Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors

Erik de Heuvel, Abhimanyu K. Singh, Ewald Edink, Tiffany van der Meer, Melanie van der Woude, Payman Sadek, Mikkel P. Krell-Jørgensen, Toine van den Bergh, Johan Veerman, Guy Caljon, Titilola D. Kalejaiye, Maikel Wijtmans, Louis Maes, Harry P. de Koning, Geert Jan Sterk, Marco Siderius, Iwan J.P. de Esch, David G. Brown, Rob Leurs

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Several 3′,5′-cyclic nucleotide phosphodiesterases (PDEs) have been validated as good drug targets for a large variety of diseases. Trypanosoma brucei PDEB1 (TbrPDEB1) has been designated as a promising drug target for the treatment of human African trypanosomiasis. Recently, the first class of selective nanomolar TbrPDEB1 inhibitors was obtained by targeting the parasite specific P-pocket. However, these biphenyl-substituted tetrahydrophthalazinone-based inhibitors did not show potent cellular activity against Trypanosoma brucei (T. brucei) parasites, leaving room for further optimization. Herein, we report the discovery of a new class of potent TbrPDEB1 inhibitors that display improved activities against T. brucei parasites. Exploring different linkers between the reported tetrahydrophthalazinone core scaffold and the amide tail group resulted in the discovery of alkynamide phthalazinones as new TbrPDEB1 inhibitors, which exhibit submicromolar activities versus T. brucei parasites and no cytotoxicity to human MRC-5 cells. Elucidation of the crystal structure of alkynamide 8b (NPD-048) bound to the catalytic domain of TbrPDEB1 shows a bidentate interaction with the key-residue Gln874 and good directionality towards the P-pocket. Incubation of trypanosomes with alkynamide 8b results in an increase of intracellular cAMP, validating a PDE-mediated effect in vitro and providing a new interesting compound series for further studies towards selective TbrPDEB1 inhibitors with potent phenotypic activity.

Original languageEnglish
Pages (from-to)1-15
Number of pages15
JournalBioorganic and Medicinal Chemistry
DOIs
Publication statusE-pub ahead of print - 18 Jun 2019

Fingerprint

Trypanosoma brucei brucei
Phosphoric Diester Hydrolases
Parasites
Cyclic Nucleotides
Cytotoxicity
Scaffolds
Amides
Pharmaceutical Preparations
Crystal structure
African Trypanosomiasis
Trypanosomiasis
Tail
Catalytic Domain

Keywords

  • Crystal structure
  • Human African trypanosomiasis
  • Neglected tropical disease
  • Structure-based drug discovery
  • Tetrahydrophthalazinone
  • Trypanosoma brucei phosphodiesterase B1

Cite this

de Heuvel, Erik ; Singh, Abhimanyu K. ; Edink, Ewald ; van der Meer, Tiffany ; van der Woude, Melanie ; Sadek, Payman ; Krell-Jørgensen, Mikkel P. ; van den Bergh, Toine ; Veerman, Johan ; Caljon, Guy ; Kalejaiye, Titilola D. ; Wijtmans, Maikel ; Maes, Louis ; de Koning, Harry P. ; Jan Sterk, Geert ; Siderius, Marco ; de Esch, Iwan J.P. ; Brown, David G. ; Leurs, Rob. / Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors. In: Bioorganic and Medicinal Chemistry. 2019 ; pp. 1-15.
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abstract = "Several 3′,5′-cyclic nucleotide phosphodiesterases (PDEs) have been validated as good drug targets for a large variety of diseases. Trypanosoma brucei PDEB1 (TbrPDEB1) has been designated as a promising drug target for the treatment of human African trypanosomiasis. Recently, the first class of selective nanomolar TbrPDEB1 inhibitors was obtained by targeting the parasite specific P-pocket. However, these biphenyl-substituted tetrahydrophthalazinone-based inhibitors did not show potent cellular activity against Trypanosoma brucei (T. brucei) parasites, leaving room for further optimization. Herein, we report the discovery of a new class of potent TbrPDEB1 inhibitors that display improved activities against T. brucei parasites. Exploring different linkers between the reported tetrahydrophthalazinone core scaffold and the amide tail group resulted in the discovery of alkynamide phthalazinones as new TbrPDEB1 inhibitors, which exhibit submicromolar activities versus T. brucei parasites and no cytotoxicity to human MRC-5 cells. Elucidation of the crystal structure of alkynamide 8b (NPD-048) bound to the catalytic domain of TbrPDEB1 shows a bidentate interaction with the key-residue Gln874 and good directionality towards the P-pocket. Incubation of trypanosomes with alkynamide 8b results in an increase of intracellular cAMP, validating a PDE-mediated effect in vitro and providing a new interesting compound series for further studies towards selective TbrPDEB1 inhibitors with potent phenotypic activity.",
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de Heuvel, E, Singh, AK, Edink, E, van der Meer, T, van der Woude, M, Sadek, P, Krell-Jørgensen, MP, van den Bergh, T, Veerman, J, Caljon, G, Kalejaiye, TD, Wijtmans, M, Maes, L, de Koning, HP, Jan Sterk, G, Siderius, M, de Esch, IJP, Brown, DG & Leurs, R 2019, 'Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors' Bioorganic and Medicinal Chemistry, pp. 1-15. https://doi.org/10.1016/j.bmc.2019.06.027

Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors. / de Heuvel, Erik; Singh, Abhimanyu K.; Edink, Ewald; van der Meer, Tiffany; van der Woude, Melanie; Sadek, Payman; Krell-Jørgensen, Mikkel P.; van den Bergh, Toine; Veerman, Johan; Caljon, Guy; Kalejaiye, Titilola D.; Wijtmans, Maikel; Maes, Louis; de Koning, Harry P.; Jan Sterk, Geert; Siderius, Marco; de Esch, Iwan J.P.; Brown, David G.; Leurs, Rob.

In: Bioorganic and Medicinal Chemistry, 18.06.2019, p. 1-15.

Research output: Contribution to JournalArticleAcademicpeer-review

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AU - de Heuvel, Erik

AU - Singh, Abhimanyu K.

AU - Edink, Ewald

AU - van der Meer, Tiffany

AU - van der Woude, Melanie

AU - Sadek, Payman

AU - Krell-Jørgensen, Mikkel P.

AU - van den Bergh, Toine

AU - Veerman, Johan

AU - Caljon, Guy

AU - Kalejaiye, Titilola D.

AU - Wijtmans, Maikel

AU - Maes, Louis

AU - de Koning, Harry P.

AU - Jan Sterk, Geert

AU - Siderius, Marco

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AU - Brown, David G.

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N2 - Several 3′,5′-cyclic nucleotide phosphodiesterases (PDEs) have been validated as good drug targets for a large variety of diseases. Trypanosoma brucei PDEB1 (TbrPDEB1) has been designated as a promising drug target for the treatment of human African trypanosomiasis. Recently, the first class of selective nanomolar TbrPDEB1 inhibitors was obtained by targeting the parasite specific P-pocket. However, these biphenyl-substituted tetrahydrophthalazinone-based inhibitors did not show potent cellular activity against Trypanosoma brucei (T. brucei) parasites, leaving room for further optimization. Herein, we report the discovery of a new class of potent TbrPDEB1 inhibitors that display improved activities against T. brucei parasites. Exploring different linkers between the reported tetrahydrophthalazinone core scaffold and the amide tail group resulted in the discovery of alkynamide phthalazinones as new TbrPDEB1 inhibitors, which exhibit submicromolar activities versus T. brucei parasites and no cytotoxicity to human MRC-5 cells. Elucidation of the crystal structure of alkynamide 8b (NPD-048) bound to the catalytic domain of TbrPDEB1 shows a bidentate interaction with the key-residue Gln874 and good directionality towards the P-pocket. Incubation of trypanosomes with alkynamide 8b results in an increase of intracellular cAMP, validating a PDE-mediated effect in vitro and providing a new interesting compound series for further studies towards selective TbrPDEB1 inhibitors with potent phenotypic activity.

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KW - Crystal structure

KW - Human African trypanosomiasis

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KW - Structure-based drug discovery

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