Hit-to-lead optimization of a novel class of potent, broad-spectrum trypanosomacides

Stephanie Russell, R. Rahmani, A.J. Jones, Harriet Newson, K. Neilde, I. Cotillo, M. Khajouei, L. Ferrins, Sana Qureishi, N. Nguyen, M.S. Martinez-Martinez, D.F. Weaver, M. Kaiser, J. Riley, J. Thomas, M. De Rycker, K.D. Read, Gavin Flematti, E. Ryan, S. Tanghe & 6 others A. Rodriguez, S.A. Charman, A. Kessler, V.M. Avery, J.B. Baell, Matthew Piggott

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Abstract

© 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.
Original languageEnglish
Pages (from-to)9686-9720
Number of pages35
JournalJournal of Medicinal Chemistry
Volume59
Issue number21
Early online date22 Aug 2016
DOIs
Publication statusPublished - Nov 2016

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Trypanosomiasis
Neglected Diseases
African Trypanosomiasis
Trypanosoma brucei brucei
Chagas Disease
Urethane
Drug Discovery
Structure-Activity Relationship
Psychological Stress
Amides
Pharmaceutical Preparations
Urea
Lead
Infection

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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. / Hit-to-lead optimization of a novel class of potent, broad-spectrum trypanosomacides. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 21. pp. 9686-9720.
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abstract = "{\circledC} 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.",
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Russell, S, Rahmani, R, Jones, AJ, Newson, H, Neilde, K, Cotillo, I, Khajouei, M, Ferrins, L, Qureishi, S, Nguyen, N, Martinez-Martinez, MS, Weaver, DF, Kaiser, M, Riley, J, Thomas, J, De Rycker, M, Read, KD, Flematti, G, Ryan, E, Tanghe, S, Rodriguez, A, Charman, SA, Kessler, A, Avery, VM, Baell, JB & Piggott, M 2016, 'Hit-to-lead optimization of a novel class of potent, broad-spectrum trypanosomacides' Journal of Medicinal Chemistry, vol. 59, no. 21, pp. 9686-9720. https://doi.org/10.1021/acs.jmedchem.6b00442

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 journalArticle

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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

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ER -