期刊
ACS INFECTIOUS DISEASES
卷 3, 期 3, 页码 225-236出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.6b00202
关键词
Trypanosoma brucei; methionyl-tRNA synthetase; medicinal chemistry
资金
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R56AI099476, R01AI114685, R01AI084004, R01AI097177]
- Fulbright Fellowship
- Northeastern University
- U.S. Department of Energy Office of Basic Energy Sciences [DE-AC02-76SF00515]
- National Institutes of Health [P41GM103393]
Human African trypanosomiasis is a neglected tropical disease that is lethal if left untreated. Existing therapeutics have limited efficacy and severe associated toxicities. 2-(2-(((3-((1H-Benzo[d]imidazol-2-yl)amino)propyl)amino)methyl)-4,6-dichloro-1H-indol-1-yl)ethan-1-ol (NEU-1053) has recently been identified from a high-throughput screen of >42,000 compounds as a highly potent and fast-acting trypanocidal agent capable of curing a bloodstream infection of Trypanosoma brucei in mice. We have designed a library of analogues to probe the structureactivity relationship and improve the predicted central nervous system (CNS) exposure of NEU-1053. We report the activity of these inhibitors of T. brucei, the efficacy of NEU-1053 in a murine CNS model of infection, and identification of the target of NEU-1053 via X-ray crystallography.
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