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Design, Synthesis and Biological Evaluation of Novel Inhibitors of Trypanosoma brucei Pteridine Reductase 1

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Design, Synthesis and Biological Evaluation of Novel Inhibitors of Trypanosoma brucei Pteridine Reductase 1. / Spinks, Daniel; Ong, Han B.; Mpamhanga, Chidochangu P.; Shanks, Emma J.; Robinson, David A.; Collie, Iain T.; Read, Kevin D.; Frearson, Julie A.; Wyatt, Paul G.; Brenk, Ruth; Fairlamb, Alan H.; Gilbert, Ian H.

In: ChemMedChem, Vol. 6, No. 2, 07.02.2011, p. 302-308.

Research output: Contribution to journalArticle

Harvard

Spinks, D, Ong, HB, Mpamhanga, CP, Shanks, EJ, Robinson, DA, Collie, IT, Read, KD, Frearson, JA, Wyatt, PG, Brenk, R, Fairlamb, AH & Gilbert, IH 2011, 'Design, Synthesis and Biological Evaluation of Novel Inhibitors of Trypanosoma brucei Pteridine Reductase 1' ChemMedChem, vol 6, no. 2, pp. 302-308.

APA

Spinks, D., Ong, H. B., Mpamhanga, C. P., Shanks, E. J., Robinson, D. A., Collie, I. T., Read, K. D., Frearson, J. A., Wyatt, P. G., Brenk, R., Fairlamb, A. H., & Gilbert, I. H. (2011). Design, Synthesis and Biological Evaluation of Novel Inhibitors of Trypanosoma brucei Pteridine Reductase 1. ChemMedChem, 6(2), 302-308doi: 10.1002/cmdc.201000450

Vancouver

Spinks D, Ong HB, Mpamhanga CP, Shanks EJ, Robinson DA, Collie IT et al. Design, Synthesis and Biological Evaluation of Novel Inhibitors of Trypanosoma brucei Pteridine Reductase 1. ChemMedChem. 2011 Feb 7;6(2):302-308.

Author

Spinks, Daniel; Ong, Han B.; Mpamhanga, Chidochangu P.; Shanks, Emma J.; Robinson, David A.; Collie, Iain T.; Read, Kevin D.; Frearson, Julie A.; Wyatt, Paul G.; Brenk, Ruth; Fairlamb, Alan H.; Gilbert, Ian H. / Design, Synthesis and Biological Evaluation of Novel Inhibitors of Trypanosoma brucei Pteridine Reductase 1.

In: ChemMedChem, Vol. 6, No. 2, 07.02.2011, p. 302-308.

Research output: Contribution to journalArticle

Bibtex - Download

@article{c4c1784247e04e6a9b6bdc46f4bda251,
title = "Design, Synthesis and Biological Evaluation of Novel Inhibitors of Trypanosoma brucei Pteridine Reductase 1",
author = "Daniel Spinks and Ong, {Han B.} and Mpamhanga, {Chidochangu P.} and Shanks, {Emma J.} and Robinson, {David A.} and Collie, {Iain T.} and Read, {Kevin D.} and Frearson, {Julie A.} and Wyatt, {Paul G.} and Ruth Brenk and Fairlamb, {Alan H.} and Gilbert, {Ian H.}",
year = "2011",
volume = "6",
number = "2",
pages = "302--308",
journal = "ChemMedChem",
issn = "1860-7179",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Design, Synthesis and Biological Evaluation of Novel Inhibitors of Trypanosoma brucei Pteridine Reductase 1

A1 - Spinks,Daniel

A1 - Ong,Han B.

A1 - Mpamhanga,Chidochangu P.

A1 - Shanks,Emma J.

A1 - Robinson,David A.

A1 - Collie,Iain T.

A1 - Read,Kevin D.

A1 - Frearson,Julie A.

A1 - Wyatt,Paul G.

A1 - Brenk,Ruth

A1 - Fairlamb,Alan H.

A1 - Gilbert,Ian H.

AU - Spinks,Daniel

AU - Ong,Han B.

AU - Mpamhanga,Chidochangu P.

AU - Shanks,Emma J.

AU - Robinson,David A.

AU - Collie,Iain T.

AU - Read,Kevin D.

AU - Frearson,Julie A.

AU - Wyatt,Paul G.

AU - Brenk,Ruth

AU - Fairlamb,Alan H.

AU - Gilbert,Ian H.

PY - 2011/2/7

Y1 - 2011/2/7

N2 - <p>Genetic studies indicate that the enzyme pteridine reductase 1 (PTR1) is essential for the survival of the protozoan parasite Trypanosoma brucei. Herein, we describe the development and optimisation of a novel series of PTR1 inhibitors, based on benzo[d]imidazol-2-amine derivatives. Data are reported on 33 compounds. This series was initially discovered by a virtual screening campaign (J. Med. Chem., 2009, 52, 4454). The inhibitors adopted an alternative binding mode to those of the natural ligands, biopterin and dihydrobiopterin, and classical inhibitors, such as methotrexate. Using both rational medicinal chemistry and structure-based approaches, we were able to derive compounds with potent activity against T. brucei PTR1 (K-i(app) = 7 nm), which had high selectivity over both human and T. brucei dihydrofolate reductase. Unfortunately, these compounds displayed weak activity against the parasites. Kinetic studies and analysis indicate that the main reason for the lack of cell potency is due to the compounds having insufficient potency against the enzyme, which can be seen from the low K-m to K-i ratio (K-m = 25 nm and K-i = 2.3 nm, respectively).</p>

AB - <p>Genetic studies indicate that the enzyme pteridine reductase 1 (PTR1) is essential for the survival of the protozoan parasite Trypanosoma brucei. Herein, we describe the development and optimisation of a novel series of PTR1 inhibitors, based on benzo[d]imidazol-2-amine derivatives. Data are reported on 33 compounds. This series was initially discovered by a virtual screening campaign (J. Med. Chem., 2009, 52, 4454). The inhibitors adopted an alternative binding mode to those of the natural ligands, biopterin and dihydrobiopterin, and classical inhibitors, such as methotrexate. Using both rational medicinal chemistry and structure-based approaches, we were able to derive compounds with potent activity against T. brucei PTR1 (K-i(app) = 7 nm), which had high selectivity over both human and T. brucei dihydrofolate reductase. Unfortunately, these compounds displayed weak activity against the parasites. Kinetic studies and analysis indicate that the main reason for the lack of cell potency is due to the compounds having insufficient potency against the enzyme, which can be seen from the low K-m to K-i ratio (K-m = 25 nm and K-i = 2.3 nm, respectively).</p>

KW - antiprotozoal agents

KW - drug discovery

KW - pteridine reductase

KW - structure-based drug design

KW - Trypanosoma brucei

KW - PARASITE LEISHMANIA-MAJOR

KW - ANTIOPPORTUNISTIC INFECTION AGENTS

KW - DIHYDROFOLATE-REDUCTASE

KW - METHOTREXATE

KW - DISCOVERY

KW - ANTITUMOR

UR - http://ukpmc.ac.uk/articles/PMC3047710

U2 - 10.1002/cmdc.201000450

DO - 10.1002/cmdc.201000450

M1 - Article

JO - ChemMedChem

JF - ChemMedChem

SN - 1860-7179

IS - 2

VL - 6

SP - 302

EP - 308

ER -

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