Discovery of Diaryl Ether Substituted Tetrahydrophthalazinones as TbrPDEB1 Inhibitors Following Structure-Based Virtual Screening

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Discovery of Diaryl Ether Substituted Tetrahydrophthalazinones as TbrPDEB1 Inhibitors Following Structure-Based Virtual Screening. / de Heuvel, Erik; Kooistra, Albert J.; Edink, Ewald; van Klaveren, Sjors; Stuijt, Jeffrey; van der Meer, Tiffany; Sadek, Payman; Mabille, Dorien; Caljon, Guy; Maes, Louis; Siderius, Marco; de Esch, Iwan J.P.; Sterk, Geert Jan; Leurs, Rob.

In: Frontiers in Chemistry, Vol. 8, 608030, 21.01.2021.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

de Heuvel, E, Kooistra, AJ, Edink, E, van Klaveren, S, Stuijt, J, van der Meer, T, Sadek, P, Mabille, D, Caljon, G, Maes, L, Siderius, M, de Esch, IJP, Sterk, GJ & Leurs, R 2021, 'Discovery of Diaryl Ether Substituted Tetrahydrophthalazinones as TbrPDEB1 Inhibitors Following Structure-Based Virtual Screening', Frontiers in Chemistry, vol. 8, 608030. https://doi.org/10.3389/fchem.2020.608030

APA

de Heuvel, E., Kooistra, A. J., Edink, E., van Klaveren, S., Stuijt, J., van der Meer, T., Sadek, P., Mabille, D., Caljon, G., Maes, L., Siderius, M., de Esch, I. J. P., Sterk, G. J., & Leurs, R. (2021). Discovery of Diaryl Ether Substituted Tetrahydrophthalazinones as TbrPDEB1 Inhibitors Following Structure-Based Virtual Screening. Frontiers in Chemistry, 8, [608030]. https://doi.org/10.3389/fchem.2020.608030

Vancouver

de Heuvel E, Kooistra AJ, Edink E, van Klaveren S, Stuijt J, van der Meer T et al. Discovery of Diaryl Ether Substituted Tetrahydrophthalazinones as TbrPDEB1 Inhibitors Following Structure-Based Virtual Screening. Frontiers in Chemistry. 2021 Jan 21;8. 608030. https://doi.org/10.3389/fchem.2020.608030

Author

de Heuvel, Erik ; Kooistra, Albert J. ; Edink, Ewald ; van Klaveren, Sjors ; Stuijt, Jeffrey ; van der Meer, Tiffany ; Sadek, Payman ; Mabille, Dorien ; Caljon, Guy ; Maes, Louis ; Siderius, Marco ; de Esch, Iwan J.P. ; Sterk, Geert Jan ; Leurs, Rob. / Discovery of Diaryl Ether Substituted Tetrahydrophthalazinones as TbrPDEB1 Inhibitors Following Structure-Based Virtual Screening. In: Frontiers in Chemistry. 2021 ; Vol. 8.

Bibtex

@article{79b5aa973979433da5f10cc0d89890f3,
title = "Discovery of Diaryl Ether Substituted Tetrahydrophthalazinones as TbrPDEB1 Inhibitors Following Structure-Based Virtual Screening",
abstract = "Several members of the 3′,5′-cyclic nucleotide phosphodiesterase (PDE) family play an essential role in cellular processes, which has labeled them as interesting targets for various diseases. The parasitic protozoan Trypanosoma brucei, causative agent of human African trypanosomiasis, contains several cyclic AMP specific PDEs from which TbrPDEB1 is validated as a drug target. The recent discovery of selective TbrPDEB1 inhibitors has increased their potential for a novel treatment for this disease. Compounds characterized by a rigid biphenyl tetrahydrophthalazinone core structure were used as starting point for the exploration of novel TbrPDEB1 inhibitors. Using a virtual screening campaign and structure-guided design, diaryl ether substituted phthalazinones were identified as novel TbrPDEB1 inhibitors with IC50 values around 1 μM against T. brucei. This study provides important structure-activity relationship (SAR) information for the future design of effective parasite-specific PDE inhibitors.",
keywords = "cAMP, medicinal chemistry, phosphodiesterase TbrPDEB1, tetrahydrophthalazinones, trypanosomiasis, virtual screening",
author = "{de Heuvel}, Erik and Kooistra, {Albert J.} and Ewald Edink and {van Klaveren}, Sjors and Jeffrey Stuijt and {van der Meer}, Tiffany and Payman Sadek and Dorien Mabille and Guy Caljon and Louis Maes and Marco Siderius and {de Esch}, {Iwan J.P.} and Sterk, {Geert Jan} and Rob Leurs",
year = "2021",
month = jan,
day = "21",
doi = "10.3389/fchem.2020.608030",
language = "English",
volume = "8",
journal = "Frontiers in Chemistry",
issn = "2296-2646",
publisher = "Frontiers Media S.A.",

