Design, synthesis and antitrypanosomal activity of some nitrofurazone 1,2,4-triazolic bioisosteric analogues

Autor(es)

Silva, Fredson T. ; Franco, Caio H. ; Favaro, Denize C. ; Freitas-Junior, Lucio H. ; Moraes, Carolina B. ; Ferreira, Elizabeth I.

• Tipo de documento: Artigo Científico
• Fonte: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 121, p. 553-560, OCT 4 2016.
• Citações Web of Science: 10

Resumo

Chagas disease, caused by Trypanosoma cruzi, is a parasitosis that predominates in Latin America. It is estimated that 25 million people are under the risk of infection and, in 2008, more than 10 thousand deaths were registered. The only two drugs available in the therapeutics, nifurtimox and benznidazole, showed to be more effective in the acute phase of the disease. However, there is no standard treatment protocol effective for the chronic phase. Nitrofurazone (NF), an antimicrobial drug, has activity against T. cruzi, although being toxic. Considering the need for new antichagasic drugs, the existence of promising new therapeutic targets, as 14 alpha-sterol demethylase and cruzain, and employing the bioisosterism and molecular hybridization approaches, four novel compounds were synthesized, characterized by melting point range, elemental analysis, IR and NMR spectroscopy. The compounds were tested against T. cruzi amastigotes in infected U2OS cells. All compounds showed selectivity towards T cruzi and showed trypanomicidal activity in low micromolar range. The compound 3 showed potency similar to benznidazole, but lower efficacy. These results highlight the importance of the 1,2,4-triazole, thiosemicarbazonic and nitro group moieties for designing new efficient compounds, potentially for the chronic phase of Chagas disease. (C) 2016 Elsevier Masson SAS. All rights reserved. (AU)

• Processo FAPESP: 11/17357-3 - Estrutura eletrônica molecular e sua relação com os parâmetros de RMN e a estabilidade conformacional
• Beneficiário: Claudio Francisco Tormena
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/11499-0 - Aplicação de bioisosterismo no planejamento de agentes antichagásicos: integração entre estratégias computacionais e experimentais
• Beneficiário: Gustavo Henrique Goulart Trossini
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/21865-7 - Antichagásicos potenciais: planejamento e síntese de bioisósteros 1,2,4-triazólicos do hidroximetilnitrofural e análogos
• Beneficiário: Fredson Torres Silva
• Modalidade de apoio: Bolsas no Brasil - Mestrado