This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow An erratum has been published
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Urbina, J. A.
Right arrow Articles by Bartrolí, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Urbina, J. A.
Right arrow Articles by Bartrolí, J.

 Previous Article  |  Next Article 

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.


This article has been cited by other articles:

  • Gonzalez, G. M., Robledo, E., Garza-Gonzalez, E., Elizondo, M., Gonzalez, J. G. (2009). Efficacy of Albaconazole against Candida albicans in a Vaginitis Model. Antimicrob. Agents Chemother. 53: 4540-4541 [Abstract] [Full Text]  
  • Pasqualotto, A. C., Denning, D. W. (2008). New and emerging treatments for fungal infections. J Antimicrob Chemother 61: i19-i30 [Abstract] [Full Text]  
  • Cammerer, S. B., Jimenez, C., Jones, S., Gros, L., Lorente, S. O., Rodrigues, C., Rodrigues, J. C. F., Caldera, A., Ruiz Perez, L. M., da Souza, W., Kaiser, M., Brun, R., Urbina, J. A., Gonzalez Pacanowska, D., Gilbert, I. H. (2007). Quinuclidine Derivatives as Potential Antiparasitics. Antimicrob. Agents Chemother. 51: 4049-4061 [Abstract] [Full Text]  
  • Ferraz, M. L., Gazzinelli, R. T., Alves, R. O., Urbina, J. A., Romanha, A. J. (2007). The Anti-Trypanosoma cruzi Activity of Posaconazole in a Murine Model of Acute Chagas' Disease Is Less Dependent on Gamma Interferon than That of Benznidazole. Antimicrob. Agents Chemother. 51: 1359-1364 [Abstract] [Full Text]  
  • Senkovich, O., Bhatia, V., Garg, N., Chattopadhyay, D. (2005). Lipophilic Antifolate Trimetrexate Is a Potent Inhibitor of Trypanosoma cruzi: Prospect for Chemotherapy of Chagas' Disease. Antimicrob. Agents Chemother. 49: 3234-3238 [Abstract] [Full Text]  
  • Guedes, P. M. d. M., Urbina, J. A., de Lana, M., Afonso, L. C. C., Veloso, V. M., Tafuri, W. L., Machado-Coelho, G. L. L., Chiari, E., Bahia, M. T. (2004). Activity of the New Triazole Derivative Albaconazole against Trypanosoma (Schizotrypanum) cruzi in Dog Hosts. Antimicrob. Agents Chemother. 48: 4286-4292 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»