Synthesis Docking and In Vitro Anticoagulant Activity Assay of Hybrid Derivatives of Pyrrolo321-ijQuinolin-2(1H)-one as New Inhibitors of Factor Xa and Factor XIa

摘要

Coagulation factor Xa and factor XIa are proven to be convenient and crucial protein targets for treatment for thrombotic disorders and thereby their inhibitors can serve as effective anticoagulant drugs. In the present work, we focused on the structure–activity relationships of derivatives of pyrrolo[3,2,1- ]quinolin-2(1 )-one and an evaluation of their activity against factor Xa and factor XIa. For this, docking-guided synthesis of nine compounds based on pyrrolo[3,2,1- ]quinolin-2(1 )-one was carried out. For the synthesis of new hybrid hydropyrrolo[3,2,1- ]quinolin-2(1 )-one derivatives, we used convenient structural modification of both the tetrahydro- and dihydroquinoline moiety by varying the substituents at the C positions. In vitro testing revealed that four derivatives were able to inhibit both coagulation factors and three compounds were selective factor XIa inhibitors. An IC value of 3.68 μM for was found for the best factor Xa inhibitor and 2 μM for the best factor XIa inhibitor.