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SYNTHESIS OF A SUGAR-BASED THIOSEMICARBAZONE SERIES AND STRUCTURE-ACTIVITY RELATIONSHIP VERSUS THE PARASITE CYSTEINE PROTEASES: RHODESAIN; CRUZAIN AND SCHISTOSOMA MANSONI CATHEPSIN B1
Fonseca, Nayara Cristina et al. | Fecha del documento: 2015
Autor
Fonseca, Nayara Cristina
Cruz, Luana Faria da
Villela, Filipe da Silva
Pereira, Glaécia Aparecida do Nascimento
Siqueira Neto, Jair Lage de
Kellar, Danielle
Suzuki, Brian M.
Ray, Debalina
Souza, Thiago Belarmino de
Alves, Ricardo José
Sales Júnior, Policarpo Ademar
Romanha, Alvaro José
Murta, Silvane Maria Fonseca
McKerrow, James H.
Caffrey, Conor R.
Oliveira, Renata Barbosa de
Ferreira, Rafaela Salgado
Afiliación
Universidade Federal de Minas Gerais. Faculdade de Farmácia. Departamento de Produtos Farmacêuticos. Belo Horizonte, MG, Brasil
Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brasil
Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brasil
Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brasil/Ministerio da Educação. Coordenação de Aperfeiçoamento de Pessoal de Nível Superior. Brasília, DF, Brasil
University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. San Diego, CA, USA
University of California. Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology. San Francisco, CA, USA
University of California. Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology. San Francisco, CA, USA
University of California. Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology. San Francisco, CA, USA
Universidade Federal de Minas Gerais. Faculdade de Farmácia. Departamento de Produtos Farmacêuticos. Belo Horizonte, MG, Brasil
Universidade Federal de Minas Gerais. Faculdade de Farmácia. Departamento de Produtos Farmacêuticos. Belo Horizonte, MG, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, Brasil/Universidade Federal de Santa Catarina. Departamento de Microbiologia, Imunologia e Parasitologia. Florianópolis, SC, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, Brasil
University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. San Diego, CA, USA
University of California. Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology. San Francisco, CA, USA
Universidade Federal de Minas Gerais. Faculdade de Farmácia. Departamento de Produtos Farmacêuticos. Belo Horizonte, MG, Brasil
Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brasil
Resumen en ingles
The pressing need for better drugs against Chagas disease, African sleeping sickness, and schistosomiasis motivates the search for inhibitors of cruzain, rhodesain, and Schistosoma mansoni CB1 (SmCB1), the major cysteine proteases from Trypanosoma cruzi, Trypanosoma brucei, and S. mansoni, respectively. Thiosemicarbazones and heterocyclic analogues have been shown to be both antitrypanocidal and inhibitory against parasite cysteine proteases. A series of compounds was synthesized and evaluated against cruzain, rhodesain, and SmCB1 through biochemical assays to determine their potency and structure-activity relationships (SAR). This approach led to the discovery of 6 rhodesain, 4 cruzain, and 5 SmCB1 inhibitors with 50% inhibitory concentrations (IC50s) of ≤ 10 μM. Among the compounds tested, the thiosemicarbazone derivative of peracetylated galactoside (compound 4i) was discovered to be a potent rhodesain inhibitor (IC50 = 1.2 ± 1.0 μM). The impact of a range of modifications was determined; removal of thiosemicarbazone or its replacement by semicarbazone resulted in virtually inactive compounds, and modifications in the sugar also diminished potency. Compounds were also evaluated in vitro against the parasites T. cruzi, T. brucei, and S. mansoni, revealing active compounds among this series.
Palabras clave en ingles
Cathepsin B/metabolism
Cysteine Proteinase
Inhibitors/chemical synthesis
Cysteine Proteinase
Inhibitors/pharmacology
Trypanocidal Agents/chemical synthesis
 
Editor
American Society for Microbiology
Referencia
FONSECA, Nayara Cristina et al. Synthesis of a sugar-based thiosemicarbazone series and structure-activity relationship versus the parasite cysteine proteases: rhodesain; cruzain and Schistosoma mansoni cathepsin B1. Antimicrob Agents Chemother., Vol. 59n. 5, p. 2666–2677, 2015.
DOI
10.1128/AAC.04601-14
ISSN
0066-4804