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.

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From the Walter Reed Army Institute of Research (WRAIR) inventory, thirteen 8-aminoquinoline analogs of primaquine were selected for screening against a panel of seven Plasmodium falciparumclones and isolates. Six of the 13 8-aminoquinolines had average 50% inhibitory concentrations between 50 and 100 nM against these P. falciparum clones and were thus an order of magnitude more potent than primaquine. However, excluding chloroquine-resistant clones and isolates, these 8-aminoquinolines were all an order of magnitude less potent than chloroquine. None of the 8-aminoquinolines was cross resistant with either chloroquine or mefloquine. In contrast to the inactive primaquine prototype, 8 of the 13 8-aminoquinolines inhibited hematin polymerization more efficiently than did chloroquine. Although alkoxy or aryloxy substituents at position 5 uniquely endowed these 13 8-aminoquinolines with impressive schizontocidal activity, the structural specificity of inhibition of both parasite growth and hematin polymerization was low.

To diagnose symptomatic visceral leishmaniasis (kala-azar) using peripheral blood rather than tissue aspirates, a polymerase chain reaction (PCR) technique was developed for which the detection limit is 1 Leishmania-infected macrophage in 8 mL of blood. For Indian, Kenyan, or Brazilian patients with parasitologically confirmed kala-azar, 57 of 63 cases before treatment had blood that was PCR-positive (90% sensitivity). None of 40 clinically healthy persons had PCR-positive blood (100% specificity). Twelve (92%) of 13 clinically cured Indian patients had negative PCR reactions 1-6 months after treatment. This PCR procedure can provide a parasitologic diagnosis for the vast majority of kala-azar cases before therapy, may identify patients who have been successfully treated by chemotherapy, and should substantially reduce the need for invasive tests.