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JAC Advance Access published online on May 15, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl180
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received October 17, 2005
Revised January 16, 2006
Accepted April 10, 2006

Original article

Antiproliferative activities of two novel quinuclidine inhibitors against Toxoplasma gondii tachyzoites in vitro

Érica S. Martins-Duarte 1, Julio A. Urbina 2, Wanderley de Souza 1, and Rossiane C. Vommaro 1 *

1 Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, CCS Universidade Federal do Rio de Janeiro, 21949-900-Rio de Janeiro-RJ, Brazil
2 Laboratório de Química Biológica, Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Apartado 21827, Caracas 1020A, Venezuela

* To whom correspondence should be addressed.
Rossiane C. Vommaro, E-mail: vommaro{at}biof.ufrj.br


  Abstract

Objectives: To study the antiproliferative effects of ER119884 and E5700, two quinuclidine-based inhibitors of squalene synthase (SQS), against Toxoplasma gondii tachyzoites in epithelial cells.

Methods: The antiproliferative effects of the quinuclidine derivatives, alone or in combination with epiminolanosterol or antifolates, were analysed, resulting in the construction of isobolograms. The ultrastructure of treated tachyzoites was analysed by transmission electron microscopy.

Results: The quinuclidine derivatives demonstrated selective anti-T. gondii activity, arresting parasite growth with IC50 values of 0.66 and 0.23 µM for ER119884 and E5700, respectively, after 24 h of interaction and 0.44 and 0.19 µM after 48 h of interaction. Both compounds induced remarkable alterations in the parasite ultrastructure, such as mitochondrial swelling and the presence of autophagosome-like structures, after 24 h of treatment. Combination of these quinuclidine derivatives with the antifolates sulfadiazine and pyrimethamine produced a synergic effect. When epiminolanosterol was combined with E5700, the effect observed was synergic, whereas the combination with ER119884 produced no interaction.

Conclusions: E5700 and ER119884 demonstrated selective activity against T. gondii tachyzoites and are a possible alternative to be used in association with the current therapy. The ultrastructural alterations observed suggest a possible interference with lipid metabolism.

Keywords: Apicomplexa; chemotherapy; ultrastructure; antifolates; sterol biosynthesis inhibitors.
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J. C. Fernandes Rodrigues, J. L. Concepcion, C. Rodrigues, A. Caldera, J. A. Urbina, and W. de Souza
In Vitro Activities of ER-119884 and E5700, Two Potent Squalene Synthase Inhibitors, against Leishmania amazonensis: Antiproliferative, Biochemical, and Ultrastructural Effects
Antimicrob. Agents Chemother., November 1, 2008; 52(11): 4098 - 4114.
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