title: Design, structure-activity relationship and in vivo efficacy of piperazine analogues of fenarimol as inhibitors of Trypanosoma cruzi.
abstract: A scaffold hopping exercise undertaken to expand the structural diversity of the fenarimol series of anti-Trypanosoma cruzi (T. cruzi) compounds led to preparation of simple 1-[phenyl(pyridin-3-yl)methyl]piperazinyl analogues of fenarimol which were investigated for their ability to inhibit T. cruzi in vitro in a whole organism assay. A range of compounds bearing amide, sulfonamide, carbamate/carbonate and aryl moieties exhibited low nM activities and two analogues were further studied for in vivo efficacy in a mouse model of T. cruzi infection. One compound, the citrate salt of 37, was efficacious in a mouse model of acute T. cruzi infection after once daily oral dosing at 20, 50 and 100 mg/kg for 5 days.
authors: Epichem Pty Ltd, Murdoch University Campus, South Street, Murdoch, Western Australia 6150, Australia. martine.keenan@epichem.com.au
authors: Martine
authors: M
authors: Keenan
authors: Paul W
authors: PW
authors: Alexander
authors: Hugo
authors: H
authors: Diao
authors: Wayne M
authors: WM
authors: Best
authors: Andrea
authors: A
authors: Khong
authors: Maria
authors: M
authors: Kerfoot
authors: R C Andrew
authors: RC
authors: Thompson
authors: Karen L
authors: KL
authors: White
authors: David M
authors: DM
authors: Shackleford
authors: Eileen
authors: E
authors: Ryan
authors: Alison D
authors: AD
authors: Gregg
authors: Susan A
authors: SA
authors: Charman
authors: Thomas W
authors: TW
authors: von Geldern
authors: Ivan
authors: I
authors: Scandale
authors: Eric
authors: E
authors: Chatelain
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D015195:Drug Design; D006801:Humans; D051379:Mice; D000077489:Piperazine; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D010879:Piperazines; D011743:Pyrimidines; D014344:Trypanocidal Agents; D000077489:Piperazine; C033789:fenarimol