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 EschR. 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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