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Synthesis and Evaluation of Indatraline‐Based Inhibitors for Trypanothione Reductase
Author(s) -
Walton Jeffrey G. A.,
Jones Deuan C.,
Kiuru Paula,
Durie Alastair J.,
Westwood Nicholas J.,
Fairlamb Alan H.
Publication year - 2011
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.201000442
Subject(s) - trypanosoma brucei , mode of action , stereochemistry , chemistry , potency , substituent , amine gas treating , pharmacology , drug , biochemistry , combinatorial chemistry , biology , in vitro , organic chemistry , gene
The search for novel compounds of relevance to the treatment of diseases caused by trypanosomatid protozoan parasites continues. Screening of a large library of known bioactive compounds has led to several drug‐like starting points for further optimisation. In this study, novel analogues of the monoamine uptake inhibitor indatraline were prepared and assessed both as inhibitors of trypanothione reductase (TryR) and against the parasite Trypanosoma brucei . Although it proved difficult to significantly increase the potency of the original compound as an inhibitor of TryR, some insight into the preferred substituent on the amine group and in the two aromatic rings of the parent indatraline was deduced. In addition, detailed mode of action studies indicated that two of the inhibitors exhibit a mixed mode of inhibition.