New series of 6-substituted coumarin derivatives as effective factor Xa inhibitors: Synthesis, in vivo antithrombotic evaluation and molecular docking

• New Coumarin derivatives were synthesized and characterized.
• The most active congeners presented prothrombin time values comparable to warfarin.
• Most compounds shared binding interactions with FXa similar to inhibitor RPR200095.

Despite recent progress in antithrombotic therapy, there’s still an unmet medical need for safe and orally available anticoagulants. Encouraged by the marked antithrombotic and anticoagulant activities of some coumarin derivatives, twenty-three new N-coumarinyl-4-amidinobenzamides 4a–f and 6-heterocycle substituted coumarin derivatives 5, 6a,b, 10a–e, 12a–e and 14a–d were synthesized and evaluated for their in vivo antithrombotic activity. The most active congeners were the unsubstituted amidine 4a (36.5 s), coumarinyl oxadiazole 5 (42.3 s), bis coumarinyl oxadiazole 6b (37.8 s) and coumarinyl pyrazole 10b (38.5 s) that presented prothrombin time (PT) values comparable to the reference drug warfarin (42.3 s). Furthermore, docking studies were undertaken to gain insight into the possible binding mode of these compounds with the coagulation factor Xa (FXa) binding site.

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