Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors (Part 2)

Erik de Heuvel, Abhimanyu K. Singh, Pierre Boronat, Albert J. Kooistra, Tiffany van der Meer, Payman Sadek, Antoni R. Blaazer, Nathan C. Shaner, Daphne S. Bindels, Guy Caljon, Louis Maes, Geert Jan Sterk, Marco Siderius, Michael Oberholzer, Iwan J.P. de Esch, David G. Brown, Rob Leurs

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Inhibitors against Trypanosoma brucei phosphodiesterase B1 (TbrPDEB1) and B2 (TbrPDEB2) have gained interest as new treatments for human African trypanosomiasis. The recently reported alkynamide tetrahydrophthalazinones, which show submicromolar activities against TbrPDEB1 and anti-T. brucei activity, have been used as starting point for the discovery of new TbrPDEB1 inhibitors. Structure-based design indicated that the alkynamide-nitrogen atom can be readily decorated, leading to the discovery of 37, a potent TbrPDEB1 inhibitor with submicromolar activities against T. brucei parasites. Furthermore, 37 is more potent against TbrPDEB1 than hPDE4 and shows no cytotoxicity on human MRC-5 cells. The crystal structures of the catalytic domain of TbrPDEB1 co-crystalized with several different alkynamides show a bidentate interaction with key-residue Gln874, but no interaction with the parasite-specific P-pocket, despite being (uniquely) a more potent inhibitor for the parasite PDE. Incubation of blood stream form trypanosomes by 37 increases intracellular cAMP levels and results in the distortion of the cell cycle and cell death, validating phosphodiesterase inhibition as mode of action.

Original languageEnglish
Pages (from-to)4013-4029
Number of pages17
JournalBioorganic and Medicinal Chemistry
Volume27
Issue number18
DOIs
Publication statusPublished - 15 Sep 2019

Fingerprint

Phosphodiesterase Inhibitors
Parasites
African Trypanosomiasis
Trypanosoma brucei brucei
Trypanosomiasis
Phosphoric Diester Hydrolases
Cell death
Cytotoxicity
Trypanosoma brucei PDEB1 protein
Catalytic Domain
Cell Cycle
Blood
Cell Death
Nitrogen
Crystal structure
Cells
Atoms

Keywords

  • Enzyme inhibitors
  • Fluorescence microscopy
  • Human African trypanosomiasis
  • Neglected tropical disease
  • Structure-based drug discovery
  • Trypanosoma brucei phosphodiesterase B1

Cite this

de Heuvel, Erik ; Singh, Abhimanyu K. ; Boronat, Pierre ; Kooistra, Albert J. ; van der Meer, Tiffany ; Sadek, Payman ; Blaazer, Antoni R. ; Shaner, Nathan C. ; Bindels, Daphne S. ; Caljon, Guy ; Maes, Louis ; Sterk, Geert Jan ; Siderius, Marco ; Oberholzer, Michael ; de Esch, Iwan J.P. ; Brown, David G. ; Leurs, Rob. / Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors (Part 2). In: Bioorganic and Medicinal Chemistry. 2019 ; Vol. 27, No. 18. pp. 4013-4029.
@article{bf5c24ca27c4460c990f2a7b1bc89083,
title = "Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors (Part 2)",
abstract = "Inhibitors against Trypanosoma brucei phosphodiesterase B1 (TbrPDEB1) and B2 (TbrPDEB2) have gained interest as new treatments for human African trypanosomiasis. The recently reported alkynamide tetrahydrophthalazinones, which show submicromolar activities against TbrPDEB1 and anti-T. brucei activity, have been used as starting point for the discovery of new TbrPDEB1 inhibitors. Structure-based design indicated that the alkynamide-nitrogen atom can be readily decorated, leading to the discovery of 37, a potent TbrPDEB1 inhibitor with submicromolar activities against T. brucei parasites. Furthermore, 37 is more potent against TbrPDEB1 than hPDE4 and shows no cytotoxicity on human MRC-5 cells. The crystal structures of the catalytic domain of TbrPDEB1 co-crystalized with several different alkynamides show a bidentate interaction with key-residue Gln874, but no interaction with the parasite-specific P-pocket, despite being (uniquely) a more potent inhibitor for the parasite PDE. Incubation of blood stream form trypanosomes by 37 increases intracellular cAMP levels and results in the distortion of the cell cycle and cell death, validating phosphodiesterase inhibition as mode of action.",
keywords = "Enzyme inhibitors, Fluorescence microscopy, Human African trypanosomiasis, Neglected tropical disease, Structure-based drug discovery, Trypanosoma brucei phosphodiesterase B1",
author = "{de Heuvel}, Erik and Singh, {Abhimanyu K.} and Pierre Boronat and Kooistra, {Albert J.} and {van der Meer}, Tiffany and Payman Sadek and Blaazer, {Antoni R.} and Shaner, {Nathan C.} and Bindels, {Daphne S.} and Guy Caljon and Louis Maes and Sterk, {Geert Jan} and Marco Siderius and Michael Oberholzer and {de Esch}, {Iwan J.P.} and Brown, {David G.} and Rob Leurs",
year = "2019",
month = "9",
day = "15",
doi = "10.1016/j.bmc.2019.06.026",
language = "English",
volume = "27",
pages = "4013--4029",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "18",

