title: From Cells to Mice to Target: Characterization of NEU-1053 (SB-443342) and Its Analogues for Treatment of Human African Trypanosomiasis.
abstract: 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 structure-activity 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.
authors.affiliation: Department of Chemistry & Chemical Biology, Northeastern University 360 Huntington Avenue, Boston, Massachusetts, United States.
authors.forename: William G
authors.initials: WG
authors.lastname: Devine
authors.affiliation: Instituto de Parasitologia y Biomedicina "Lopez-Neyra", Consejo Superior de Investigaciones Cientificas (CSIC) , Granada 18100, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: Diaz-Gonzalez
authors.affiliation: Instituto de Parasitologia y Biomedicina "Lopez-Neyra", Consejo Superior de Investigaciones Cientificas (CSIC) , Granada 18100, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Ceballos-Perez
authors.affiliation: Instituto de Parasitologia y Biomedicina "Lopez-Neyra", Consejo Superior de Investigaciones Cientificas (CSIC) , Granada 18100, Spain.
authors.forename: Domingo
authors.initials: D
authors.lastname: Rojas
authors.affiliation: Department of Chemistry & Chemical Biology, Northeastern University 360 Huntington Avenue, Boston, Massachusetts, United States.
authors.forename: Takashi
authors.initials: T
authors.lastname: Satoh
authors.affiliation: Department of Chemistry & Chemical Biology, Northeastern University 360 Huntington Avenue, Boston, Massachusetts, United States.
authors.forename: Westley
authors.initials: W
authors.lastname: Tear
authors.forename: Ranae M
authors.initials: RM
authors.lastname: Ranade
authors.affiliation: Laboratorio de Enzimología de Parásitos, Facultad de Ciencias, Universidad de los Andes , Mérida, Venezuela.
authors.forename: Ximena
authors.initials: X
authors.lastname: Barros-Álvarez
authors.forename: Wim G J
authors.initials: WG
authors.lastname: Hol
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Buckner
authors.affiliation: Instituto de Parasitologia y Biomedicina "Lopez-Neyra", Consejo Superior de Investigaciones Cientificas (CSIC) , Granada 18100, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Navarro
authors.affiliation: Department of Chemistry & Chemical Biology, Northeastern University 360 Huntington Avenue, Boston, Massachusetts, United States.
authors.forename: Michael P
authors.identifier: 0000-0001-9943-7197
authors.initials: MP
authors.lastname: Pollastri
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D058069:Neglected Diseases; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: D054852:Small Molecule Libraries; D014344:Trypanocidal Agents
keywords: Trypanosoma brucei; medicinal chemistry; methionyl-tRNA synthetase