title: Substituted 2-phenylimidazopyridines: a new class of drug leads for human African trypanosomiasis.
abstract: A phenotypic screen of a compound library for antiparasitic activity on Trypanosoma brucei, the causative agent of human African trypanosomiasis, led to the identification of substituted 2-(3-aminophenyl)oxazolopyridines as a starting point for hit-to-lead medicinal chemistry. A total of 110 analogues were prepared, which led to the identification of 64, a substituted 2-(3-aminophenyl)imidazopyridine. This compound showed antiparasitic activity in vitro with an EC50 of 2 nM and displayed reasonable druglike properties when tested in a number of in vitro assays. The compound was orally bioavailable and displayed good plasma and brain exposure in mice. Compound 64 cured mice infected with Trypanosoma brucei when dosed orally down to 2.5 mg/kg. Given its potent antiparasitic properties and its ease of synthesis, compound 64 represents a new lead for the development of drugs to treat human African trypanosomiasis.
authors.affiliation: Departments of †Chemistry, ‡Medicine, and §Biochemistry, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Hari Babu
authors.initials: HB
authors.lastname: Tatipaka
authors.forename: J Robert
authors.initials: JR
authors.lastname: Gillespie
authors.forename: Arnab K
authors.initials: AK
authors.lastname: Chatterjee
authors.forename: Neil R
authors.initials: NR
authors.lastname: Norcross
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Hulverson
authors.forename: Ranae M
authors.initials: RM
authors.lastname: Ranade
authors.forename: Pendem
authors.initials: P
authors.lastname: Nagendar
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Creason
authors.forename: Joshua
authors.initials: J
authors.lastname: McQueen
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Duster
authors.forename: Advait
authors.initials: A
authors.lastname: Nagle
authors.forename: Frantisek
authors.initials: F
authors.lastname: Supek
authors.forename: Valentina
authors.initials: V
authors.lastname: Molteni
authors.forename: Tanja
authors.initials: T
authors.lastname: Wenzler
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Richard
authors.initials: R
authors.lastname: Glynne
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Buckner
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D062126:Databases, Chemical; D004285:Dogs; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000254:growth & development; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects / Q000254:growth & development; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000469:parasitology
chemical_list: D007093:Imidazoles; D011725:Pyridines; D014344:Trypanocidal Agents