Discovery of antichagasic inhibitors by high-throughput screening with Trypanosoma cruzi glucokinase

Autor(es)

Mercaldi, Gustavo F. ^[1] ; D'Antonio, Edward L. ^[2] ; Aguessi, Annelie ^[3] ; Rodriguez, Ana ^[3] ; Cordeiro, Artur T. ^[1]

Afiliação do(s) autor(es)

^[1] Brazilian Biosci Natl Lab, Brazilian Ctr Res Energy & Mat, BR-13083970 Campinas, SP - Brazil

^[2] Univ South Carolina Beaufort, Dept Nat Sci, 1 Univ Blvd, Bluffton, SC 29909 - USA

^[3] NYU, Sch Med, Dept Microbiol, 430 East 29th St, New York, NY 10016 - USA

• Tipo de documento: Artigo Científico
• Fonte: Bioorganic & Medicinal Chemistry Letters; v. 29, n. 15, p. 1948-1953, AUG 1 2019.
• Citações Web of Science: 0

Resumo

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 cosubstrate 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. (AU)

• Processo FAPESP: 16/14271-4 - Aperfeiçoamento dos inibidores da enzima G6PDH para desenvolvimento de fármacos contra Chagas
• Beneficiário: Artur Torres Cordeiro
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/03151-8 - Aminoacil-tRNA Sintetases como Alvos para o Desenvolvimento de Agrobactericidas destinados ao Controle de Doenças de Plantas Causadas por espécies de Xanthomonas
• Beneficiário: Gustavo Fernando Mercaldi
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado