title: New series of 6-substituted coumarin derivatives as effective factor Xa inhibitors: synthesis, in vivo antithrombotic evaluation and molecular docking.
abstract: 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.
authors: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt.
authors: Kamelia M
authors: KM
authors: Amin
authors: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt.
authors: Nagwa M
authors: NM
authors: Abdel Gawad
authors: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt. Electronic address: doaaezzat2004@yahoo.com.
authors: Doaa E
authors: DE
authors: Abdel Rahman
authors: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt.
authors: Mohamed K M
authors: MK
authors: El Ashry
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D003374:Coumarins / Q000737:chemistry*; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011517:Prothrombin Time; D013329:Structure-Activity Relationship; D014859:Warfarin / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D003374:Coumarins; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D014859:Warfarin; C030123:coumarin; D015951:Factor Xa
keywords: Anticoagulant; Coumarin; Factor Xa; Prothrombin time