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

Autor: de Heuvel E; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands., Singh AK; School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK., Boronat P; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands., Kooistra AJ; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands., van der Meer T; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands., Sadek P; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands., Blaazer AR; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands., Shaner NC; University of California, San Diego, School of Medicine, Department of Neuroscience, 9500 Gilman Drive La Jolla, CA 92093-0662, USA., Bindels DS; Scintillon Institute, 6868 Nancy Ridge Drive, San Diego CA-92117, USA., Caljon G; Laboratory for Microbiology, Parasitology and Hygiene, University of Antwerp, 2610 Wilrijk, Belgium., Maes L; Laboratory for Microbiology, Parasitology and Hygiene, University of Antwerp, 2610 Wilrijk, Belgium., Sterk GJ; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands., Siderius M; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands., Oberholzer M; Scintillon Institute, 6868 Nancy Ridge Drive, San Diego CA-92117, USA., de Esch IJP; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands., Brown DG; School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK., Leurs R; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands. Electronic address: r.leurs@vu.nl.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2019 Sep 15; Vol. 27 (18), pp. 4013-4029. Date of Electronic Publication: 2019 Jul 05.
DOI: 10.1016/j.bmc.2019.06.026
Abstrakt: 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.
(Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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