Design and synthesis of broad spectrum trypanosomatid selective inhibitors

Andrew L. Fraser; Stefanie K. Menzies; Elizabeth F. B. King; Lindsay Tulloch; Eoin R. Gould; Marija Zacharova; Terry K. Smith; Gordon J. Florence

doi:10.1021/acsinfecdis.7b00187

Design and synthesis of broad spectrum trypanosomatid selective inhibitors

Andrew L. Fraser, Stefanie K. Menzies, Elizabeth F. B. King, Lindsay Tulloch, Eoin R. Gould, Marija Zacharova, Terry K. Smith, Gordon J. Florence

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

Abstract

Neglected tropical diseases caused by parasitic infections are an ongoing and increasing concern that have a devastating effect on the developing world due to their burden on human and animal health. In this work, we detail the preparation of a focused library of substituted-tetrahydropyran derivatives and their evaluation as selective chemical tools for trypanosomatid inhibition and the follow-on development of photo-affinity probes capable of labeling target protein(s) in vitro. Several of these functionalised compounds maintain low micromolar activity against Trypanosoma brucei, Trypanosoma cruzi, Leishmania major and Leishmania donovani. In addition we demonstrate the utility of the photo-affinity probes for target identification through preliminary cellular localization studies.

Original language	English
Pages (from-to)	560-567
Number of pages	8
Journal	ACS Infectious Diseases
Volume	4
Issue number	4
Early online date	9 Jan 2018
DOIs	https://doi.org/10.1021/acsinfecdis.7b00187
Publication status	Published - 13 Apr 2018

Keywords

Trypanosomatid
Natural Products
Drug Design
Chemical Tools
Photo-affinity

UN SDGs

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

Access to Document

10.1021/acsinfecdis.7b00187

ID-2017-001875-revised
Copyright © 2018 American Chemical Society. This work has been made available online in accordance with the publisher’s policies. This is the author created accepted version manuscript following peer review and as such may differ slightly from the final published version. The final published version of this work is available at: https://doi.org/10.1021/acsinfecdis.7b00187
Accepted author manuscript, 2.03 MB

EU KINDRED: EU KINDRED-Management
Smith, T. K. (PI)
European Commission
1/09/13 → 31/08/16
Project: Standard
Natural Product Drug Discovery: Natural Product Drug Discovery: Design and Development of Novel Tryoanosoma brucei Inhibitors
Florence, G. J. (PI)
The Leverhulme Trust
1/03/13 → 30/11/18
Project: Standard

Gordon John Florence
- gjf1st-andrews.acuk
- School of Chemistry - Senior Lecturer
- Biomedical Sciences Research Complex
- EaSTCHEM
Person: Academic, Academic - Research

Cite this

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title = "Design and synthesis of broad spectrum trypanosomatid selective inhibitors",

abstract = "Neglected tropical diseases caused by parasitic infections are an ongoing and increasing concern that have a devastating effect on the developing world due to their burden on human and animal health. In this work, we detail the preparation of a focused library of substituted-tetrahydropyran derivatives and their evaluation as selective chemical tools for trypanosomatid inhibition and the follow-on development of photo-affinity probes capable of labeling target protein(s) in vitro. Several of these functionalised compounds maintain low micromolar activity against Trypanosoma brucei, Trypanosoma cruzi, Leishmania major and Leishmania donovani. In addition we demonstrate the utility of the photo-affinity probes for target identification through preliminary cellular localization studies.",

keywords = "Trypanosomatid, Natural Products, Drug Design, Chemical Tools, Photo-affinity",

author = "Fraser, {Andrew L.} and Menzies, {Stefanie K.} and King, {Elizabeth F. B.} and Lindsay Tulloch and Gould, {Eoin R.} and Marija Zacharova and Smith, {Terry K.} and Florence, {Gordon J.}",

note = "This work was funded by the Leverhulme Trust (GJF) and the European Community{\textquoteright}s Seventh Framework Programme under grant agreement No. 602773 [Project KINDRED] (TKS).",

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doi = "10.1021/acsinfecdis.7b00187",

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AU - Fraser, Andrew L.

AU - Menzies, Stefanie K.

AU - King, Elizabeth F. B.

AU - Tulloch, Lindsay

AU - Gould, Eoin R.

AU - Zacharova, Marija

AU - Smith, Terry K.

AU - Florence, Gordon J.

N1 - This work was funded by the Leverhulme Trust (GJF) and the European Community’s Seventh Framework Programme under grant agreement No. 602773 [Project KINDRED] (TKS).

PY - 2018/4/13

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N2 - Neglected tropical diseases caused by parasitic infections are an ongoing and increasing concern that have a devastating effect on the developing world due to their burden on human and animal health. In this work, we detail the preparation of a focused library of substituted-tetrahydropyran derivatives and their evaluation as selective chemical tools for trypanosomatid inhibition and the follow-on development of photo-affinity probes capable of labeling target protein(s) in vitro. Several of these functionalised compounds maintain low micromolar activity against Trypanosoma brucei, Trypanosoma cruzi, Leishmania major and Leishmania donovani. In addition we demonstrate the utility of the photo-affinity probes for target identification through preliminary cellular localization studies.

AB - Neglected tropical diseases caused by parasitic infections are an ongoing and increasing concern that have a devastating effect on the developing world due to their burden on human and animal health. In this work, we detail the preparation of a focused library of substituted-tetrahydropyran derivatives and their evaluation as selective chemical tools for trypanosomatid inhibition and the follow-on development of photo-affinity probes capable of labeling target protein(s) in vitro. Several of these functionalised compounds maintain low micromolar activity against Trypanosoma brucei, Trypanosoma cruzi, Leishmania major and Leishmania donovani. In addition we demonstrate the utility of the photo-affinity probes for target identification through preliminary cellular localization studies.

KW - Trypanosomatid

KW - Natural Products

KW - Drug Design

KW - Chemical Tools

KW - Photo-affinity

U2 - 10.1021/acsinfecdis.7b00187

DO - 10.1021/acsinfecdis.7b00187

M3 - Article

SN - 2373-8227

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SP - 560

EP - 567

JO - ACS Infectious Diseases

JF - ACS Infectious Diseases

IS - 4

ER -

Design and synthesis of broad spectrum trypanosomatid selective inhibitors

Abstract

Keywords

UN SDGs

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Projects

EU KINDRED: EU KINDRED-Management

Natural Product Drug Discovery: Natural Product Drug Discovery: Design and Development of Novel Tryoanosoma brucei Inhibitors

Profiles

Gordon John Florence

Cite this