Design, structure-activity relationship and in vivo efficacy of piperazine analogues of fenarimol as inhibitors of Trypanosoma cruzi

  • Bioorg Med Chem. 2013 Apr 1;21(7):1756-63. doi: 10.1016/j.bmc.2013.01.050.
Martine Keenan  1 ,  Paul W Alexander ,  Hugo Diao ,  Wayne M Best ,  Andrea Khong ,  Maria Kerfoot ,  R C Andrew Thompson ,  Karen L White ,  David M Shackleford ,  Eileen Ryan ,  Alison D Gregg ,  Susan A Charman ,  Thomas W von Geldern ,  Ivan Scandale ,  Eric Chatelain
Affiliations
  • 1. Epichem Pty Ltd, Murdoch University Campus, South Street, Murdoch, Western Australia 6150, Australia. [email protected]
PMID: 23462713 DOI: 10.1016/j.bmc.2013.01.050
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.