Advanced search
Start date
Betweenand
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

Full text
Author(s):
Mercaldi, Gustavo F. [1] ; D'Antonio, Edward L. [2] ; Aguessi, Annelie [3] ; Rodriguez, Ana [3] ; Cordeiro, Artur T. [1]
Total Authors: 5
Affiliation:
[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
Total Affiliations: 3
Document type: Journal article
Source: Bioorganic & Medicinal Chemistry Letters; v. 29, n. 15, p. 1948-1953, AUG 1 2019.
Web of Science Citations: 0
Abstract

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)

FAPESP's process: 16/14271-4 - Optimization G6PDH inhibitors towards the development of drugs against Chagas diseases
Grantee:Artur Torres Cordeiro
Support type: Regular Research Grants
FAPESP's process: 16/03151-8 - Aminoacil-tRNA synthetases as targets for development of Agrobactericides intented for control of plant diseases caused by Xanthomonas species
Grantee:Gustavo Fernando Mercaldi
Support type: Scholarships in Brazil - Post-Doctorate