Design, synthesis and biological evaluation of Piperazinylanthranilamides as potential factor Xa inhibitors

Abstract

Direct inhibition of FXa has emerged as an effective strategy to achieve anticoagulation maintaining normal hemostasis with minimal bleeding risks. A novel series of anthranilamide derivatives have been designed and synthesized wherein the bonding order of carbonyl and amino groups of both P1 and P4 motifs in the anthranilamide core structure has been reversed. In order to improve the selectivity for FXa, haloaromatic groups present in the reported FXa inhibitors were retained, while substituted phenylpiperazinylamides were used as S4 binding ligands to improve the physicochemical properties of the resulting compounds. Compounds (6y and 7f) exhibited the most potent FXa inhibitory activities with IC50 values of 0.6 µM and 0.74 µM exhibiting high selectivity over thrombin. Both compounds displayed good anticoagulant activity in rats. Compound (6y) displayed a safety profile similar to the standard drug rivaroxaban in bleeding risk assessment. Simulation studies like molecular docking and molecular dynamics supported strong binding of the analogs to the enzyme FXa