title: Analogues of fenarimol are potent inhibitors of Trypanosoma cruzi and are efficacious in a murine model of Chagas disease.
abstract: We report the discovery of nontoxic fungicide fenarimol (1) as an inhibitor of  Trypanosoma cruzi  ( T. cruzi ), the causative agent of Chagas disease, and the results of structure-activity investigations leading to potent analogues with low nM IC(50)s in a  T. cruzi  whole cell in vitro assay. Lead compounds suppressed blood parasitemia to virtually undetectable levels after once daily oral dosing in mouse models of  T. cruzi  infection. Compounds are chemically tractable, allowing rapid optimization of target biological activity and drug characteristics. Chemical and biological studies undertaken in the development of the fenarimol series toward the goal of delivering a new drug candidate for Chagas disease are reported.
authors.affiliation: Epichem Pty Ltd, South Street, Murdoch, WA 6150, Australia. martine.keenan@epichem.com.au
authors.forename: Martine
authors.initials: M
authors.lastname: Keenan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Abbott
authors.forename: Paul W
authors.initials: PW
authors.lastname: Alexander
authors.forename: Tanya
authors.initials: T
authors.lastname: Armstrong
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Best
authors.forename: Bradley
authors.initials: B
authors.lastname: Berven
authors.forename: Adriana
authors.initials: A
authors.lastname: Botero
authors.forename: Jason H
authors.initials: JH
authors.lastname: Chaplin
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Eric
authors.initials: E
authors.lastname: Chatelain
authors.forename: Thomas W
authors.initials: TW
authors.lastname: von Geldern
authors.forename: Maria
authors.initials: M
authors.lastname: Kerfoot
authors.forename: Andrea
authors.initials: A
authors.lastname: Khong
authors.forename: Tien
authors.initials: T
authors.lastname: Nguyen
authors.forename: Joshua D
authors.initials: JD
authors.lastname: McManus
authors.forename: Julia
authors.initials: J
authors.lastname: Morizzi
authors.forename: Eileen
authors.initials: E
authors.lastname: Ryan
authors.forename: Ivan
authors.initials: I
authors.lastname: Scandale
authors.forename: R Andrew
authors.initials: RA
authors.lastname: Thompson
authors.forename: Sen Z
authors.initials: SZ
authors.lastname: Wang
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
mesh_terms: D000818:Animals; D002460:Cell Line; D014355:Chagas Disease / Q000188:drug therapy* / Q000378:metabolism / Q000469:parasitology; D004195:Disease Models, Animal; D008401:Gas Chromatography-Mass Spectrometry; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D019906:Nuclear Magnetic Resonance, Biomolecular; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D011743:Pyrimidines; D014344:Trypanocidal Agents