Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides

Stephanie Russell, Raphaël Rahmani (Lead / Corresponding author), Amy J. Jones, Harriet L. Newson, Kevin Neilde, Ignacio Cotillo, Marzieh Rahmani Khajouei, Lori Ferrins, Sana Qureishi, Nghi Nguyen, Maria S. Martinez-Martinez, Donald F. Weaver, Marcel Kaiser, Jennifer Riley, John Thomas, Manu De Rycker, Kevin D. Read, Gavin R. Flematti, Eileen Ryan, Scott TangheAna Rodriguez, Susan A. Charman, Albane Kessler, Vicky M. Avery, Jonathan B. Baell (Lead / Corresponding author), Matthew J. Piggott (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)


The parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for significant human suffering in the form of human African trypanosomiasis (HAT) and Chagas disease. Drugs currently available to treat these neglected diseases leave much to be desired. Herein we report optimization of a novel class of N-(2-(2-phenylthiazol-4-yl)ethyl)amides, carbamates, and ureas, which rapidly, selectively, and potently kill both species of trypanosome. The mode of action of these compounds is unknown but does not involve CYP51 inhibition. They do, however, exhibit clear structure-activity relationships, consistent across both trypanosome species. Favorable physicochemical parameters place the best compounds in CNS drug-like chemical space but, as a class, they exhibit poor metabolic stability. One of the best compounds (64a) cleared all signs of T. cruzi infection in mice when CYP metabolism was inhibited, with sterile cure achieved in one mouse. This family of compounds thus shows significant promise for trypanosomiasis drug discovery.

Original languageEnglish
Pages (from-to)9686-9720
Number of pages35
JournalJournal of Medicinal Chemistry
Issue number21
Early online date22 Aug 2016
Publication statusPublished - 10 Nov 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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