ABSTRACT
Three Annonaceous acetogenins exhibited in vitro antimalarial activities on a chloroquine-resistant Plasmodium falciparum strain, with IC50s ranging from 5 to 10 microM. Structure-activity relationships showed that maximal antimalarial activity occurred in the presence of at least one tetrahydrofuran moiety and a synergistic action with chloroquine was observed. These acetogenins partially inhibited the P. falciparum adenylate translocase.
Subject(s)
Aminoquinolines/pharmacology , Antimalarials/pharmacology , Electron Transport Complex I/antagonists & inhibitors , Fatty Alcohols/pharmacology , Lactones/pharmacology , Plant Extracts/pharmacology , Plasmodium falciparum/drug effects , Plasmodium falciparum/enzymology , Acetogenins , Aminoquinolines/chemistry , Animals , Antimalarials/chemistry , Drug Resistance, Microbial , Humans , Malaria, Falciparum/drug therapy , Malaria, Falciparum/microbiology , Microbial Sensitivity Tests , Mitochondrial ADP, ATP Translocases/antagonists & inhibitors , Mitochondrial ADP, ATP Translocases/metabolism , Plasmodium falciparum/isolation & purification , Sensitivity and Specificity , Structure-Activity RelationshipABSTRACT
Gossypol, a disesquiterpene extracted from cotton seeds, is known to inhibit strongly the Plasmodium falciparum lactate dehydrogenase, but its high toxicity has stopped any antimalarial drug development. A series of Schiffs bases was synthesized from gossypol by modification of the aldehyde groups responsible for its toxicity. A total of 13 compounds showing low cytotoxicity were then selected and were compared with gossypol for activity against 2 chloroquine-resistant strains of P. falciparum (PFB, FCB1). These in vitro activities were evaluated using an isotope-based drug-susceptibility semiautomated microdilution test followed by determination of IC50 values (50% inhibitory concentration). In all, 12 of the 13 compounds tested were active; 3 of them displayed antimalarial activity comparable with that of gossypol itself.
