Synthesis of Quinolinyl Chalcones and Evaluation of Their Antimalarial Activity.-Quinolinyl chalcones (III) are prepared by the Claisen-Schmidt condensation and evaluated for activity against the P. falciparum cystein protease falcipain and activity against cultured P. falciparum parasites. Active chalcones inhibit the activity of falcipain at mid-micromolar concentrations, with (IIIc) as the most potent compound. Additionally, two compounds are tested for in vivo efficacy in a rodent P. berghei model. The mechanism of action is not clear because the activity does not correlate with the inhibition of falcipain. -(DOMINGUEZ, JOSE N.; CHARRIS, JAIME E.; LOBO, GRICELA; DE DOMINGUEZ, NEIRA GAMBOA; MORENO, MARIA M.; RIGGIONE, FLAVIA; SANCHEZ, ERLINDA; OLSON, JED; ROSENTHAL, PHILIP J.; Eur.
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.
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