Journal of Antimicrobial Chemotherapy, Vol 41, 197-205, Copyright © 1998 by The British Society for Antimicrobial Chemotherapy
A Liendo, K Lazardi and JA Urbina
We investigated the in-vitro antiproliferative effects and mechanism of
action of both enantiomers of the bis-triazole derivative ICI 195,739
against epimastigotes and amastigotes of Trypanosoma cruzi, the
aetiological agent of Chagas' disease. It has recently been shown that the
R(+) enantiomer, D0870, can induce radical parasitological cure in murine
models of the acute and chronic forms of the disease. D0870 dose-
dependently affected the growth rate of the epimastigote form (IC50 = 0.1
microM; MIC = 1-3 microM). The S(-) enantiomer was much less active (IC50 =
3 microM). Growth arrest and cell lysis induced by D0870 coincided with the
complete depletion of endogenous 4,14-desmethyl sterols and their
replacement by 4,14-trimethyl and dimethyl sterols. The S(-) enantiomer
produced qualitatively similar changes but to a lesser extent. D0870
inhibited the incorporation of radioactivity from [2-14C]acetate into the
epimastigote's 4,14-desmethyl sterols with an IC50 of 50 nM while the
corresponding concentration for the S(-) enantiomer was 3 microM. D0870
eradicated the intracellular (amastigote) form of the parasite from
cultured Vero cells at 10 nM; a 100-fold higher concentration of the S(-)
enantiomer was required to produce a similar effect, and deleterious
effects of the host cells were observed at > 100 nM. At the MIC of D0870
the endogenous amastigote sterols (ergosta-7-en-3beta-ol,
24-ethyl-cholesta-7-en-3beta- ol and ergosta-7, 24(24[1])-dien-3beta-ol)
were also largely replaced by lanosterol and 24-methyl-dihydrolanosterol.
Combinations of D0870 and inhibitors of sterol delta24(25) sterol
methyltransferase (such as 22,26-azasterol and
24(R,S),25-epiminolanosterol) acted synergically against the intracellular
forms. Taken together these results indicate that, although both
enantiomers have anti-T. cruzi activity, the specific activity of the R(+)
enantiomer (D0870) is nearly two orders of magnitude higher than that of
its S(-) analogue. However, as the in- vitro activity of D0870 is
comparable to that of standard azoles, such as ketoconazole, its remarkable
in-vivo antiparasitic activity may only be explained by its particular
pharmacokinetic properties.
ORIGINAL ARTICLES
In-vitro antiproliferative effects and mechanism of action of the bis- triazole D0870 and its S(-) enantiomer against Trypanosoma cruzi
Seccion de Parasitologia, Instituto de Zoologia Tropical, Facultad de Ciencias, Universidad Central de Venezuela, Caracas.
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