In vitro antiproliferative effects and mechanism of action of the new triazole derivative UR-9825 against the protozoan parasite Trypanosoma (Schizotrypanum) cruzi

We describe the in vitro antiproliferative effects of the new triazole deri vative UR-9825 against the protozoan parasite Trypanosoma (Schizotrypanum) cruzi, the causative agent of Chagas' disease in Latin America. The compoun d was found to be extremely active against the cultured (epimastigote) form of the parasite, equivalent to that present in the reduviid vector, with a MIC of 30 nM, a concentration 33-fold lower than that required with the re ference compound ketoconazole. At that MIG, growth arrest coincided with de pletion of the parasite's 4,14-desmethyl endogenous sterols (ergosterol, 24 -ethylcholesta-5,7,22-trien-3b-ol, and precursors) and their replacement by methylated sterols (lanosterol, 24-methylenedihydrolanosterol, and obtusif oliol), as revealed by high-resolution gas chromatography coupled with mass spectrometry. This indicated that the primary mechanism of action of UR-98 25 was inhibition of the parasite's sterol C14 alpha demethylase, as seen w ith other azole derivatives. The phospholipid composition of growth-arreste d epimastigotes was also altered, when compared to controls, with a signifi cant increase in the content of phosphatidylethanolamine and phosphatidylse rine and a concomitant reduction of the content of phosphatidylcholine. The clinically relevant intracellular amastigote form, grown in cultured Vero cells at 37 degrees C, was even more sensitive to UR-9825, with a MIC of 10 nM, comparable to that for ketoconazole. The results showed that UR-9825 i s among the most potent azole derivatives tested against this parasite and support in vivo studies with this compound.