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Antimicrobial Agents and Chemotherapy, September 2000, p. 2498-2502, Vol. 44, No. 9
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

In Vitro Antiproliferative Effects and Mechanism of Action of the New Triazole Derivative UR-9825 against the Protozoan Parasite Trypanosoma (Schizotrypanum) cruzi

Julio A. Urbina,1,* Renee Lira,1 Gonzalo Visbal,1 and Javier Bartrolí2

Laboratorio de Química Biológica, Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Caracas 1020A, Venezuela,1 and Research Center, Uriach & Cia, 08026 Barcelona, Spain2

Received 27 January 2000/Returned for modification 4 May 2000/Accepted 20 June 2000

We describe the in vitro antiproliferative effects of the new triazole derivative UR-9825 against the protozoan parasite Trypanosoma (Schizotrypanum) cruzi, the causative agent of Chagas' disease in Latin America. The compound 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 reference compound ketoconazole. At that MIC, growth arrest coincided with depletion 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 obtusifoliol), as revealed by high-resolution gas chromatography coupled with mass spectrometry. This indicated that the primary mechanism of action of UR-9825 was inhibition of the parasite's sterol C14alpha demethylase, as seen with other azole derivatives. The phospholipid composition of growth-arrested epimastigotes was also altered, when compared to controls, with a significant increase in the content of phosphatidylethanolamine and phosphatidylserine and a concomitant reduction of the content of phosphatidylcholine. The clinically relevant intracellular amastigote form, grown in cultured Vero cells at 37°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 is among the most potent azole derivatives tested against this parasite and support in vivo studies with this compound.

* Corresponding author. Mailing address: Laboratorio de Química Biológica, Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigacíones Científicas, Apartado 21827, Caracas 1020A, Venezuela. Phone: 58-2-5041479. Fax: 58-2-5041093. E-mail: jaurbina{at}cbb.ivic.ve.

Antimicrobial Agents and Chemotherapy, September 2000, p. 2498-2502, Vol. 44, No. 9
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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