Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides
Author(s)
Russell, Stephanie
Rahmani, Raphael
Jones, Amy J
Newson, Harriet L
Neilde, Kevin
Cotillo, Ignacio
Khajouei, Marzieh Rahmani
Ferrins, Lori
Qureishi, Sana
Nghi, Nguyen
Martinez-Martinez, Maria S
Weaver, Donald F
Kaiser, Marcel
Riley, Jennifer
Thomas, John
De Rycker, Manu
Read, Kevin D
Flematti, Gavin R
Ryan, Eileen
Tanghe, Scott
Rodriguez, Ana
Charman, Susan A
Kessler, Albane
Avery, Vicky M
Baell, Jonathan B
Piggott, Matthew J
Griffith University Author(s)
Year published
2016
Metadata
Show full item recordAbstract
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 ...
View more >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.
View less >
View more >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.
View less >
Journal Title
Journal of Medicinal Chemistry
Volume
59
Subject
Medicinal and biomolecular chemistry
Medicinal and biomolecular chemistry not elsewhere classified
Organic chemistry
Pharmacology and pharmaceutical sciences