title: Two analogues of fenarimol show curative activity in an experimental model of Chagas disease.
abstract: Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development.
authors.affiliation: Epichem Pty Ltd. , Murdoch University Campus, South Street, Murdoch, Western Australia 6150, Australia.
authors.forename: Martine
authors.initials: M
authors.lastname: Keenan
authors.forename: Jason H
authors.initials: JH
authors.lastname: Chaplin
authors.forename: Paul W
authors.initials: PW
authors.lastname: Alexander
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Abbott
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Best
authors.forename: Andrea
authors.initials: A
authors.lastname: Khong
authors.forename: Adriana
authors.initials: A
authors.lastname: Botero
authors.forename: Catherine
authors.initials: C
authors.lastname: Perez
authors.forename: Scott
authors.initials: S
authors.lastname: Cornwall
authors.forename: R Andrew
authors.initials: RA
authors.lastname: Thompson
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.forename: Maria
authors.initials: M
authors.lastname: Koltun
authors.forename: Francis C K
authors.initials: FC
authors.lastname: Chiu
authors.forename: Julia
authors.initials: J
authors.lastname: Morizzi
authors.forename: Eileen
authors.initials: E
authors.lastname: Ryan
authors.forename: Michael
authors.initials: M
authors.lastname: Campbell
authors.forename: Thomas W
authors.initials: TW
authors.lastname: von Geldern
authors.forename: Ivan
authors.initials: I
authors.lastname: Scandale
authors.forename: Eric
authors.initials: E
authors.lastname: Chatelain
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D011743:Pyrimidines; D014344:Trypanocidal Agents; C033789:fenarimol