TY - JOUR
T1 - Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides
AU - Russell, Stephanie
AU - Rahmani, Raphaël
AU - Jones, Amy J.
AU - Newson, Harriet L.
AU - Neilde, Kevin
AU - Cotillo, Ignacio
AU - Rahmani Khajouei, Marzieh
AU - Ferrins, Lori
AU - Qureishi, Sana
AU - Nguyen, Nghi
AU - Martinez-Martinez, Maria S.
AU - Weaver, Donald F.
AU - Kaiser, Marcel
AU - Riley, Jennifer
AU - Thomas, John
AU - De Rycker, Manu
AU - Read, Kevin D.
AU - Flematti, Gavin R.
AU - Ryan, Eileen
AU - Tanghe, Scott
AU - Rodriguez, Ana
AU - Charman, Susan A.
AU - Kessler, Albane
AU - Avery, Vicky M.
AU - Baell, Jonathan B.
AU - Piggott, Matthew J.
N1 - supported by the National Health and MedicalResearch Council of Australia (NHMRC), IRIISS grant no.361646; NHMRC senior research fellowship 1020411 (J.B.B.), NHMRC project grant 1025581; NHMRC project grant 1079351; Victorian State Government OIS grant; the Tres Journal of Medicinal Chemistry Article DOI: 10.1021/acs.jmedchem.6b00442 J. Med. Chem. 2016, 59, 9686−97209714, Cantos Open Lab Foundation, Project grant TC150. M.d.R., K.R., and J.T. are supported by a Wellcome Trust Strategic grant 100476.
PY - 2016/11/10
Y1 - 2016/11/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84994894955&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.6b00442
DO - 10.1021/acs.jmedchem.6b00442
M3 - Article
C2 - 27548560
AN - SCOPUS:84994894955
SN - 0022-2623
VL - 59
SP - 9686
EP - 9720
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 21
ER -