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Investigation of Trypanothione Reductase as a Drug Target in Trypanosoma brucei
Author(s) -
Spinks Daniel,
Shanks Emma J.,
Cleghorn Laura A. T.,
McElroy Stuart,
Jones Deuan,
James Daniel,
Fairlamb Alan H.,
Frearson Julie A.,
Wyatt Paul G.,
Gilbert Ian H.
Publication year - 2009
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200900262
Subject(s) - trypanosoma brucei , african trypanosomiasis , enzyme , drug discovery , quinoline , trypanosoma , drug , drug target , biochemistry , biology , potency , trypanosomiasis , reductase , pharmacology , chemistry , in vitro , virology , organic chemistry , gene
Abstract There is an urgent need for new drugs for the treatment of tropical parasitic diseases such as human African trypanosomiasis, which is caused by Trypanosoma brucei . The enzyme trypanothione reductase (TryR) is a potential drug target within these organisms. Herein we report the screening of a 62 000 compound library against T. brucei TryR. Further work was undertaken to optimise potency and selectivity of two novel‐compound series arising from the enzymatic and whole parasite screens and mammalian cell counterscreens. Both of these series, containing either a quinoline or pyrimidinopyrazine scaffold, yielded low micromolar inhibitors of the enzyme and growth of the parasite. The challenges of inhibiting TryR with druglike molecules is discussed.

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