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

Department of Drug Design and Pharmacology

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

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

Standard

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 & Medicinal Chemistry, Vol. 27, No. 18, 15.09.2019, p. 4013-4029.

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

Harvard

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 & Medicinal Chemistry, vol. 27, no. 18, pp. 4013-4029. https://doi.org/10.1016/j.bmc.2019.06.026

APA

de Heuvel, E., Singh, A. K., Boronat, P., Kooistra, A. J., van der Meer, T., Sadek, P., Blaazer, A. R., Shaner, N. C., Bindels, D. S., Caljon, G., Maes, L., Sterk, G. J., Siderius, M., Oberholzer, M., de Esch, I. J. P., Brown, D. G., & Leurs, R. (2019). Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors (Part 2). Bioorganic & Medicinal Chemistry, 27(18), 4013-4029. https://doi.org/10.1016/j.bmc.2019.06.026

Vancouver

de Heuvel E, Singh AK, Boronat P, Kooistra AJ, van der Meer T, Sadek P et al. Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors (Part 2). Bioorganic & Medicinal Chemistry. 2019 Sep 15;27(18):4013-4029. https://doi.org/10.1016/j.bmc.2019.06.026

Author

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 & Medicinal Chemistry. 2019 ; Vol. 27, No. 18. pp. 4013-4029.

Bibtex

@article{52a5d6fa34534577979003b73e443d13,

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.",

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 = sep,

day = "15",

doi = "10.1016/j.bmc.2019.06.026",

language = "English",

volume = "27",

pages = "4013--4029",

journal = "Bioorganic & Medicinal Chemistry",

issn = "0968-0896",

publisher = "Pergamon Press",

number = "18",

}

RIS

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.

U2 - 10.1016/j.bmc.2019.06.026

DO - 10.1016/j.bmc.2019.06.026

M3 - Journal article

C2 - 31378593

VL - 27

SP - 4013

EP - 4029

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

SN - 0968-0896

IS - 18

ER -

ID: 235972128