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Potential antichagasic agents: mutual prodrugs of hydroxymethylnitrofurazone and of nitric oxide releasing group

Grant number: 09/06489-6
Support type:Scholarships in Brazil - Master
Effective date (Start): November 01, 2009
Effective date (End): February 28, 2011
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Elizabeth Igne Ferreira
Grantee:Ricardo Augusto Massarico Serafim
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Chagas disease is a pathology caused by Trypanosoma cruzi. Nowadays, 21 countries have been considered as endemic regions, where 28 million people live under the risk of being infected, 15 million people are infected and more than 41 thousands new cases are registered each ear. However, there are only two drugs available, nifurtimox and benznidazole, which show many side-effects. In Brazil, only the later has been used. This scarce therapeutic armamentarium against Chagas disease lead to the importance of searching for more effective chemotehrapeutic agents for its treatment. This said, the objective of this project comprehends the synthesis of dual activity compounds against T. cruzi, by means of the prodrug design, in which the active compounds are nitroheterocyclic derivative bioisosteres, that have been synthesized in our research group. The proposed derivatives are mutual prodrugs of hydroxymethyl nitrofurazone and of its bioisosteres, which have been promising as cruzain inhibitors, with groups that release nitric oxide. The resultant prodrugs can act by inhibiting cruzain and by cytotoxicity caused by the released nitric oxide. The compounds will be evaluated as enzyme inhibitors, and in epimastigotes/tripomastigotes and in macrophage and fibroblast toxicity assays. (AU)