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

Author(s)

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

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 121, p. 553-560, OCT 4 2016.
• Web of Science Citations: 10

Abstract

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)

• FAPESP's process: 11/17357-3 - Relationship between molecular electronic structure, NMR parameters and conformational stability
• Grantee: Claudio Francisco Tormena
• Support Opportunities: Regular Research Grants
• FAPESP's process: 11/11499-0 - Bioisosterism in the design of new antichagasic agents: integration of computational and experimental strategies
• Grantee: Gustavo Henrique Goulart Trossini
• Support Opportunities: Regular Research Grants
• FAPESP's process: 12/21865-7 - Potential antichagasic compounds: design and synthesis of 1,2,4-triazolic bioisosteres of hydroxymethylnitrofurazone and analogues
• Grantee: Fredson Torres Silva
• Support Opportunities: Scholarships in Brazil - Master