Acyclic phosph(on)ate inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase

Keith Clinch; Douglas R. Crump; Gary B. Evans; Keith Z. Hazleton; Jennifer M. Mason; Vern L. Schramm; Peter C. Tyler

doi:10.1016/j.bmc.2013.02.016

Acyclic phosph(on)ate inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase

Keith Clinch, Douglas R. Crump, Gary B. Evans, Keith Z. Hazleton, Jennifer M. Mason, Vern L. Schramm, Peter C. Tyler

Biochemistry

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

34 Scopus citations

Abstract

The pathogenic protozoa responsible for malaria lack enzymes for the de novo synthesis of purines and rely on purine salvage from the host. In Plasmodium falciparum (Pf), hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) converts hypoxanthine to inosine monophosphate and is essential for purine salvage making the enzyme an anti-malarial drug target. We have synthesized a number of simple acyclic aza-C-nucleosides and shown that some are potent inhibitors of Pf HGXPRT while showing excellent selectivity for the Pf versus the human enzyme.

Original language	English (US)
Pages (from-to)	5629-5646
Number of pages	18
Journal	Bioorganic and Medicinal Chemistry
Volume	21
Issue number	17
DOIs	https://doi.org/10.1016/j.bmc.2013.02.016
State	Published - Sep 1 2013

Keywords

HGXPRTase
Malaria
Phosphoribosyltransferase
Protozoa
Purine salvage

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)

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10.1016/j.bmc.2013.02.016

Cite this

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title = "Acyclic phosph(on)ate inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase",

abstract = "The pathogenic protozoa responsible for malaria lack enzymes for the de novo synthesis of purines and rely on purine salvage from the host. In Plasmodium falciparum (Pf), hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) converts hypoxanthine to inosine monophosphate and is essential for purine salvage making the enzyme an anti-malarial drug target. We have synthesized a number of simple acyclic aza-C-nucleosides and shown that some are potent inhibitors of Pf HGXPRT while showing excellent selectivity for the Pf versus the human enzyme.",

keywords = "HGXPRTase, Malaria, Phosphoribosyltransferase, Protozoa, Purine salvage",

author = "Keith Clinch and Crump, {Douglas R.} and Evans, {Gary B.} and Hazleton, {Keith Z.} and Mason, {Jennifer M.} and Schramm, {Vern L.} and Tyler, {Peter C.}",

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T1 - Acyclic phosph(on)ate inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase

AU - Clinch, Keith

AU - Crump, Douglas R.

AU - Evans, Gary B.

AU - Hazleton, Keith Z.

AU - Mason, Jennifer M.

AU - Schramm, Vern L.

AU - Tyler, Peter C.

PY - 2013/9/1

Y1 - 2013/9/1

N2 - The pathogenic protozoa responsible for malaria lack enzymes for the de novo synthesis of purines and rely on purine salvage from the host. In Plasmodium falciparum (Pf), hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) converts hypoxanthine to inosine monophosphate and is essential for purine salvage making the enzyme an anti-malarial drug target. We have synthesized a number of simple acyclic aza-C-nucleosides and shown that some are potent inhibitors of Pf HGXPRT while showing excellent selectivity for the Pf versus the human enzyme.

AB - The pathogenic protozoa responsible for malaria lack enzymes for the de novo synthesis of purines and rely on purine salvage from the host. In Plasmodium falciparum (Pf), hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) converts hypoxanthine to inosine monophosphate and is essential for purine salvage making the enzyme an anti-malarial drug target. We have synthesized a number of simple acyclic aza-C-nucleosides and shown that some are potent inhibitors of Pf HGXPRT while showing excellent selectivity for the Pf versus the human enzyme.

KW - HGXPRTase

KW - Malaria

KW - Phosphoribosyltransferase

KW - Protozoa

KW - Purine salvage

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Acyclic phosph(on)ate inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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