Computer-aided design, synthesis and enzymatic analysis of new triazole derivatives as potential factor Xa inhibitors.

FABIÁN SANTA ROMO; YANINA MOGLIE; FLAVIA ZACCONI

Atenas

Simposio; VIII EFMC International Symposium on Advances in Synthetic and Medicinal Chemistry; 2019

European Federation for Medicinal Chemistry, Hellenic Society of Medicinal Chemistry, CHEMBRIDGE CORPORATION

The World Health Organization (WHO) reported that thrombosis diseases have increased its cases up to 25 % of people. Relevant diseases in thrombosis pathology include acute coronary syndrome (ACS), venous thromboembolism (VTE), deep vein thrombosis (DVT); all of them caused by clots, this can trigger strokes whose travel through arterial circulation. Giving rise to serious diseases like acute myocardial infarction (AMI) [1].Factor Xa (FXa) plays a key role in haemostasis, due to it´s a central part of the blood coagulation cascade which catalyzes the production of thrombin and leads to clot formation and wound closure. Clotting is a sequential process that involves the interaction of coagulation factors [2]. Inhibition of FXa should prevent the production of new thrombin without affecting its basal level, ensuring primary haemostasis, unlike injectable heparins or the most commonly used oral anticoagulant in the US, such as warfarin. In this research novel aryl azides were synthesized incorporating a lactamic ring with different heteroatoms in position 4 as starting materials. A variety of 1,2,3-triazoles were prepared using copper nanoparticles as catalyst (10 mol %) from different aryl azides synthesized in the first microwave synthesis step [3-4]. The products of the 1,3-dipolar cycloaddition of aryl azides and different terminal alkynes were obtained in good to excellent yields (70-97%). By using computational tools allows us to develop new synthetic ligands to interact with high specificity with the S1 and S4 pockets enzyme. The aryl lactam core shows favorable π- π interactions with the S4 pocket. Moreover, FXa inhibition assays were performed in order to obtain the IC50 values of the corresponding new derivatives [5].