Catechol pyrazolinones as trypanocidals: fragment-based design, synthesis, and pharmacological evaluation of nanomolar inhibitors of trypanosomal phosphodiesterase b1

K.M. Orrling, C.J.W. Jansen, X.L. Vu, V. Balmer, P. Bregy, A. Shanmugham, P. England, D. Bailey, P. Cos, L. Maes, E. Adams, E. van den Bogaart, E. Chatelain, J.R. Ioset, A. van de Stolpe, S. Zorg, J. Veerman, T. Seebeck, G.J. Sterk, I.J.P. de Esch & 1 others R. Leurs

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. We used homology modeling and docking studies to guide fragment growing into the parasite-specific P-pocket in the enzyme binding site. The resulting catechol pyrazolinones act as potent TbrPDEB1 inhibitors with IC
Original languageEnglish
Pages (from-to)8745-8756
JournalJournal of Medicinal Chemistry
Volume55
DOIs
Publication statusPublished - 2012

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African Trypanosomiasis
Phosphodiesterase Inhibitors
Parasites
Pharmacology
Trypanosoma brucei brucei
Phosphoric Diester Hydrolases
Life Cycle Stages
Binding Sites
Enzymes
catechol
Study Guide

Cite this

Orrling, K.M. ; Jansen, C.J.W. ; Vu, X.L. ; Balmer, V. ; Bregy, P. ; Shanmugham, A. ; England, P. ; Bailey, D. ; Cos, P. ; Maes, L. ; Adams, E. ; van den Bogaart, E. ; Chatelain, E. ; Ioset, J.R. ; van de Stolpe, A. ; Zorg, S. ; Veerman, J. ; Seebeck, T. ; Sterk, G.J. ; de Esch, I.J.P. ; Leurs, R. / Catechol pyrazolinones as trypanocidals: fragment-based design, synthesis, and pharmacological evaluation of nanomolar inhibitors of trypanosomal phosphodiesterase b1. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55. pp. 8745-8756.
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title = "Catechol pyrazolinones as trypanocidals: fragment-based design, synthesis, and pharmacological evaluation of nanomolar inhibitors of trypanosomal phosphodiesterase b1",
abstract = "Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. We used homology modeling and docking studies to guide fragment growing into the parasite-specific P-pocket in the enzyme binding site. The resulting catechol pyrazolinones act as potent TbrPDEB1 inhibitors with IC",
author = "K.M. Orrling and C.J.W. Jansen and X.L. Vu and V. Balmer and P. Bregy and A. Shanmugham and P. England and D. Bailey and P. Cos and L. Maes and E. Adams and {van den Bogaart}, E. and E. Chatelain and J.R. Ioset and {van de Stolpe}, A. and S. Zorg and J. Veerman and T. Seebeck and G.J. Sterk and {de Esch}, I.J.P. and R. Leurs",
year = "2012",
doi = "10.1021/jm301059b",
language = "English",
volume = "55",
pages = "8745--8756",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",

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Orrling, KM, Jansen, CJW, Vu, XL, Balmer, V, Bregy, P, Shanmugham, A, England, P, Bailey, D, Cos, P, Maes, L, Adams, E, van den Bogaart, E, Chatelain, E, Ioset, JR, van de Stolpe, A, Zorg, S, Veerman, J, Seebeck, T, Sterk, GJ, de Esch, IJP & Leurs, R 2012, 'Catechol pyrazolinones as trypanocidals: fragment-based design, synthesis, and pharmacological evaluation of nanomolar inhibitors of trypanosomal phosphodiesterase b1' Journal of Medicinal Chemistry, vol. 55, pp. 8745-8756. https://doi.org/10.1021/jm301059b

Catechol pyrazolinones as trypanocidals: fragment-based design, synthesis, and pharmacological evaluation of nanomolar inhibitors of trypanosomal phosphodiesterase b1. / Orrling, K.M.; Jansen, C.J.W.; Vu, X.L.; Balmer, V.; Bregy, P.; Shanmugham, A.; England, P.; Bailey, D.; Cos, P.; Maes, L.; Adams, E.; van den Bogaart, E.; Chatelain, E.; Ioset, J.R.; van de Stolpe, A.; Zorg, S.; Veerman, J.; Seebeck, T.; Sterk, G.J.; de Esch, I.J.P.; Leurs, R.

In: Journal of Medicinal Chemistry, Vol. 55, 2012, p. 8745-8756.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Catechol pyrazolinones as trypanocidals: fragment-based design, synthesis, and pharmacological evaluation of nanomolar inhibitors of trypanosomal phosphodiesterase b1

AU - Orrling, K.M.

AU - Jansen, C.J.W.

AU - Vu, X.L.

AU - Balmer, V.

AU - Bregy, P.

AU - Shanmugham, A.

AU - England, P.

AU - Bailey, D.

AU - Cos, P.

AU - Maes, L.

AU - Adams, E.

AU - van den Bogaart, E.

AU - Chatelain, E.

AU - Ioset, J.R.

AU - van de Stolpe, A.

AU - Zorg, S.

AU - Veerman, J.

AU - Seebeck, T.

AU - Sterk, G.J.

AU - de Esch, I.J.P.

AU - Leurs, R.

PY - 2012

Y1 - 2012

N2 - Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. We used homology modeling and docking studies to guide fragment growing into the parasite-specific P-pocket in the enzyme binding site. The resulting catechol pyrazolinones act as potent TbrPDEB1 inhibitors with IC

AB - Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. We used homology modeling and docking studies to guide fragment growing into the parasite-specific P-pocket in the enzyme binding site. The resulting catechol pyrazolinones act as potent TbrPDEB1 inhibitors with IC

U2 - 10.1021/jm301059b

DO - 10.1021/jm301059b

M3 - Article

VL - 55

SP - 8745

EP - 8756

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

ER -