Portal de Periódicos da CAPES

Artigo Acesso aberto Produção Nacional Revisado por pares

BIBTEX RIS

Synthesis of a Sugar-Based Thiosemicarbazone Series and Structure-Activity Relationship versus the Parasite Cysteine Proteases Rhodesain, Cruzain, and Schistosoma mansoni Cathepsin B1

2015; American Society for Microbiology; Volume: 59; Issue: 5 Linguagem: Inglês

10.1128/aac.04601-14

1098-6596

Nayara Cristina Fonseca, Luana Faria da Cruz, Filipe da Silva Villela, Glaécia Aparecida do Nascimento Pereira, Jair L. Siqueira-Neto, Danielle Kellar, Brian M. Suzuki, Debalina Ray, Thiago Belarmino de Souza, Ricardo José Alves, Policarpo Ademar Sales, Álvaro J. Romanha, Silvane Maria Fonseca Murta, James H. McKerrow, Conor R. Caffrey, Renata Barbosa de Oliveira, Rafaela Salgado Ferreira,

Parasites and Host Interactions

ABSTRACT 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 (IC 50 s) of ≤10 μM. Among the compounds tested, the thiosemicarbazone derivative of peracetylated galactoside (compound 4i) was discovered to be a potent rhodesain inhibitor (IC 50 = 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.