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

Martine Keenan; Paul W Alexander; Hugo Diao; Wayne Morris Best; Andrea Khong; Maria Kerfoot; Richard Christopher Andrew Thompson; Karen Louise White; David Shackleford; Eileen Ryan; Alison Dianne Gregg; Susan Ann Charman; Thomas W von Geldern; Ivan Scandale; Eric Chatelain

doi:10.1016/j.bmc.2013.01.050

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

Martine Keenan, Paul W Alexander, Hugo Diao, Wayne Morris Best, Andrea Khong, Maria Kerfoot, Richard Christopher Andrew Thompson, Karen Louise White, David Shackleford, Eileen Ryan, Alison Dianne Gregg, Susan Ann Charman, Thomas W von Geldern, Ivan Scandale, Eric Chatelain

Centre for Drug Candidate Optimisation

Research output: Contribution to journal › Article › Research › peer-review

27 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1756 - 1763
Number of pages	8
Journal	Bioorganic & Medicinal Chemistry
Volume	21
Issue number	7
DOIs	https://doi.org/10.1016/j.bmc.2013.01.050
Publication status	Published - 2013

Access to Document

10.1016/j.bmc.2013.01.050

Cite this

Keenan, M., Alexander, P. W., Diao, H., Best, W. M., Khong, A., Kerfoot, M., Thompson, R. C. A., White, K. L., Shackleford, D., Ryan, E., Gregg, A. D., Charman, S. A., von Geldern, T. W., Scandale, I., & Chatelain, E. (2013). Design, structure-activity relationship and in vivo efficacy of piperazine analogues of fenarimol as inhibitors of Trypanosoma cruzi. Bioorganic & Medicinal Chemistry, 21(7), 1756 - 1763. https://doi.org/10.1016/j.bmc.2013.01.050

@article{bfdc06c23f8d44159bcba5bcb35d09fa,

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.",

author = "Martine Keenan and Alexander, {Paul W} and Hugo Diao and Best, {Wayne Morris} and Andrea Khong and Maria Kerfoot and Thompson, {Richard Christopher Andrew} and White, {Karen Louise} and David Shackleford and Eileen Ryan and Gregg, {Alison Dianne} and Charman, {Susan Ann} and {von Geldern}, {Thomas W} and Ivan Scandale and Eric Chatelain",

year = "2013",

doi = "10.1016/j.bmc.2013.01.050",

language = "English",

volume = "21",

pages = "1756 -- 1763",

journal = "Bioorganic & Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier",

number = "7",

}

Keenan, M, Alexander, PW, Diao, H, Best, WM, Khong, A, Kerfoot, M, Thompson, RCA, White, KL, Shackleford, D, Ryan, E, Gregg, AD, Charman, SA, von Geldern, TW, Scandale, I & Chatelain, E 2013, 'Design, structure-activity relationship and in vivo efficacy of piperazine analogues of fenarimol as inhibitors of Trypanosoma cruzi', Bioorganic & Medicinal Chemistry, vol. 21, no. 7, pp. 1756 - 1763. https://doi.org/10.1016/j.bmc.2013.01.050

TY - JOUR

T1 - Design, structure-activity relationship and in vivo efficacy of piperazine analogues of fenarimol as inhibitors of Trypanosoma cruzi

AU - Keenan, Martine

AU - Alexander, Paul W

AU - Diao, Hugo

AU - Best, Wayne Morris

AU - Khong, Andrea

AU - Kerfoot, Maria

AU - Thompson, Richard Christopher Andrew

AU - White, Karen Louise

AU - Shackleford, David

AU - Ryan, Eileen

AU - Gregg, Alison Dianne

AU - Charman, Susan Ann

AU - von Geldern, Thomas W

AU - Scandale, Ivan

AU - Chatelain, Eric

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

UR - http://www.sciencedirect.com/science/article/pii/S0968089613000898

U2 - 10.1016/j.bmc.2013.01.050

DO - 10.1016/j.bmc.2013.01.050

M3 - Article

SN - 0968-0896

VL - 21

SP - 1756

EP - 1763

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 7

ER -

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

Abstract

Access to Document

Other files and links

Cite this