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Improved Tricyclic Inhibitors of Trypanothione Reductase by Screening and Chemical Synthesis
Author(s) -
Richardson John L.,
Nett Isabelle R. E.,
Jones Deuan C.,
Abdille Mohamed H.,
Gilbert Ian H.,
Fairlamb Alan 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.200900097
Subject(s) - tricyclic , glutathione reductase , chemistry , antiparasitic , glutathione , pharmacology , reductase , enzyme , antiparasitic agent , biochemistry , thioredoxin reductase , trypanosoma brucei , stereochemistry , biology , medicine , glutathione peroxidase , pathology , gene
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 n M ) with an improved potency against T. brucei (EC 50 =775 n M ).