Synthesis and Thrombin, Factor Xa and U46619 Inhibitory Effects of Non-Amidino and Amidino N2-Thiophenecarbonyl- and N2-Tosylanthranilamides

Abstract

Thrombin (factor IIa) and factor Xa (FXa) are key enzymes at the junction of the intrinsic and extrinsic coagulation pathways and are the most attractive pharmacological targets for the development of novel anticoagulants. Twenty non-amidino N2-thiophencarbonyl- and N2-tosyl anthranilamides 1–20 and six amidino N2-thiophencarbonyl- and N2-tosylanthranilamides 21–26 were synthesized to evaluate their activated partial thromboplastin time (aPTT) and prothrombin time (PT) using human plasma at a concentration of 30 µg/mL in vitro. As a result, compounds 5, 9, and 21–23 were selected to study the further antithrombotic activity. The anticoagulant properties of 5, 9, and 21–23 significantly exhibited a concentration-dependent prolongation of in vitro PT and aPTT, in vivo bleeding time, and ex vivo clotting time. These compounds concentration-dependently inhibited the activities of thrombin and FXa and inhibited the generation of thrombin and FXa in human endothelial cells. In addition, data showed that 5, 9, and 21–23 significantly inhibited thrombin catalyzed fibrin polymerization and mouse platelet aggregation and inhibited platelet aggregation induced by U46619 in vitro and ex vivo. Among the derivatives evaluated, N-(3′-amidinophenyl)-2-((thiophen-2′′-yl)carbonylamino)benzamide (21) was the most active compound.

Synthesis, crystal structure, Hirshfeld surface analysis, MEP study and molecular docking ofN-{3-[(4-methoxyphenyl)carbamoyl]phenyl}-3-nitrobenzamide as a promising inhibitor of hfXa

“…Some benzamide compounds are used in the area of neurology for their powerful neuroprotective effects (Hirata et al, 2018). Other diamide compounds analogous to the product obtained in this work have been tested as potential options for antithrombotic treatments by acting as direct inhibitors of coagulation factor Xa (Xing et al, 2018;Lee et al, 2017). This study was undertaken with the aim of providing new compounds with possible pharmaceutical applications.…”