Enantioselective Synthesis, Computational Molecular Docking and In Vitro Anticoagulant Activity of Warfarin-based Derivatives

Abstract

Abstract: Warfarin containing a 4-hydroxycoumarin moiety possesses excellent anticoagulant activity, with the (S) enantiomer being the eutomer. The present work is designed to synthesize warfarin based derivatives enantioselectivity to explore their anticoagulant potential. The substituted chalcones were reacted with 4-hydroxycoumarin in the presence of the chiral organocatalyst 9-amino-9-deoxyepiquinine to afford warfarin-based analogues 5a- 5k. The structures of synthesized compounds 5a-5k were confirmed by Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance spectroscopy (1H NMR), carbon-13 nuclear magnetic resonance spectroscopy (13C NMR) and electron ionization mass spectroscopy (EIMS) data. The enantiomeric excess (ee) has been found in the range of 16-99% as determined by chiral high-performance liquid chromatography (HPLC) analysis. The in vitro anticoagulant activity of the products 5a-5k was evaluated by plasma recalcification time (PRT) method, and it was found that most of the derivatives showed good anticoagulant activity, specifically compound 5b exhibited excellent results compared to that of warfarin. Compound 5b displayed an IC50 value of 249.88 μM, which is better than that of warfarin (IC50 408.70 μM). The molecular docking studies have been performed against vitamin K epoxide reductase with PDBID 3kp9. The synthesized compounds bind well in the active binding site of the target enzyme. The derivative 5b showed π-π stacking interactions with the amino acid phenylalanine (Phe 114). The antimicrobial activity of synthesized compounds has also been evaluated, and results showed moderate antimicrobial activity. Based on our results, it is proposed that derivative 5b may act as a lead compound to design more potent anticoagulant derivatives.