Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 20, Issue 5, Pages 1760-1766Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2012.01.009
Keywords
Trypanothione reductase; Mesoionic compounds; Leishmania sp.; Trypanosoma cruzi
Funding
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
- Conselho Nacional de Desenvolvimento Cientiifico e Tecnologico (CNPq)
- Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)
- Fundacao Oswaldo Cruz (FIOCRUZ)
- INCT-INOFAR
- Fundacao para a Ciencia e Tecnologia
- Instituto de Biologia Molecular e Celular of Universidade do Porto
- COSTDrugs2
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The biological activities of a series of mesoionic 1,3,4-thiadiazolium-2-aminide derivatives have been studied. The most active compounds (MI-HH; MI-3-OCH3; MI-4-OCH3 and MI-4-NO2) were evaluated to determine their effect on trypanothione reductase (TryR) activity in Leishmania sp. and Trypanosoma cruzi. Among the assayed compounds, only MI-4-NO2 showed enzyme inhibition effect on extracts from different cultures of parasites, which was confirmed using the recombinant enzyme from T. cruzi (TcTryR) and Leishmania infantum (LiTryR). The enzyme kinetics determined with LiTryR demonstrated a non-competitive inhibition profile of MI-4-NO2. A molecular docking study showed that the mesoionic compounds could effectively dock into the substrate binding site together with the substrate molecule. The mesoionic compounds were also effective ligands of the NADPH and FAD binding sites and the NADPH binding site was predicted as the best of all three binding sites. Based on the theoretical results, an explanation at the molecular level is proposed for the MI-4-NO2 enzyme inhibition effect. Given TryR as a molecular target, it is important to continue the study of mesoionic compounds as part of a drug discovery campaign against Leishmaniasis or Chagas' disease. (C) 2012 Elsevier Ltd. All rights reserved.
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