title: Synthesis of a sugar-based thiosemicarbazone series and structure-activity relationship versus the parasite cysteine proteases rhodesain, cruzain, and Schistosoma mansoni cathepsin B1.
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 (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.
authors.affiliation: Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Nayara Cristina
authors.initials: NC
authors.lastname: Fonseca
authors.affiliation: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Luana Faria
authors.initials: LF
authors.lastname: da Cruz
authors.affiliation: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Filipe
authors.initials: F
authors.lastname: da Silva Villela
authors.affiliation: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil CAPES Foundation, Ministry of Education of Brazil, Brasília, DF, Brazil.
authors.forename: Glaécia Aparecida
authors.initials: GA
authors.lastname: do Nascimento Pereira
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, San Diego, California, USA.
authors.forename: Jair Lage
authors.initials: JL
authors.lastname: de Siqueira-Neto
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Kellar
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Suzuki
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Debalina
authors.initials: D
authors.lastname: Ray
authors.affiliation: Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Thiago Belarmino
authors.initials: TB
authors.lastname: de Souza
authors.affiliation: Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Ricardo José
authors.initials: RJ
authors.lastname: Alves
authors.affiliation: Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, MG, Brazil.
authors.forename: Policarpo Ademar
authors.initials: PA
authors.lastname: Sales Júnior
authors.affiliation: Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, MG, Brazil Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Alvaro José
authors.initials: AJ
authors.lastname: Romanha
authors.affiliation: Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, MG, Brazil.
authors.forename: Silvane Maria Fonseca
authors.initials: SM
authors.lastname: Murta
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, San Diego, California, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Conor R
authors.initials: CR
authors.lastname: Caffrey
authors.affiliation: Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Renata Barbosa
authors.initials: RB
authors.lastname: de Oliveira
authors.affiliation: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil rafaelasf@icb.ufmg.br.
authors.forename: Rafaela Salgado
authors.initials: RS
authors.lastname: Ferreira
mesh_terms: D000818:Animals; D002401:Cathepsin B / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D015800:Protozoan Proteins / Q000378:metabolism*; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000201:enzymology*; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi; C446033:rhodesain; D002401:Cathepsin B