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

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
Externally published	Yes

Keywords

HGXPRTase
Malaria
Phosphoribosyltransferase
Protozoa
Purine salvage

ASJC Scopus subject areas

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

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10.1016/j.bmc.2013.02.016

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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",

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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

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