Synthesis and antimalarial activity of substituted pyrazole derivatives.
The development of new antimalarial drugs is an urgent priority considering the increasing prevalence of drug-resistant Plasmodium falciparum parasites. A series of pyrazoles are described as part of efforts directed toward the synthesis of some potent antimalarial agents. The replacement of the ester group as a substituent in the pyrazole ring by nitrile group caused a precipitous loss of activity as antimalarial due to the lack of hydrogen-bond formation. Further modification of the heterocyclic ring to give substituted aryl derivatives afforded potent antimalarial derivatives: methyl 5-amino-3-anisidinepyrazole-4-carboxylic acid 3a (IC50: 0.149 mumol/l) and methyl 5-amino-3-(m anisidin)pyrazole-4-carboxylic acid 3c (IC50: 0.15 mumol/l). The synthesis, structure-activity relationships (SAR), X-ray crystallography and pharmacological activity associated with these series of compounds are discussed.
Laboratorio de Síntesis Orgánica, Facultad de Farmacia, Universidad Central de Venezuela. dominguj@camelot.rect.ucv.ve
José N
JN
Domínguez
Jaime E
JE
Charris
Mario
M
Caparelli
Flavia
F
Riggione
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004912:Erythrocytes / Q000469:parasitology; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
D000962:Antimalarials; D007202:Indicators and Reagents; D011720:Pyrazoles