Two analogues of fenarimol show curative activity in an experimental model of chagas disease

Martine Keenan; Jason Hugh Chaplin; Paul W Alexander; Michael J Abbott; Wayne Morris Best; Andrea Khong; Adriana Botero; Catherine Perez; Scott Cornwall; Richard Christopher Andrew Thompson; Karen Louise White; David Shackleford; Maria Koltun; Francis Chi Keung Chiu; Julia Morizzi; Eileen Ryan; Michael Campbell; Thomas W von Geldern; Ivan Scandale; Eric Chatelain; Susan Ann Charman

doi:10.1021/jm401610c

Two analogues of fenarimol show curative activity in an experimental model of chagas disease

Martine Keenan, Jason Hugh Chaplin, Paul W Alexander, Michael J Abbott, Wayne Morris Best, Andrea Khong, Adriana Botero, Catherine Perez, Scott Cornwall, Richard Christopher Andrew Thompson, Karen Louise White, David Shackleford, Maria Koltun, Francis Chi Keung Chiu, Julia Morizzi, Eileen Ryan, Michael Campbell, Thomas W von Geldern, Ivan Scandale, Eric ChatelainSusan Ann Charman

Centre for Drug Candidate Optimisation

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

41 Citations (Scopus)

Abstract

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development.

Original language	English
Pages (from-to)	10158 - 10170
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	24
DOIs	https://doi.org/10.1021/jm401610c
Publication status	Published - 2013

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Keenan, M., Chaplin, J. H., Alexander, P. W., Abbott, M. J., Best, W. M., Khong, A., Botero, A., Perez, C., Cornwall, S., Thompson, R. C. A., White, K. L., Shackleford, D., Koltun, M., Chiu, F. C. K., Morizzi, J., Ryan, E., Campbell, M., von Geldern, T. W., Scandale, I., ... Charman, S. A. (2013). Two analogues of fenarimol show curative activity in an experimental model of chagas disease. Journal of Medicinal Chemistry, 56(24), 10158 - 10170. https://doi.org/10.1021/jm401610c

@article{f5774a3e4bc249f9a6dd9ec13f30aebd,

title = "Two analogues of fenarimol show curative activity in an experimental model of chagas disease",

abstract = "Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development.",

author = "Martine Keenan and Chaplin, {Jason Hugh} and Alexander, {Paul W} and Abbott, {Michael J} and Best, {Wayne Morris} and Andrea Khong and Adriana Botero and Catherine Perez and Scott Cornwall and Thompson, {Richard Christopher Andrew} and White, {Karen Louise} and David Shackleford and Maria Koltun and Chiu, {Francis Chi Keung} and Julia Morizzi and Eileen Ryan and Michael Campbell and {von Geldern}, {Thomas W} and Ivan Scandale and Eric Chatelain and Charman, {Susan Ann}",

year = "2013",

doi = "10.1021/jm401610c",

language = "English",

volume = "56",

pages = "10158 -- 10170",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "24",

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Keenan, M, Chaplin, JH, Alexander, PW, Abbott, MJ, Best, WM, Khong, A, Botero, A, Perez, C, Cornwall, S, Thompson, RCA, White, KL, Shackleford, D, Koltun, M, Chiu, FCK, Morizzi, J, Ryan, E, Campbell, M, von Geldern, TW, Scandale, I, Chatelain, E & Charman, SA 2013, 'Two analogues of fenarimol show curative activity in an experimental model of chagas disease', Journal of Medicinal Chemistry, vol. 56, no. 24, pp. 10158 - 10170. https://doi.org/10.1021/jm401610c

TY - JOUR

T1 - Two analogues of fenarimol show curative activity in an experimental model of chagas disease

AU - Keenan, Martine

AU - Chaplin, Jason Hugh

AU - Alexander, Paul W

AU - Abbott, Michael J

AU - Best, Wayne Morris

AU - Khong, Andrea

AU - Botero, Adriana

AU - Perez, Catherine

AU - Cornwall, Scott

AU - Thompson, Richard Christopher Andrew

AU - White, Karen Louise

AU - Shackleford, David

AU - Koltun, Maria

AU - Chiu, Francis Chi Keung

AU - Morizzi, Julia

AU - Ryan, Eileen

AU - Campbell, Michael

AU - von Geldern, Thomas W

AU - Scandale, Ivan

AU - Chatelain, Eric

AU - Charman, Susan Ann

PY - 2013

Y1 - 2013

N2 - Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development.

AB - Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development.

UR - http://pubs.acs.org.ezproxy.lib.monash.edu.au/doi/ipdf/10.1021/jm401610c

U2 - 10.1021/jm401610c

DO - 10.1021/jm401610c

M3 - Article

SN - 0022-2623

VL - 56

SP - 10158

EP - 10170

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 24

ER -

Two analogues of fenarimol show curative activity in an experimental model of chagas disease

Abstract

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