Indirubin derivatives are potent and selective anti-Trypanosoma cruzi agents.

Abstract:

:Current treatment for combatting Chagas disease, a life-threatening illness caused by the kinetoplastid protozoan parasite Trypanosoma cruzi is inadequate, and thus the discovery of new antiparasitic compounds is of prime importance. Previous studies identified the indirubins, a class of ATP kinase inhibitors, as potent growth inhibitors of the related kinetoplastid Leishmania. Herein, we evaluated the inhibitory activity of a series of 69 indirubin analogues screened against T. cruzi trypomastigotes and intracellular amastigotes. Seven indirubins were identified as potent T. cruzi inhibitors (low μΜ, nM range). Cell death analysis of specific compounds [3'oxime-6-bromoindirubin(6-BIO) analogues 10, 11 and 17, bearing a bulky extension on the oxime moiety and one 7 substituted analogue 32], as evaluated by electron microscopy and flow cytometry, showed a different mode of action between compound 32 compared to the three 6-BIO oxime- substituted indirubins, suggesting that indirubins may kill the parasite by different mechanisms dependent on their substitution. Moreover, the efficacy of four compounds that show the most potent anti-parasitic effect in both trypomastigotes and intracellular amastigotes (10, 11, 17, 32), was evaluated in a mouse model of T. cruzi infection. Compound 11 (3'piperazine-6-BIO) displayed the best in vivo efficacy (1/6 mortality, 94.5% blood parasitaemia reduction, 12 dpi) at a dose five times reduced over the reference drug benznidazole (20 mg/kg vs100 mg/kg). We propose 3'piperazine-6-BIO as a potential lead for the development of new treatments of Chagas disease.

journal_name

Virulence

journal_title

Virulence

authors

Efstathiou A,Meira CS,Gaboriaud-Kolar N,Bastos TM,Rocha VPC,Vougogiannopoulou K,Skaltsounis AL,Smirlis D,Soares MBP

doi

10.1080/21505594.2018.1532242

subject

Has Abstract

pub_date

2018-01-01 00:00:00

pages

1658-1668

issue

1

eissn

2150-5594

issn

2150-5608

journal_volume

9

pub_type

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