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

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.

Structural Fractal Analysis of the Active Site of Acetylcholinesterase in Complexes with Huperzine A, Galantamine, and Donepezil

“…[17,59] As an AS model, we used the following series of ten AARs: Arg37, His38, Leu39, His57, Tyr59, Tyr143, Asp189, Ser195, Gly218 and Tyr228. [59,60] The results of fractal analysis of AS are presented in Tables S3 and S4 and Figure 5. As follows from these data, structural changes are only observed in the van der Waals region of IDH, and they are related to two AARs, namely, Asp189 и Arg37.…”

In Search of Non-covalent Inhibitors of SARS-CoV-2 Main Protease: Computer Aided Drug Design Using Docking and Quantum Chemistry

“…The compounds are small drug-like molecules. Among them there are hydroquinoline derivatives with antibacterial, antifungal, anticoagulant activity [22,25,34,37,38], aminopyrimidines and pyrrolo[3,2,1-ij]quinolin-2-ones, which are factor Xa and protein kinases inhibitors [50,54], various plant growth stimulants of the getarylcarboxylic acid class [63,64].…”

“…SOL was used for CSAR 2011-2012 docking competition with other docking programs Gold, AutoDock, AutoDock Vina, ICMVLS, Glide and others and for two of three target-proteins SOL results are among the best ones [8,53]. SOL is successfully used for development of new inhibitors of several targets with the experimental in vitro confirmation: thrombin [45], urokinase (uPA) [4,55] and the blood coagulation factors Xa and XIa [22,38,54]. SOL is adapted to screen large databases of ligands on Lomonosov supercomputer [62] of M.V.…”

Recent Trends in Enzyme Inhibition and Activation in Drug Design

“…Thus a series of pyrrolo [3,2,1-ij]quinolin-2(1H)-one was synthesized, studied their structure-activity relationships and evaluated their inhibitory activity as inhibitors of coagulation factors Xa and XIa. Four derivatives were able to inhibit both factors Xa and XIa with IC50 of 3.68 µM and 2 µM for the best two Xa and XIa inhibitors respectively [18].…”