COMPUTATIONAL DESIGN, SYNTHESIS AND ENZYMATIC ANALYSIS OF DISUBSTITUTED AMINES TRIAZOLES AS POTENTIAL FACTOR XA INHIBITORS

FABIÁN SANTA ROMO; YANINA MOGLIE; FLAVIA ZACCONI

Ljubljana, Eslovenia

Simposio; XXV EFMC International Symposium on Medicinal Chemistry; 2018

Slovenian Pharmaceutical Society

Factor Xa (FXa) plays a key role in haemostasis, it is 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. Therefore, FXa is a focus target for the development anticoagulants due to its central position in the blood coagulation cascade.1 FXa has emerged as an attractive target for developing safer anticoagulant drugs. 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 warfarin. In this work novel arylazides were synthesized incorporating a lactamic ring (1) with different heteroatoms inposition 4 as starting materials for the new derivatives. The pharmacophore fragment of these compounds was considered essential to achieve the FXa inhibitor activity.2 From the arylazides synthesized in the first step, aseries of triazoles (3) were prepared using copper nanoparticles as catalyst, to obtain 1,2,3-triazoles product of the dipolar cycloaddition3 by using a variety of terminal alkynes with good yields (70-85%).In our research using the 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 present favorable π- π interactions with the S4 pocket and hydrophobic interactions produce by the aliphatic chain with residues GLY193, GLN192, CYS191, ALA190, ASP189, VAL213, SER214 and TRP215 present in S1 pocket.Moreover, FXa inhibition assays were performed in order to obtain the IC50 values of the corresponding new derivatives.