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

M. Keenan; P.W. Alexander; H. Diao; W.M. Best; A. Khong; M. Kerfoot; R.C.A. Thompson; K.L. White; D.M. Shackleford; E. Ryan; A.D. Gregg; S.A. Charman; T.W. von Geldern; I. Scandale; E. Chatelain

doi:10.1016/j.bmc.2013.01.050

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

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

M. Keenan, P.W. Alexander, H. Diao, W.M. Best, A. Khong, M. Kerfoot, R.C.A. Thompson, K.L. White, D.M. Shackleford, E. Ryan, …

Bioorganic & Medicinal Chemistry Letters, Vol.21(7), pp.1756-1763

2013

DOI: https://doi.org/10.1016/j.bmc.2013.01.050

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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.

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Title: Design, structure–activity relationship and in vivo efficacy of piperazine analogues of fenarimol as inhibitors of Trypanosoma cruzi
Authors/Creators: M. Keenan (Author/Creator)
P.W. Alexander (Author/Creator)
H. Diao (Author/Creator)
W.M. Best (Author/Creator)
A. Khong (Author/Creator)
M. Kerfoot (Author/Creator)
R.C.A. Thompson (Author/Creator)
K.L. White (Author/Creator)
D.M. Shackleford (Author/Creator)
E. Ryan (Author/Creator)
A.D. Gregg (Author/Creator)
S.A. Charman (Author/Creator)
T.W. von Geldern (Author/Creator)
I. Scandale (Author/Creator)
E. Chatelain (Author/Creator)
Publication Details: Bioorganic & Medicinal Chemistry Letters, Vol.21(7), pp.1756-1763
Publisher: Elsevier BV
Identifiers: 991005543678307891
Copyright: © 2013 Elsevier Ltd.
Murdoch Affiliation: School of Veterinary and Life Sciences
Language: English
Resource Type: Journal article

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Collaboration types: International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.261 Parasitology - Trypanosoma & Leishmania; 1.261.596 Trypanosoma Biology
Web Of Science research areas: Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic
ESI research areas: Chemistry