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 journalArticle

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.

LanguageEnglish
Pages3025-3030
Number of pages6
JournalBioorganic & Medicinal Chemistry Letters
Volume28
Issue number18
Early online date3 Aug 2018
DOIs
Publication statusPublished - 1 Oct 2018

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Chagas Disease
Parasites
Nifurtimox
Trypanosoma cruzi
Screening
Chronic Disease
Throughput
Population
benzonidazole
Lead

Keywords

  • Chagas’ disease
  • SAR studies
  • Trypanosoma cruzi

Cite this

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title = "2,4-Diamino-6-methylpyrimidines for the potential treatment of Chagas’ disease",
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.",
keywords = "Chagas’ 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 {\circledC} 2018. Published by Elsevier Ltd.",
year = "2018",
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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.

N1 - Copyright © 2018. Published by Elsevier Ltd.

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

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VL - 28

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JO - Bioorganic & Medicinal Chemistry Letters

T2 - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

SN - 0960-894X

IS - 18

ER -