Design, synthesis and trypanocidal activity of lead compounds based on inhibitors of parasite glycolysis

Matthew W. Nowicki; Lindsay B. Tulloch; Liam Worralll; Iain W. McNae; Véronique Hannaert; Paul A. M. Michels; Linda A. Fothergill-Gilmore; Malcolm D. Walkinshaw; Nicholas J. Turner

doi:10.1016/j.bmc.2008.03.045

Design, synthesis and trypanocidal activity of lead compounds based on inhibitors of parasite glycolysis

Matthew W. Nowicki, Lindsay B. Tulloch, Liam Worralll, Iain W. McNae, Véronique Hannaert, Paul A. M. Michels, Linda A. Fothergill-Gilmore, Malcolm D. Walkinshaw, Nicholas J. Turner (Lead / Corresponding author)

Drug Discovery Unit

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

58 Citations (Scopus)

Abstract

The glycolytic pathway has been considered a potential drug target against the parasitic protozoan species of Trypanosoma and Leishmania. We report the design and the synthesis of inhibitors targeted against Trypanosoma brucei phosphofructokinase (PFK) and Leishmania mexicana pyruvate kinase (PyK). Stepwise library synthesis and inhibitor design from a rational starting point identified furanose sugar amino amides as a novel class of inhibitors for both enzymes with IC(50) values of 23microM and 26microM against PFK and PyK, respectively. Trypanocidal activity also showed potency in the low micromolar range and confirms these inhibitors as promising candidates for the development towards the design of anti-trypanosomal drugs.

Original language	English
Pages (from-to)	5050-5061
Number of pages	12
Journal	Bioorganic & Medicinal Chemistry
Volume	16
Issue number	9
Early online date	21 Mar 2008
DOIs	https://doi.org/10.1016/j.bmc.2008.03.045
Publication status	Published - 1 May 2008

Keywords

Animals
Dose-Response Relationship, Drug
Drug Design
Enzyme Inhibitors/chemical synthesis
Glycolysis
Inhibitory Concentration 50
Lead/chemistry
Leishmania mexicana/drug effects
Models, Molecular
Molecular Structure
Organometallic Compounds/chemical synthesis
Parasitic Sensitivity Tests
Phosphofructokinases/antagonists & inhibitors
Pyruvate Kinase/antagonists & inhibitors
Stereoisomerism
Structure-Activity Relationship
Trypanocidal Agents/chemical synthesis
Trypanosoma brucei brucei/drug effects
Pyruvate kinase
Phosphofructokinase
Inhibitors
Leishmania
Trypanosome
Parasite
Drug development

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10.1016/j.bmc.2008.03.045

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title = "Design, synthesis and trypanocidal activity of lead compounds based on inhibitors of parasite glycolysis",

abstract = "The glycolytic pathway has been considered a potential drug target against the parasitic protozoan species of Trypanosoma and Leishmania. We report the design and the synthesis of inhibitors targeted against Trypanosoma brucei phosphofructokinase (PFK) and Leishmania mexicana pyruvate kinase (PyK). Stepwise library synthesis and inhibitor design from a rational starting point identified furanose sugar amino amides as a novel class of inhibitors for both enzymes with IC(50) values of 23microM and 26microM against PFK and PyK, respectively. Trypanocidal activity also showed potency in the low micromolar range and confirms these inhibitors as promising candidates for the development towards the design of anti-trypanosomal drugs.",

keywords = "Animals, Dose-Response Relationship, Drug, Drug Design, Enzyme Inhibitors/chemical synthesis, Glycolysis, Inhibitory Concentration 50, Lead/chemistry, Leishmania mexicana/drug effects, Models, Molecular, Molecular Structure, Organometallic Compounds/chemical synthesis, Parasitic Sensitivity Tests, Phosphofructokinases/antagonists & inhibitors, Pyruvate Kinase/antagonists & inhibitors, Stereoisomerism, Structure-Activity Relationship, Trypanocidal Agents/chemical synthesis, Trypanosoma brucei brucei/drug effects, Pyruvate kinase, Phosphofructokinase, Inhibitors, Leishmania, Trypanosome, Parasite, Drug development",

author = "Nowicki, {Matthew W.} and Tulloch, {Lindsay B.} and Liam Worralll and McNae, {Iain W.} and V{\'e}ronique Hannaert and Michels, {Paul A. M.} and Fothergill-Gilmore, {Linda A.} and Walkinshaw, {Malcolm D.} and Turner, {Nicholas J.}",

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doi = "10.1016/j.bmc.2008.03.045",

language = "English",

volume = "16",

pages = "5050--5061",

journal = "Bioorganic & Medicinal Chemistry",

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AU - Nowicki, Matthew W.

AU - Tulloch, Lindsay B.

AU - Worralll, Liam

AU - McNae, Iain W.

AU - Hannaert, Véronique

AU - Michels, Paul A. M.

AU - Fothergill-Gilmore, Linda A.

AU - Walkinshaw, Malcolm D.

AU - Turner, Nicholas J.

PY - 2008/5/1

Y1 - 2008/5/1

N2 - The glycolytic pathway has been considered a potential drug target against the parasitic protozoan species of Trypanosoma and Leishmania. We report the design and the synthesis of inhibitors targeted against Trypanosoma brucei phosphofructokinase (PFK) and Leishmania mexicana pyruvate kinase (PyK). Stepwise library synthesis and inhibitor design from a rational starting point identified furanose sugar amino amides as a novel class of inhibitors for both enzymes with IC(50) values of 23microM and 26microM against PFK and PyK, respectively. Trypanocidal activity also showed potency in the low micromolar range and confirms these inhibitors as promising candidates for the development towards the design of anti-trypanosomal drugs.

AB - The glycolytic pathway has been considered a potential drug target against the parasitic protozoan species of Trypanosoma and Leishmania. We report the design and the synthesis of inhibitors targeted against Trypanosoma brucei phosphofructokinase (PFK) and Leishmania mexicana pyruvate kinase (PyK). Stepwise library synthesis and inhibitor design from a rational starting point identified furanose sugar amino amides as a novel class of inhibitors for both enzymes with IC(50) values of 23microM and 26microM against PFK and PyK, respectively. Trypanocidal activity also showed potency in the low micromolar range and confirms these inhibitors as promising candidates for the development towards the design of anti-trypanosomal drugs.

KW - Animals

KW - Dose-Response Relationship, Drug

KW - Drug Design

KW - Enzyme Inhibitors/chemical synthesis

KW - Glycolysis

KW - Inhibitory Concentration 50

KW - Lead/chemistry

KW - Leishmania mexicana/drug effects

KW - Models, Molecular

KW - Molecular Structure

KW - Organometallic Compounds/chemical synthesis

KW - Parasitic Sensitivity Tests

KW - Phosphofructokinases/antagonists & inhibitors

KW - Pyruvate Kinase/antagonists & inhibitors

KW - Stereoisomerism

KW - Structure-Activity Relationship

KW - Trypanocidal Agents/chemical synthesis

KW - Trypanosoma brucei brucei/drug effects

KW - Pyruvate kinase

KW - Phosphofructokinase

KW - Inhibitors

KW - Leishmania

KW - Trypanosome

KW - Parasite

KW - Drug development

U2 - 10.1016/j.bmc.2008.03.045

DO - 10.1016/j.bmc.2008.03.045

M3 - Article

C2 - 18387804

SN - 0968-0896

VL - 16

SP - 5050

EP - 5061

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 9

ER -

Design, synthesis and trypanocidal activity of lead compounds based on inhibitors of parasite glycolysis

Abstract

Keywords

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