2,4-Diamino-6-methylpyrimidines for the potential treatment of Chagas’ disease

Michael G. Thomas; Manu De Rycker; Ignacio Cotillo Torrejon; John Thomas; Jennifer Riley; Daniel Spinks; Kevin D. Read; Tim J. Miles; Ian H. Gilbert; Paul G. Wyatt

doi:10.1016/j.bmcl.2018.08.005

2,4-Diamino-6-methylpyrimidines for the potential treatment of Chagas’ disease

Michael G. Thomas, Manu De Rycker, Ignacio Cotillo Torrejon, John Thomas, Jennifer Riley, Daniel Spinks, Kevin D. Read, Tim J. Miles, Ian H. Gilbert, Paul G. Wyatt (Lead / Corresponding author)

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

5 Citations (Scopus)

142 Downloads (Pure)

Abstract

Chagas’ disease, caused by the protozoan parasite Trypanosoma cruzi, affects 8–10 million people across the Latin American population and is responsible for around 12,500 deaths per annum. The current frontline treatments, benznidazole and nifurtimox, are associated with side effects and lack efficacy in the chronic stage of the disease, leading to an urgent need for new treatments. A high throughput screening campaign against the physiologically relevant intracellular form of the parasite identified a series of 2,4-diamino-6-methylpyrimidines. Demonstrating the series did not work through the anti-target TcCYP51, and was generally cytocidal, confirmed its suitability for further development. This study reports the optimisation of selectivity and metabolic stability of the series and identification of a suitable lead for further optimisation.

Original language	English
Pages (from-to)	3025-3030
Number of pages	6
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	28
Issue number	18
Early online date	3 Aug 2018
DOIs	https://doi.org/10.1016/j.bmcl.2018.08.005
Publication status	Published - 1 Oct 2018

Keywords

Chagas’ disease
SAR studies
Trypanosoma cruzi

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.bmcl.2018.08.005

Author Accepted Manuscript
© 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Accepted author manuscript, 462 KBLicence: CC BY-NC-ND

A Translational Engine for Biomedical Discoveries (Strategic Grant)
Fairlamb, A. (Investigator) & Gilbert, I. (Investigator)
1/01/13 → 30/09/15
Project: Research
Discovery and Development of Drug Candidates for Neglected Diseases (joint with industrial partner)
Brenk, R. (Investigator), Fairlamb, A. (Investigator), Ferguson, M. (Investigator), Field, M. (Investigator), Gilbert, I. (Investigator), Gray, D. (Investigator), Hopkins, A. (Investigator), Horn, D. (Investigator), Read, K. (Investigator), Wyatt, P. (Investigator) & van Aalten, D. (Investigator)
1/02/11 → 1/07/17
Project: Research

Cite this

@article{1f2436c9e59b497dbac101a59c7a7e2c,

title = "2,4-Diamino-6-methylpyrimidines for the potential treatment of Chagas{\textquoteright} disease",

abstract = "Chagas{\textquoteright} disease, caused by the protozoan parasite Trypanosoma cruzi, affects 8–10 million people across the Latin American population and is responsible for around 12,500 deaths per annum. The current frontline treatments, benznidazole and nifurtimox, are associated with side effects and lack efficacy in the chronic stage of the disease, leading to an urgent need for new treatments. A high throughput screening campaign against the physiologically relevant intracellular form of the parasite identified a series of 2,4-diamino-6-methylpyrimidines. Demonstrating the series did not work through the anti-target TcCYP51, and was generally cytocidal, confirmed its suitability for further development. This study reports the optimisation of selectivity and metabolic stability of the series and identification of a suitable lead for further optimisation.",

keywords = "Chagas{\textquoteright} disease, SAR studies, Trypanosoma cruzi",

author = "Thomas, {Michael G.} and {De Rycker}, Manu and {Cotillo Torrejon}, Ignacio and John Thomas and Jennifer Riley and Daniel Spinks and Read, {Kevin D.} and Miles, {Tim J.} and Gilbert, {Ian H.} and Wyatt, {Paul G.}",

note = "Copyright {\textcopyright} 2018. Published by Elsevier Ltd.",

year = "2018",

month = oct,

day = "1",

doi = "10.1016/j.bmcl.2018.08.005",

language = "English",

volume = "28",

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journal = "Bioorganic & Medicinal Chemistry Letters",

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T1 - 2,4-Diamino-6-methylpyrimidines for the potential treatment of Chagas’ disease

AU - Thomas, Michael G.

AU - De Rycker, Manu

AU - Cotillo Torrejon, Ignacio

AU - Thomas, John

AU - Riley, Jennifer

AU - Spinks, Daniel

AU - Read, Kevin D.

AU - Miles, Tim J.

AU - Gilbert, Ian H.

AU - Wyatt, Paul G.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Chagas’ disease, caused by the protozoan parasite Trypanosoma cruzi, affects 8–10 million people across the Latin American population and is responsible for around 12,500 deaths per annum. The current frontline treatments, benznidazole and nifurtimox, are associated with side effects and lack efficacy in the chronic stage of the disease, leading to an urgent need for new treatments. A high throughput screening campaign against the physiologically relevant intracellular form of the parasite identified a series of 2,4-diamino-6-methylpyrimidines. Demonstrating the series did not work through the anti-target TcCYP51, and was generally cytocidal, confirmed its suitability for further development. This study reports the optimisation of selectivity and metabolic stability of the series and identification of a suitable lead for further optimisation.

AB - Chagas’ disease, caused by the protozoan parasite Trypanosoma cruzi, affects 8–10 million people across the Latin American population and is responsible for around 12,500 deaths per annum. The current frontline treatments, benznidazole and nifurtimox, are associated with side effects and lack efficacy in the chronic stage of the disease, leading to an urgent need for new treatments. A high throughput screening campaign against the physiologically relevant intracellular form of the parasite identified a series of 2,4-diamino-6-methylpyrimidines. Demonstrating the series did not work through the anti-target TcCYP51, and was generally cytocidal, confirmed its suitability for further development. This study reports the optimisation of selectivity and metabolic stability of the series and identification of a suitable lead for further optimisation.

KW - Chagas’ disease

KW - SAR studies

KW - Trypanosoma cruzi

U2 - 10.1016/j.bmcl.2018.08.005

DO - 10.1016/j.bmcl.2018.08.005

M3 - Article

C2 - 30104093

SN - 0960-894X

VL - 28

SP - 3025

EP - 3030

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 18

ER -

2,4-Diamino-6-methylpyrimidines for the potential treatment of Chagas’ disease

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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Projects

A Translational Engine for Biomedical Discoveries (Strategic Grant)

Discovery and Development of Drug Candidates for Neglected Diseases (joint with industrial partner)

Cite this