Design, Synthesis and Biological Evaluation of Trypanosoma brucei Trypanothione Synthetase Inhibitors

✍ Scribed by Daniel Spinks; Dr. Leah S. Torrie; Dr. Stephen Thompson; Dr. Justin R. Harrison; Prof. Julie A. Frearson; Dr. Kevin D. Read; Prof. Alan H. Fairlamb; Prof. Paul G. Wyatt; Prof. Ian H. Gilbert

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 318 KB
• Volume: 7
• Category: Article
• ISSN: 1860-7179
• DOI: 10.1002/cmdc.201100420

✦ Synopsis

Trypanothione synthetase (TryS) is essential for the survival of the protozoan parasite Trypanosoma brucei, which causes human African trypanosomiasis. It is one of only a handful of chemically validated targets for T. brucei in vivo. To identify novel inhibitors of __Tb__TryS we screened our in-house diverse compound library that contains 62 000 compounds. This resulted in the identification of six novel hit series of __Tb__TryS inhibitors. Herein we describe the SAR exploration of these hit series, which gave rise to one common series with potency against the enzyme target. Cellular studies on these inhibitors confirmed on-target activity, and the compounds have proven to be very useful tools for further study of the trypanothione pathway in kinetoplastids.