}

de Heuvel, E, Singh, AK, Boronat, P, Kooistra, AJ, van der Meer, T, Sadek, P, Blaazer, AR, Shaner, NC, Bindels, DS, Caljon, G, Maes, L, Sterk, GJ, Siderius, M, Oberholzer, M, de Esch, IJP, Brown, DG & Leurs, R 2019, 'Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors (Part 2)' Bioorganic and Medicinal Chemistry, vol. 27, no. 18, pp. 4013-4029. https://doi.org/10.1016/j.bmc.2019.06.026

Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors (Part 2). / de Heuvel, Erik; Singh, Abhimanyu K.; Boronat, Pierre; Kooistra, Albert J.; van der Meer, Tiffany; Sadek, Payman; Blaazer, Antoni R.; Shaner, Nathan C.; Bindels, Daphne S.; Caljon, Guy; Maes, Louis; Sterk, Geert Jan; Siderius, Marco; Oberholzer, Michael; de Esch, Iwan J.P.; Brown, David G.; Leurs, Rob.

In: Bioorganic and Medicinal Chemistry, Vol. 27, No. 18, 15.09.2019, p. 4013-4029.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors (Part 2)

AU - de Heuvel, Erik

AU - Singh, Abhimanyu K.

AU - Boronat, Pierre

AU - Kooistra, Albert J.

AU - van der Meer, Tiffany

AU - Sadek, Payman

AU - Blaazer, Antoni R.

AU - Shaner, Nathan C.

AU - Bindels, Daphne S.

AU - Caljon, Guy

AU - Maes, Louis

AU - Sterk, Geert Jan

AU - Siderius, Marco

AU - Oberholzer, Michael

AU - de Esch, Iwan J.P.

AU - Brown, David G.

AU - Leurs, Rob

PY - 2019/9/15

Y1 - 2019/9/15

N2 - Inhibitors against Trypanosoma brucei phosphodiesterase B1 (TbrPDEB1) and B2 (TbrPDEB2) have gained interest as new treatments for human African trypanosomiasis. The recently reported alkynamide tetrahydrophthalazinones, which show submicromolar activities against TbrPDEB1 and anti-T. brucei activity, have been used as starting point for the discovery of new TbrPDEB1 inhibitors. Structure-based design indicated that the alkynamide-nitrogen atom can be readily decorated, leading to the discovery of 37, a potent TbrPDEB1 inhibitor with submicromolar activities against T. brucei parasites. Furthermore, 37 is more potent against TbrPDEB1 than hPDE4 and shows no cytotoxicity on human MRC-5 cells. The crystal structures of the catalytic domain of TbrPDEB1 co-crystalized with several different alkynamides show a bidentate interaction with key-residue Gln874, but no interaction with the parasite-specific P-pocket, despite being (uniquely) a more potent inhibitor for the parasite PDE. Incubation of blood stream form trypanosomes by 37 increases intracellular cAMP levels and results in the distortion of the cell cycle and cell death, validating phosphodiesterase inhibition as mode of action.

AB - Inhibitors against Trypanosoma brucei phosphodiesterase B1 (TbrPDEB1) and B2 (TbrPDEB2) have gained interest as new treatments for human African trypanosomiasis. The recently reported alkynamide tetrahydrophthalazinones, which show submicromolar activities against TbrPDEB1 and anti-T. brucei activity, have been used as starting point for the discovery of new TbrPDEB1 inhibitors. Structure-based design indicated that the alkynamide-nitrogen atom can be readily decorated, leading to the discovery of 37, a potent TbrPDEB1 inhibitor with submicromolar activities against T. brucei parasites. Furthermore, 37 is more potent against TbrPDEB1 than hPDE4 and shows no cytotoxicity on human MRC-5 cells. The crystal structures of the catalytic domain of TbrPDEB1 co-crystalized with several different alkynamides show a bidentate interaction with key-residue Gln874, but no interaction with the parasite-specific P-pocket, despite being (uniquely) a more potent inhibitor for the parasite PDE. Incubation of blood stream form trypanosomes by 37 increases intracellular cAMP levels and results in the distortion of the cell cycle and cell death, validating phosphodiesterase inhibition as mode of action.

KW - Enzyme inhibitors

KW - Fluorescence microscopy

KW - Human African trypanosomiasis

KW - Neglected tropical disease

KW - Structure-based drug discovery

KW - Trypanosoma brucei phosphodiesterase B1

UR - http://www.scopus.com/inward/record.url?scp=85071055083&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071055083&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2019.06.026

DO - 10.1016/j.bmc.2019.06.026

M3 - Article

VL - 27

SP - 4013

EP - 4029

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 18

ER -