English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

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 &gt; 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.

In-vitro antiproliferative effects and mechanism of action of the bis- triazole D0870 and its S(-) enantiomer against Trypanosoma cruzi