstruction, compromising the blood supply and disturbing the cellular metabolism in affected areas. The treatment of cardiovascular diseases presents numerous challenges, resulting in the need for more efficacious, safe, and user-friendly medications, especially within specialized contexts. Therefore, this study aims to investigate the antithrombotic activity (antiplatelet aggregation and anticoagulant) of an isoxazole analogue derived from tetrahydrofuran neolignans (AINT 4), in an in vitro experimental model. The synthesis of AINT 4 was carried out from cycloaddition reactions between terminal acetylenes 12 and chlorooximes 13 with substitution patterns found in neolignans. The predictive analysis (in silico) of bioavailability and oral toxicity of AINT 4 was evaluated using the SwissADME® software and Osiris® Property Explorer, respectively. The evaluation of platelet aggregation was carried out by turbidimetry, with AINT 4 being evaluated in different concentrations, using different agonists such as ADP and adrenaline, while the evaluation of coagulation was carried out in plasma using a semi-automated coagulation system. Statistical analysis was performed using analysis of variance (ANOVA), complemented by the Tukey-Kramer test, with a significance level lower than 0.05. The results showed that AINT 4 significantly inhibited platelet aggregation with both ADP (mean inhibition of 22.27%) and EPI (mean inhibition of 17.47%) at the tested concentrations. Furthermore, AINT 4 exhibited a noteworthy reduction in prothrombin time. Additionally, AINT 4 has shown to have an effect on platelet activation, resulting in an average reduction of 27% in the production of reactive oxygen species (ROS). Therefore, these findings indicate the antithrombotic activity of AINT 4.