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Discovery of antichagasic inhibitors by high-throughput screening with Trypanosoma cruzi glucokinase.
Mercaldi, Gustavo F; D'Antonio, Edward L; Aguessi, Annelie; Rodriguez, Ana; Cordeiro, Artur T.
Afiliação
  • Mercaldi GF; Brazilian Center for Research in Energy and Materials, Brazilian Biosciences National Laboratory, Campinas, SP 13083-970, Brazil.
  • D'Antonio EL; Department of Natural Sciences, University of South Carolina Beaufort, 1 University Boulevard, Bluffton, SC 29909, USA. Electronic address: edantonio@uscb.edu.
  • Aguessi A; Department of Microbiology, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA.
  • Rodriguez A; Department of Microbiology, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA.
  • Cordeiro AT; Brazilian Center for Research in Energy and Materials, Brazilian Biosciences National Laboratory, Campinas, SP 13083-970, Brazil.
Bioorg Med Chem Lett ; 29(15): 1948-1953, 2019 08 01.
Article em En | MEDLINE | ID: mdl-31133533
A high-throughput screening (HTS) campaign was carried out for Trypanosoma cruzi glucokinase (TcGlcK), a potential drug-target of the pathogenic protozoan parasite. Glycolysis and the pentose phosphate pathway (PPP) are important metabolic pathways for T. cruzi and the inhibition of the glucose kinases (i.e. glucokinase and hexokinase) may be a strategic approach for drug discovery. Glucose kinases phosphorylate d-glucose with co-substrate ATP to yield G6P, and moreover, the produced G6P enters both pathways for catabolism. The TcGlcK - HTS campaign revealed 25 novel enzyme inhibitors that were distributed in nine chemical classes and were discovered from a primary screen of 13,040 compounds. Thirteen of these compounds were found to have low micromolar IC50 enzyme - inhibition values; strikingly, four of those compounds exhibited low toxicity towards NIH-3T3 murine host cells and notable in vitro trypanocidal activity. These compounds were of three chemical classes: (a) the 3-nitro-2-phenyl-2H-chromene scaffold, (b) the N-phenyl-benzenesulfonamide scaffold, and (c) the gossypol scaffold. Two compounds from the 3-nitro-2-phenyl-2H-chromene scaffold were determined to be hit-to-lead candidates that can proceed further down the early-stage drug discovery process.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Chagas / Inibidores Enzimáticos / Ensaios de Triagem em Larga Escala / Glucoquinase Tipo de estudo: Diagnostic_studies / Screening_studies Idioma: En Revista: Bioorg Med Chem Lett Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Brasil País de publicação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Chagas / Inibidores Enzimáticos / Ensaios de Triagem em Larga Escala / Glucoquinase Tipo de estudo: Diagnostic_studies / Screening_studies Idioma: En Revista: Bioorg Med Chem Lett Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Brasil País de publicação: Reino Unido