}

RIS

TY - JOUR

T1 - Discovery of Diaryl Ether Substituted Tetrahydrophthalazinones as TbrPDEB1 Inhibitors Following Structure-Based Virtual Screening

AU - de Heuvel, Erik

AU - Kooistra, Albert J.

AU - Edink, Ewald

AU - van Klaveren, Sjors

AU - Stuijt, Jeffrey

AU - van der Meer, Tiffany

AU - Sadek, Payman

AU - Mabille, Dorien

AU - Caljon, Guy

AU - Maes, Louis

AU - Siderius, Marco

AU - de Esch, Iwan J.P.

AU - Sterk, Geert Jan

AU - Leurs, Rob

PY - 2021/1/21

Y1 - 2021/1/21

N2 - Several members of the 3′,5′-cyclic nucleotide phosphodiesterase (PDE) family play an essential role in cellular processes, which has labeled them as interesting targets for various diseases. The parasitic protozoan Trypanosoma brucei, causative agent of human African trypanosomiasis, contains several cyclic AMP specific PDEs from which TbrPDEB1 is validated as a drug target. The recent discovery of selective TbrPDEB1 inhibitors has increased their potential for a novel treatment for this disease. Compounds characterized by a rigid biphenyl tetrahydrophthalazinone core structure were used as starting point for the exploration of novel TbrPDEB1 inhibitors. Using a virtual screening campaign and structure-guided design, diaryl ether substituted phthalazinones were identified as novel TbrPDEB1 inhibitors with IC50 values around 1 μM against T. brucei. This study provides important structure-activity relationship (SAR) information for the future design of effective parasite-specific PDE inhibitors.

AB - Several members of the 3′,5′-cyclic nucleotide phosphodiesterase (PDE) family play an essential role in cellular processes, which has labeled them as interesting targets for various diseases. The parasitic protozoan Trypanosoma brucei, causative agent of human African trypanosomiasis, contains several cyclic AMP specific PDEs from which TbrPDEB1 is validated as a drug target. The recent discovery of selective TbrPDEB1 inhibitors has increased their potential for a novel treatment for this disease. Compounds characterized by a rigid biphenyl tetrahydrophthalazinone core structure were used as starting point for the exploration of novel TbrPDEB1 inhibitors. Using a virtual screening campaign and structure-guided design, diaryl ether substituted phthalazinones were identified as novel TbrPDEB1 inhibitors with IC50 values around 1 μM against T. brucei. This study provides important structure-activity relationship (SAR) information for the future design of effective parasite-specific PDE inhibitors.

KW - cAMP

KW - medicinal chemistry

KW - phosphodiesterase TbrPDEB1

KW - tetrahydrophthalazinones

KW - trypanosomiasis

KW - virtual screening

U2 - 10.3389/fchem.2020.608030

DO - 10.3389/fchem.2020.608030

M3 - Journal article

C2 - 33553105

AN - SCOPUS:85100524138

VL - 8

JO - Frontiers in Chemistry

JF - Frontiers in Chemistry

SN - 2296-2646

M1 - 608030

ER -

ID: 259677007