US EPA

7458827 

Journal Article 

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

Amin, KM; Abdel Gawad, NM; Abdel Rahman, DE; El Ashry, MKM 

2014 

Yes 

Bioorganic Chemistry
ISSN: 0045-2068
EISSN: 1090-2120 

Academic Press Inc. 

52 

31-43 

English 

10.1016/j.bioorg.2013.11.002 

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. © 2013 Elsevier Inc. All rights reserved. 

Anticoagulant; Coumarin; Factor Xa; Prothrombin time; 3 (4 bromophenyl) 5 (4 chlorophenyl) n (2 oxo 2h chromen 6 yl) 4,5 dihydropyrazole 1 carboxamide; 3 (4 bromophenyl) 5 (4 methoxyphenyl) n (2 oxo 2h chromen 6 yl) 4,5 dihydropyrazole 1 carboxamide; 4 (2 oxo 2h chromen 6 yl)semicarbazide; 4 (2 oxo 2h chromen 6 ylamino) 1h imidazol 2(5h) one; 4 cyano n (2 oxo 2h chromen 6 yl)benzamide; 4 [5 (chloromethyl) 1,2,4 oxadiazol 3 yl] n (2 oxo 2h chromen 6 yl)benzamide; 4 [5 [(benzo[d]thiazol 2 ylamino)methyl] 1,2,4 oxadiazol 3 yl] n (2 oxo 2h chromen 6 yl)benzamide; 4 [amino (ethylimino) methyl] n (2 oxo 2h chromen 6 yl)benzamide; 4 [amino (hydroxyimino) methyl] n (2 oxo 2h chromen 6 yl)benzamide; 4 [amino (imino) methyl] n (2 oxo 2h chromen 6 yl)benzamide; 4 [amino (isopropylimino) methyl] n (2 oxo 2 chromen 6 yl)benzamide; 4 [amino (methylimino) methyl] n 2 (2 oxo 2h chromen 6 yl)benzamide; 4 [amino (tert butylimino) methyl] n (2 oxo 2h chromen 6 yl)benzamide; 5 (4 chlorophenyl) 3 (4 methoxyphenyl) n (2 oxo 2h chromen 6 yl) 4,5 dihydropyrazole 1 carboxamide; 5 (4 dimethylaminophenyl) n (2 oxo 2h chromen 6yl) 3 (4 methylphenyl) 4,5 dihydropyrazole 1 carboxamide; 6 (2 imino 2,5 dihydro 1h imidazol 4 ylamino) 2h chromen 2 one; 6 (2 thioxo 2,5 dihydro 1h imidazol 4 ylamino) 2h chromen 2 one; 6 aminocoumarin; 6 nitrocoumarin; amidine; anticoagulant agent; bis coumarinyl oxadiazole; blood clotting factor 10a inhibitor; coumarin derivative; coumarinyl pyrazole; n (2 oxo 2h chromen 6 yl)carbamate; razaxaban; unclassified drug; unindexed drug; warfarin; ximelagatran; acylation; alkylation; animal experiment; anticoagulant therapy; anticoagulation; article; blood clotting time; controlled study; cyclization; diazotization; drug binding site; drug screening; drug structure; drug synthesis; in vivo study; male; molecular docking; nonhuman; priority journal; prothrombin time; rat; Anticoagulant; Coumarin; Factor Xa; Prothrombin time; Animals; Anticoagulants; Binding Sites; Coumarins; Factor Xa; Fibrinolytic Agents; Male; Mice; Molecular Docking Simulation; Molecular Structure; Prothrombin Time; Structure-Activity Relationship; Warfarin