Abstract
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 language | English |
|---|---|
| Pages (from-to) | 9686-9720 |
| Number of pages | 35 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 59 |
| Issue number | 21 |
| Early online date | 22 Aug 2016 |
| DOIs | |
| Publication status | Published - Nov 2016 |
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Hit-to-lead optimization of a novel class of potent, broad-spectrum trypanosomacides. / Russell, Stephanie; Rahmani, R.; Jones, A.J.; Newson, Harriet; Neilde, K.; Cotillo, I.; Khajouei, M.; Ferrins, L.; Qureishi, Sana; Nguyen, N.; Martinez-Martinez, M.S.; Weaver, D.F.; Kaiser, M.; Riley, J.; Thomas, J.; De Rycker, M.; Read, K.D.; Flematti, Gavin; Ryan, E.; Tanghe, S.; Rodriguez, A.; Charman, S.A.; Kessler, A.; Avery, V.M.; Baell, J.B.; Piggott, Matthew.
In: Journal of Medicinal Chemistry, Vol. 59, No. 21, 11.2016, p. 9686-9720.Research output: Contribution to journal › Article
TY - JOUR
T1 - Hit-to-lead optimization of a novel class of potent, broad-spectrum trypanosomacides
AU - Russell, Stephanie
AU - Rahmani, R.
AU - Jones, A.J.
AU - Newson, Harriet
AU - Neilde, K.
AU - Cotillo, I.
AU - Khajouei, M.
AU - Ferrins, L.
AU - Qureishi, Sana
AU - Nguyen, N.
AU - Martinez-Martinez, M.S.
AU - Weaver, D.F.
AU - Kaiser, M.
AU - Riley, J.
AU - Thomas, J.
AU - De Rycker, M.
AU - Read, K.D.
AU - Flematti, Gavin
AU - Ryan, E.
AU - Tanghe, S.
AU - Rodriguez, A.
AU - Charman, S.A.
AU - Kessler, A.
AU - Avery, V.M.
AU - Baell, J.B.
AU - Piggott, Matthew
PY - 2016/11
Y1 - 2016/11
N2 - © 2016 American Chemical Society.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 - © 2016 American Chemical Society.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.
U2 - 10.1021/acs.jmedchem.6b00442
DO - 10.1021/acs.jmedchem.6b00442
M3 - Article
VL - 59
SP - 9686
EP - 9720
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 21
ER -