| Autor: |
Fonseca, Nayara Cristina, da Cruz, Luana Faria, da Silva Villela, Filipe, do Nascimento Pereira, Glaécia Aparecida, de Siqueira-Neto, Jair Lage, Kellar, Danielle, Suzuki, Brian M., Ray, Debalina, de Souza, Thiago Belarmino, Alves, Ricardo José, Júnior, Policarpo Ademar Sales, Romanha, Alvaro José, Murta, Silvane Maria Fonseca, McKerrow, James H., Caffrey, Conor R., de Oliveira, Renata Barbosa, Ferreira, Rafaela Salgado |
| Zdroj: |
Antimicrobial Agents and Chemotherapy; February 2015, Vol. 59 Issue: 5 p2666-2677, 12p |
| Abstrakt: |
ABSTRACTThe pressing need for better drugs against Chagas disease, African sleeping sickness, and schistosomiasis motivates the search for inhibitors of cruzain, rhodesain, and Schistosoma mansoniCB1 (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 vitroagainst the parasites T. cruzi, T. brucei, and S. mansoni, revealing active compounds among this series. |
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