Improved Tricyclic Inhibitors of Trypanothione Reductase by Screening and Chemical Synthesis

John L. Richardson; Isabelle R. E. Nett; Deuan C. Jones; Mohamed H. Abdille; Ian H. Gilbert; Alan H. Fairlamb

doi:10.1002/cmdc.200900097

Improved Tricyclic Inhibitors of Trypanothione Reductase by Screening and Chemical Synthesis

John L. Richardson, Isabelle R. E. Nett, Deuan C. Jones, Mohamed H. Abdille, Ian H. Gilbert, Alan H. Fairlamb

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

66 Citations (Scopus)

Abstract

Trypanothione reductase (TryR) is a key validated enzyme in the trypanothione-based redox metabolism of pathogenic trypanosomes and leishmania parasites. This system is absent in humans, being replaced with glutathione and glutathione reductase, and as such offers a target for selective inhibition. As part of a program to discover antiparasitic drugs, the LOPAC1280 library of 1266 compounds was screened against TryR and the top hits evaluated against glutathione reductase and T. brucei parasites. The top hits included a number of known tricyclic neuroleptic drugs along with other new scaffolds for TryR. Three novel druglike hits were identified and SAR studies on one of these using information from the tricyclic neuroleptic agents led to the discovery of a competitive inhibitor K-i=330 nM) with an improved potency against T. brucei (EC50 = 775 nM).

Original language	English
Pages (from-to)	1333-1340
Number of pages	8
Journal	ChemMedChem
Volume	4
Issue number	8
DOIs	https://doi.org/10.1002/cmdc.200900097
Publication status	Published - Aug 2009

Keywords

drug discovery
inhibitors
oxidoreductases
trypanosoma brucei
trypanothione reductase
BLOOD-STREAM FORMS
TRYPANOSOMA-CRUZI
GLUTATHIONE-REDUCTASE
LEISHMANIA-DONOVANI
ANTITRYPANOSOMAL ACTIVITY
COMPETITIVE INHIBITORS
CRITHIDIA-FASCICULATA
SUBSTRATE-SPECIFICITY
POLYAMINE DERIVATIVES
AFRICAN TRYPANOSOMES

Access to Document

10.1002/cmdc.200900097

Aref#d: 19815. Wellcome Trust Centre for Drug Discovery (Strategic Award)
Fairlamb, A. (Investigator), Ferguson, M. (Investigator) & Frearson, J. (Investigator)
1/01/08 → 31/12/12
Project: Research
Aref#d: 18185. Characterization and validation of drug targets in the Kinetoplastida (Principal Research Fellowship/Programme Grant)
Fairlamb, A. (Investigator)
1/10/06 → 30/09/17
Project: Research

Cite this

@article{1a205346e3d149d58436e90e2854c9d1,

title = "Improved Tricyclic Inhibitors of Trypanothione Reductase by Screening and Chemical Synthesis",

abstract = "Trypanothione reductase (TryR) is a key validated enzyme in the trypanothione-based redox metabolism of pathogenic trypanosomes and leishmania parasites. This system is absent in humans, being replaced with glutathione and glutathione reductase, and as such offers a target for selective inhibition. As part of a program to discover antiparasitic drugs, the LOPAC1280 library of 1266 compounds was screened against TryR and the top hits evaluated against glutathione reductase and T. brucei parasites. The top hits included a number of known tricyclic neuroleptic drugs along with other new scaffolds for TryR. Three novel druglike hits were identified and SAR studies on one of these using information from the tricyclic neuroleptic agents led to the discovery of a competitive inhibitor K-i=330 nM) with an improved potency against T. brucei (EC50 = 775 nM).",

keywords = "drug discovery, inhibitors, oxidoreductases, trypanosoma brucei, trypanothione reductase, BLOOD-STREAM FORMS, TRYPANOSOMA-CRUZI, GLUTATHIONE-REDUCTASE, LEISHMANIA-DONOVANI, ANTITRYPANOSOMAL ACTIVITY, COMPETITIVE INHIBITORS, CRITHIDIA-FASCICULATA, SUBSTRATE-SPECIFICITY, POLYAMINE DERIVATIVES, AFRICAN TRYPANOSOMES",

author = "Richardson, {John L.} and Nett, {Isabelle R. E.} and Jones, {Deuan C.} and Abdille, {Mohamed H.} and Gilbert, {Ian H.} and Fairlamb, {Alan H.}",

year = "2009",

month = aug,

doi = "10.1002/cmdc.200900097",

language = "English",

volume = "4",

pages = "1333--1340",

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issn = "1860-7179",

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AU - Richardson, John L.

AU - Nett, Isabelle R. E.

AU - Jones, Deuan C.

AU - Abdille, Mohamed H.

AU - Gilbert, Ian H.

AU - Fairlamb, Alan H.

PY - 2009/8

Y1 - 2009/8

N2 - Trypanothione reductase (TryR) is a key validated enzyme in the trypanothione-based redox metabolism of pathogenic trypanosomes and leishmania parasites. This system is absent in humans, being replaced with glutathione and glutathione reductase, and as such offers a target for selective inhibition. As part of a program to discover antiparasitic drugs, the LOPAC1280 library of 1266 compounds was screened against TryR and the top hits evaluated against glutathione reductase and T. brucei parasites. The top hits included a number of known tricyclic neuroleptic drugs along with other new scaffolds for TryR. Three novel druglike hits were identified and SAR studies on one of these using information from the tricyclic neuroleptic agents led to the discovery of a competitive inhibitor K-i=330 nM) with an improved potency against T. brucei (EC50 = 775 nM).

AB - Trypanothione reductase (TryR) is a key validated enzyme in the trypanothione-based redox metabolism of pathogenic trypanosomes and leishmania parasites. This system is absent in humans, being replaced with glutathione and glutathione reductase, and as such offers a target for selective inhibition. As part of a program to discover antiparasitic drugs, the LOPAC1280 library of 1266 compounds was screened against TryR and the top hits evaluated against glutathione reductase and T. brucei parasites. The top hits included a number of known tricyclic neuroleptic drugs along with other new scaffolds for TryR. Three novel druglike hits were identified and SAR studies on one of these using information from the tricyclic neuroleptic agents led to the discovery of a competitive inhibitor K-i=330 nM) with an improved potency against T. brucei (EC50 = 775 nM).

KW - drug discovery

KW - inhibitors

KW - oxidoreductases

KW - trypanosoma brucei

KW - trypanothione reductase

KW - BLOOD-STREAM FORMS

KW - TRYPANOSOMA-CRUZI

KW - GLUTATHIONE-REDUCTASE

KW - LEISHMANIA-DONOVANI

KW - ANTITRYPANOSOMAL ACTIVITY

KW - COMPETITIVE INHIBITORS

KW - CRITHIDIA-FASCICULATA

KW - SUBSTRATE-SPECIFICITY

KW - POLYAMINE DERIVATIVES

KW - AFRICAN TRYPANOSOMES

U2 - 10.1002/cmdc.200900097

DO - 10.1002/cmdc.200900097

M3 - Article

C2 - 19557801

SN - 1860-7179

VL - 4

SP - 1333

EP - 1340

JO - ChemMedChem

JF - ChemMedChem

IS - 8

ER -

Improved Tricyclic Inhibitors of Trypanothione Reductase by Screening and Chemical Synthesis

Abstract

Keywords

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Projects

Aref#d: 19815. Wellcome Trust Centre for Drug Discovery (Strategic Award)

Aref#d: 18185. Characterization and validation of drug targets in the Kinetoplastida (Principal Research Fellowship/Programme Grant)

Cite this