Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors

De Heuvel, E. et al. (2019) Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors. Bioorganic and Medicinal Chemistry, 27(18), pp. 3998-4012. (doi: 10.1016/j.bmc.2019.06.027) (PMID:31327675)

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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.

Item Type:Articles
Additional Information:This work was supported by TI Pharma [grant number T4-302] and the European Commission 7th Framework Programme FP7-HEALTH-2013-INNOVATION-1 under project reference 602666 "Parasite-specific cyclic nucleotide phosphodiesterase inhibitors to target Neglected Parasitic Diseases" (PDE4NPD).
Glasgow Author(s) Enlighten ID:Kalejaiye, Miss Titilola and De Koning, Professor Harry
Authors: De Heuvel, E., Singh, A. K., Edink, E., van der Meer, T., van der Woude, M., Sadek, P., Krell-Jørgensen, M. P., van den Bergh, T., Veerman, J., Caljon, G., Kalejaiye, T. D., Wijtmans, M., Maes, L., De Koning, H. P., Sterk, G. J., Siderius, M., de Esch, I. J.P., Brown, D. G., and Leurs, R.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Bioorganic and Medicinal Chemistry
ISSN (Online):1464-3391
Published Online:18 June 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Bioorganic and Medicinal Chemistry 27(18):3998-4012
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
620151PDE4NTD: Phosphodieasease inhibitors for the treatment of Neglected Parasitic Diseases.Harry De KoningEuropean Commission (EC)602666III - PARASITOLOGY