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Eur J Med Chem. 2014 Jan;71:282-9. doi: 10.1016/j.ejmech.2013.11.011. Epub 2013 Nov 16.

Synthesis and evaluation of the antiparasitic activity of bis-(arylmethylidene) cycloalkanones.

Author information

  • 1Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Belo Horizonte 31.270-901, MG, Brazil.
  • 2Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Belo Horizonte 31.270-901, MG, Brazil.
  • 3Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
  • 4Centro de Pesquisas René Rachou, FIOCRUZ, Avenida Augusto de Lima, 1.715, Barro Preto, Belo Horizonte 30.190-002, MG, Brazil.
  • 5Departamento de Microbiologia, Imunologia e Parasitologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Setor F, Bloco A, Florianópolis 88.040-970, SC, Brazil.
  • 6Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Belo Horizonte 31.270-901, MG, Brazil. Electronic address: renatabo@farmacia.ufmg.br.

Abstract

A series of bis-(arylmethylidene)-cycloalkanones was synthesized by cross-aldol condensation. The activity of the compounds was evaluated against amastigotes forms of Trypanosoma cruzi and promastigotes forms of Leishmania amazonensis. The cytotoxicity of the active compounds on uninfected fibroblasts or macrophages was established in vitro to evaluate the selectivity of their antiparasitic effects. Six compounds displayed trypanocidal activity against amastigotes intracellular forms of T. cruzi with IC₅₀ values ranging from 7.0 to 249 μM. Besides these six compounds, eight other molecules exhibited significant leishmanicidal activity (IC₅₀ values ranging from 0.6 to 110.4 μM). Two compounds can be considered as promising antiparasitic lead molecules because they showed IC₅₀ values in the low-micromolar range (≤1.2 μM) with an adequate SI (≥19.9). To understand the mechanism of action of these compounds, two possible molecular targets were investigated: trypanothione reductase (TR) and cruzain.

Copyright © 2013 Elsevier Masson SAS. All rights reserved.

KEYWORDS:

Antileishmanial activity; BJGPXDMLZSYWLM-OZNQKUEASA-N; BRBMTEYZYVZFJD-IWGRKNQJSA-N; Bis-(arylmethylidene)-cycloalkanones; CETXDHNPPYXEOF-OZNQKUEASA-N; CTKKGXDAWIAYSA-JSAVKQRWSA-N; CVTOCKKPVXJIJK-HBKJEHTGSA-N; CYVVJSKZRBZHAV-UNZYHPAISA-N; DYLUMQZRSQEPTH-UHFFFAOYSA-N; GPXHIYXWGUYGHF-MXWIWYRXSA-N; IEJNKQYBMJIRJU-MXWIWYRXSA-N; IXIITVGWLWCRQL-IWGRKNQJSA-N; Leishmania amazonensis; MFRNIFJHZVDERH-UHFFFAOYSA-N; MOGZMXKHFUIRHE-RYQLWAFASA-N; OPTXWXOODPUHHD-UHFFFAOYSA-N; QBJZDRXWVFLWLM-AYKLPDECSA-N; SGFZCAFEUGISMF-WXGDAXOSSA-N; Trypanocidal; Trypanosoma cruzi; UKIUACHVRRQMGB-DCIPZJNNSA-N; UMLFTCYAQPPZER-UHFFFAOYSA-N; VJTIKIQJUZWNSW-JOBJLJCHSA-N; WRGGDYGLRCBKGJ-NWILIBCHSA-N; XRJCFZUOXQVWGF-NWILIBCHSA-N; XYPVBKDHERGKJG-UHFFFAOYSA-N; ZXCMCPINSJLVEY-WGDLNXRISA-N

PMID:
24321832
[PubMed - indexed for MEDLINE]
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