Coumarin, chromone, and 4(3H)-pyrimidinone novel bicyclic and tricyclic derivatives as antiplatelet agents: synthesis, biological evaluation, and comparative molecular field analysis.
As a further part of our chemical and biological studies in this field, we describe the multistep preparations of the properly substituted 2-(1-piperazinyl)chromone 1b, 4-(1-piperazinyl)coumarins 5c-h, their linear benzo-fused analogues 4a,b and 8a,b, bicyclic (15e-g) and tricyclic (15h,i) fused derivatives of 6-(1-piperazinyl)pyrimidin-4(3H)-one, and of the 4H-pyrido[1,2-a]pyrimidine derivatives 9b,c. The in vitro evaluation of their inhibitory properties towards human platelet aggregation induced in platelet-rich plasma by ADP, collagen, or the Ca (2+)ionophore A23187 showed the high activity of compounds 5d-g and 15f,g,i, among which the coumarins 5g and 5d proved to be, in that order, the most effective in vitro antiplatelet agents until now synthesized by us. Thus, in order to consider also the 4-aminocoumarin structural class, we developed a new statistically significant 3-D QSAR model, more general than the one previously obtained, through a further CoMFA study based on the antiplatelet activity data and molecular steric and electrostatic potentials of both the previously studied and herein described compounds.
Roma
Giorgio
G
Dipartimento di Scienze Farmaceutiche, Università di Genova, viale Benedetto XV, 16132 Genoa, Italy. roma@unige.it
Braccio
Mario Di
MD
Carrieri
Antonio
A
Grossi
Giancarlo
G
Leoncini
Giuliana
G
Grazia Signorello
Maria
M
Carotti
Angelo
A
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002867:Chromones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003094:Collagen / Q000494:pharmacology; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity; D013237:Stereoisomerism
D002867:Chromones; D003374:Coumarins; D010975:Platelet Aggregation Inhibitors; D011744:Pyrimidinones; D000001:Calcimycin; D000244:Adenosine Diphosphate; D003094:Collagen