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, Matthew J. Piggott

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 languageEnglish
Pages (from-to)9686-9720
Number of pages35
JournalJournal of Medicinal Chemistry
Volume59
Issue number21
Early online date22 Aug 2016
DOIs
Publication statusPublished - 10 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

Cite this

Russell, S., Rahmani, R., Jones, A. J., Newson, H. L., Neilde, K., Cotillo, I., ... Piggott, M. J. (2016). Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides. Journal of Medicinal Chemistry, 59(21), 9686-9720. https://doi.org/10.1021/acs.jmedchem.6b00442
Russell, Stephanie ; Rahmani, Raphaël ; Jones, Amy J. ; Newson, Harriet L. ; Neilde, Kevin ; Cotillo, Ignacio ; Rahmani Khajouei, Marzieh ; Ferrins, Lori ; Qureishi, Sana ; Nguyen, Nghi ; 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. / 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 = "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.",
author = "Stephanie Russell and Rapha{\"e}l Rahmani and Jones, {Amy J.} and Newson, {Harriet L.} and Kevin Neilde and Ignacio Cotillo and {Rahmani Khajouei}, Marzieh and Lori Ferrins and Sana Qureishi and Nghi Nguyen and Martinez-Martinez, {Maria S.} and Weaver, {Donald F.} and Marcel Kaiser and Jennifer Riley and John Thomas and {De Rycker}, Manu and Read, {Kevin D.} and Flematti, {Gavin R.} and Eileen Ryan and Scott Tanghe and Ana Rodriguez and Charman, {Susan A.} and Albane Kessler and Avery, {Vicky M.} and Baell, {Jonathan B.} and Piggott, {Matthew J.}",
note = "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.",
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Russell, S, Rahmani, R, Jones, AJ, Newson, HL, Neilde, K, Cotillo, I, Rahmani 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, GR, Ryan, E, Tanghe, S, Rodriguez, A, Charman, SA, Kessler, A, Avery, VM, Baell, JB & Piggott, MJ 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, Raphaël (Lead / Corresponding author); Jones, Amy J.; Newson, Harriet L.; Neilde, Kevin; Cotillo, Ignacio; Rahmani Khajouei, Marzieh; Ferrins, Lori; Qureishi, Sana; Nguyen, Nghi; 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. (Lead / Corresponding author); Piggott, Matthew J. (Lead / Corresponding author).

In: Journal of Medicinal Chemistry, Vol. 59, No. 21, 10.11.2016, p. 9686-9720.

Research output: Contribution to journalArticle

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.

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U2 - 10.1021/acs.jmedchem.6b00442

DO - 10.1021/acs.jmedchem.6b00442

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AN - SCOPUS:84994894955

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JF - Journal of Medicinal Chemistry

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