Antiproliferative activities of two novel quinuclidine inhibitors against Toxoplasma gondii tachyzoites in vitro.
OBJECTIVE
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 microM for ER119884 and E5700, respectively, after 24 h of interaction and 0.44 and 0.19 microM 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.
Martins-Duarte
Erica S
ES
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.
Urbina
Julio A
JA
de Souza
Wanderley
W
Vommaro
Rossiane C
RC
D000818:Animals; D002460:Cell Line; D003049:Coccidiostats / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000166:cytology; D008253:Macaca mulatta; D011725:Pyridines / Q000494:pharmacology*; D011812:Quinuclidines / Q000494:pharmacology*; D014122:Toxoplasma / Q000166:cytology / Q000187:drug effects*
C489151:3-((2-benzyl-6-(3-hydroxy-4-methoxypyrrolidin-1-yl)pyridin-3-yl)ethynyl)quinuclidin-3-ol; C489152:3-((2-benzyl-6-(3-methoxypropyloxy)pyridin-3-yl)ethynyl)quinuclidin-3-ol; D003049:Coccidiostats; D011725:Pyridines; D011812:Quinuclidines