Amide-functionalized 1,2,4-Triazol-5-amines as Covalent Inhibitors of Blood Coagulation Factor XIIa and Thrombin

To counteract thrombosis,
new safe and efficient antithrombotics
are required. We herein report the design, synthesis, and biological
activity of a series of amide-functionalized acylated 1,2,4-triazol-5-amines
as selective inhibitors of blood coagulation factor XIIa and thrombin.
The introduction of an amide moiety into the main scaffold of 3-aryl
aminotriazoles added certain three-dimensional properties to synthesized
compounds and allowed them to reach binding sites in FXIIa and thrombin
previously unaddressed by non-functionalized 1,2,4-triazol-5-amines.
Among synthesized compounds, one quinoxaline-derived aminotriazole
bearing N-butylamide moiety inhibited FXIIa with
the IC50 value of 28 nM, whereas the N-phenylamide-derived aminotriazole inhibited thrombin with the IC50 value of 41 nM. Performed mass-shift experiments and molecular
modeling studies proved the covalent mechanism of FXIIa and thrombin
inhibition by synthesized compounds. In plasma coagulation tests,
developed aminotriazoles showed anticoagulant properties mainly affecting
the intrinsic blood coagulation pathway, activation of which is associated
with thrombosis but is negligible for hemostasis.