Synthesis, Docking, and In Vitro Anticoagulant Activity Assay of Hybrid Derivatives of Pyrrolo[3,2,1- ij]Quinolin-2(1 H)-one as New Inhibitors of Factor Xa and Factor XIa

Molecules. 2020 Apr 19;25(8):1889. doi: 10.3390/molecules25081889.

Abstract

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-ij]quinolin-2(1H)-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-ij]quinolin-2(1H)-one was carried out. For the synthesis of new hybrid hydropyrrolo[3,2,1-ij]quinolin-2(1H)-one derivatives, we used convenient structural modification of both the tetrahydro- and dihydroquinoline moiety by varying the substituents at the C6,8,9 positions. In vitro testing revealed that four derivatives were able to inhibit both coagulation factors and three compounds were selective factor XIa inhibitors. An IC50 value of 3.68 μM for was found for the best factor Xa inhibitor and 2 μM for the best factor XIa inhibitor.

Keywords: anticoagulants; factor XIa; factor Xa; molecular docking; pyrroloquinolinones.

MeSH terms

  • Anticoagulants
  • Drug Design
  • Factor XIa / antagonists & inhibitors
  • Factor XIa / chemistry*
  • Factor Xa / chemistry*
  • Factor Xa Inhibitors / chemistry*
  • Hydrogen Bonding
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry*
  • Quinolines / chemical synthesis
  • Quinolines / chemistry*
  • Structure-Activity Relationship

Substances

  • Anticoagulants
  • Factor Xa Inhibitors
  • Pyrroles
  • Quinolines
  • pyrroloquinoline
  • Factor XIa
  • Factor Xa