Design, synthesis and antitrypanosomal activity of some nitrofurazone 1,2,4-triazolic bioisosteric analogues.
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 14α-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.
School of Pharmaceutical Sciences, University of São Paulo, Avenida Prof. Lineu Prestes, 580, Bl. 13, São Paulo, São Paulo, Brazil.
Fredson T
FT
Silva
National Laboratory of Biosciences, National Center for Research on Energy and Materials, Rua Giuseppe Máximo Scolfaro, 10000, Campinas, São Paulo, Brazil.
Caio H
CH
Franco
Institute of Chemistry, University of São Paulo, Avenida Prof. Lineu Prestes, 748, São Paulo, São Paulo, Brazil; Department of Chemistry, Institute of Exact Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Denize C
DC
Favaro
National Laboratory of Biosciences, National Center for Research on Energy and Materials, Rua Giuseppe Máximo Scolfaro, 10000, Campinas, São Paulo, Brazil.
Lucio H
LH
Freitas-Junior
National Laboratory of Biosciences, National Center for Research on Energy and Materials, Rua Giuseppe Máximo Scolfaro, 10000, Campinas, São Paulo, Brazil.
Carolina B
CB
Moraes
School of Pharmaceutical Sciences, University of São Paulo, Avenida Prof. Lineu Prestes, 580, Bl. 13, São Paulo, São Paulo, Brazil. Electronic address: hajudan@usp.br.
Elizabeth I
EI
Ferreira
D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D006835:Hydrazones / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D009583:Nitrofurazone / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000737:chemistry*; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
D006835:Hydrazones; D014230:Triazoles; D014344:Trypanocidal Agents; C045575:1,2,4-triazole; D009583:Nitrofurazone
Bioisosterism; Chagas disease; Molecular hybridization; Nitroheterocyclic compounds