Synthesis and in vitro antiplatelet activity of new 4-(1-piperazinyl)coumarin derivatives. Human platelet phosphodiesterase 3 inhibitory properties of the two most effective compounds described and molecular modeling study on their interactions with phosphodiesterase 3A catalytic site.
The synthesis and in vitro antiplatelet activity significant data of coumarin derivatives 5i-x and quinolin-2(1H)-one derivatives 22a,b, as well as the corresponding structure-activity relationships are described. The recently reported 8-methyl-4-(1-piperazinyl)-7-(3-pyridylmethoxy)coumarin 5f and its potent 7-(2-morpholinoethoxy)-substituted new analogue 5u were notably more effective inhibitors of pure human platelet PDE3 than milrinone and cilostazol: these data were related, through a molecular modeling study, with the molecular interactions of the four compounds with the human PDE3A catalytic site.
Roma
Giorgio
G
Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV n. 3, I-16132 Genoa, Italy. roma@unige.it
Di Braccio
Mario
M
Grossi
Giancarlo
G
Piras
Daniela
D
Leoncini
Giuliana
G
Bruzzese
Debora
D
Signorello
Maria Grazia
MG
Fossa
Paola
P
Mosti
Luisa
L
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000097:blood / Q000737:chemistry; D020134:Catalytic Domain; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C521969:8-methyl-4-(1-piperazinyl)-7-(3-pyridylmethoxy)coumarin; C521970:8-methyl-7-(2-morpholinoethoxy)-4-(1-piperazinyl)-2H-1-benzopyran-2-one; D003374:Coumarins; D009025:Morpholines; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517287:PDE3A protein, human