Although leishmaniasis is a major tropical disease, the currently available drugs are toxic and inadequate.We show that the antimicrotubule herbicide trifluralin has antileishmania activity. The present study aimed at deducing the relationship between the structure of the molecule and its antiprotozoan activity. Nine dinitroanilines, all of which were analogs of trifluralin, were compared. We found that pendimethalin was 2.5-fold more potent than trifluralin, and the higher efficacy may be correlated with molecular structural features that increase the accessibility to one nitro group. This association was further supported by molecular modeling. Moreover, trifluralin samples from two sources differed in their activities by more than threefold, and gas column chromatography showed that impurities were present in the more potent sample.Leishmaniasis is a major tropical disease affecting 12 million people (33). Pentavalent antimonial agents and pentamidine have been the recommended treatment for this disease since the second world war (8). However, they cause severe adverse side effects and failure of treatment is not uncommon; therefore, better, less toxic therapeutic drugs are urgently needed. We discovered that trifluralin and oryzalin, antimicrotubule dinitroaniline herbicides, inhibit leishmania proliferation and infectivity (4-7). Moreover, in addition to being effective against Leishmania spp., trifluralin is effective against the in vitro proliferation of Trypanosoma brucei trypomastigotes (6, 14) and the intraerythrocytic forms of the malaria parasite Plasmodium falciparum (22). Thus, trifluralin is effective against several species of protozoan parasites.Trifluralin and oryzalin belong to a class of compounds known as the dinitroanilines ( Fig. 1 MATERIALS AND METHODSDinitroanilines. Trifluralin and benfluralin were obtained from two sources: Dow Elanco and Riedel-de Haen. Oryzalin and ethalfluralin were provided by Dow Elanco, and dinitramine and prodiamine were provided by Sandoz. Fluchloralin, nitralin, pendimethalin, and profluralin were purchased from Riedel-de Haen through the U.S. distributor Crescent Chemicals (Hauppauge, N.Y.).Promastigote assay. Dinitroanilines were dissolved according to the following protocol. The compounds were first dissolved in acetone as a 100 mM solution. Then they were diluted in 0.1% acetone-liver infusion tryptose (27) medium that had been prewarmed to 65°C. Solutions of 1 mM (1/100 dilution) and 0.5 mM (1/2 dilution) were made from the acetone stocks and then were made to the final concentrations by using 10-fold serial dilutions.
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