In vitro antimalarial activity of chalcones and their derivatives.
A series of chalcones and their derivatives have been synthesized and identified as novel potential antimalarials using both molecular modeling and in vitro testing against the intact parasite. A large number of chalcones and their derivatives were prepared using one-step Claisen-Schmidt condensations of aldehydes with methyl ketones. These condensates were screened in vitro against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum and shown to be active at concentrations in the nanomolar range. The most active chalcone derivative, 1-(2,5-dichlorophenyl)-3-(4-quinolinyl)-2-propen-1-one (7), had an IC50 value of 200 nM against both a chloroquine-resistant strain (W2) and a chloroquine-sensitive strain (D6). The resistance indexes for all compounds were substantially lower than for chloroquine, suggesting that this series will be active against chloroquine-resistant malaria. Structure-activity relationships (SAR) of the chalcones in the context of a homology-based model structure of the malaria trophozoite cysteine protease, the most likely target enzyme, are presented.
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143-0446, USA.
R
R
Li
G L
GL
Kenyon
F E
FE
Cohen
X
X
Chen
B
B
Gong
J N
JN
Dominguez
E
E
Davidson
G
G
Kurzban
R E
RE
Miller
E O
EO
Nuzum
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism; D002599:Chalcone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D047188:Chalcones; D002738:Chloroquine / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D011485:Protein Binding; D013329:Structure-Activity Relationship
C097597:1-(2,5-dichlorophenyl)-3-(4-quinolinyl)-2-propen-1-one; D000962:Antimalarials; D047188:Chalcones; D015853:Cysteine Proteinase Inhibitors; D002599:Chalcone; D002738:Chloroquine; D002401:Cathepsin B