Design and Synthesis of Broad Spectrum Trypanosomatid Selective Inhibitors

A. L. Fraser; S. K. Menzies; E. F. B. King; L. B. Tulloch; E. R. Gould; M. K. Zacharova; T. K. Smith; G. J. Florence

doi:10.1021/acsinfecdis.7b00187

Design and Synthesis of Broad Spectrum Trypanosomatid Selective Inhibitors

A. L. Fraser
, S. K. Menzies
, E. F. B. King
, L. B. Tulloch
, E. R. Gould
, M. K. Zacharova
, T. K. Smith (Lead / Corresponding author)
, G. J. Florence (Lead / Corresponding author)

Drug Discovery Unit

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

10 Citations (Scopus)

191 Downloads (Pure)

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 photoaffinity probes capable of labeling target protein(s) in vitro. Several of these functionalized compounds maintain low micromolar activity against Trypanosoma brucei, Trypanosoma cruzi, Leishmania major, and Leishmania donovani. In addition, we demonstrate the utility of the photoaffinity 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	19 Jan 2018
DOIs	https://doi.org/10.1021/acsinfecdis.7b00187
Publication status	Published - 13 Apr 2018

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

Trypanosomatid
Natural Products
Drug Design
Chemical Tools
Photo-affinity

Access to Document

10.1021/acsinfecdis.7b00187

Author Accepted ManuscriptAccepted author manuscript, 2.11 MB

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 photoaffinity probes capable of labeling target protein(s) in vitro. Several of these functionalized compounds maintain low micromolar activity against Trypanosoma brucei, Trypanosoma cruzi, Leishmania major, and Leishmania donovani. In addition, we demonstrate the utility of the photoaffinity probes for target identification through preliminary cellular localization studies.",

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

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doi = "10.1021/acsinfecdis.7b00187",

language = "English",

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journal = "ACS Infectious Diseases",

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TY - JOUR

T1 - Design and Synthesis of Broad Spectrum Trypanosomatid Selective Inhibitors

AU - Fraser, A. L.

AU - Menzies, S. K.

AU - King, E. F. B.

AU - Tulloch, L. B.

AU - Gould, E. R.

AU - Zacharova, M. K.

AU - Smith, T. K.

AU - Florence, G. J.

PY - 2018/4/13

Y1 - 2018/4/13

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 photoaffinity probes capable of labeling target protein(s) in vitro. Several of these functionalized compounds maintain low micromolar activity against Trypanosoma brucei, Trypanosoma cruzi, Leishmania major, and Leishmania donovani. In addition, we demonstrate the utility of the photoaffinity 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 photoaffinity probes capable of labeling target protein(s) in vitro. Several of these functionalized compounds maintain low micromolar activity against Trypanosoma brucei, Trypanosoma cruzi, Leishmania major, and Leishmania donovani. In addition, we demonstrate the utility of the photoaffinity probes for target identification through preliminary cellular localization studies.

KW - Trypanosomatid

KW - Natural Products

KW - Drug Design

KW - Chemical Tools

KW - Photo-affinity

UR - http://europepmc.org/abstract/med/29313667

U2 - 10.1021/acsinfecdis.7b00187

DO - 10.1021/acsinfecdis.7b00187

M3 - Article

C2 - 29313667

SN - 2373-8227

VL - 4

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

UN SDGs

Keywords

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