Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors (Part 2)
| Autor: | P. Boronat, Louis Maes, I.J.P. de Esch, Marco Siderius, David G. Brown, Rob Leurs, A.R. Blaazer, Payman Sadek, Geert Jan Sterk, E. de Heuvel, Daphne S. Bindels, M. Oberholzer, Albert J. Kooistra, Nathan C. Shaner, T. van der Meer, Guy Caljon, A.K. Singh |
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| Přispěvatelé: | AIMMS, Medicinal chemistry, Innovations in Human Health & Life Sciences, Chemistry and Pharmaceutical Sciences |
| Rok vydání: | 2019 |
| Předmět: |
Phosphodiesterase Inhibitors
Clinical Biochemistry Protozoan Proteins Pharmaceutical Science PROTEIN Chemistry Medicinal Trypanosoma brucei phosphodiesterase B1 Biochemistry TRYPANOSOMA-BRUCEI PHOSPHODIESTERASES Drug Discovery Pharmacology & Pharmacy DOCKING Cytotoxicity FRAGMENT Fluorescence microscopy 0303 health sciences biology Chemistry Pharmacology. Therapy Phosphodiesterase Enzyme inhibitors Cell cycle 3. Good health Structure-based drug discovery Physical Sciences Molecular Medicine Life Sciences & Biomedicine Intracellular EXPRESSION Programmed cell death Biochemistry & Molecular Biology 030303 biophysics Neglected tropical disease Chemistry Organic Trypanosoma brucei 03 medical and health sciences Structure-Activity Relationship SDG 3 - Good Health and Well-being Hydrolase DRUGGABLE TARGETS Humans Mode of action Molecular Biology Biology 030304 developmental biology DRUG-RESISTANCE Science & Technology ANALOGS Organic Chemistry Human African trypanosomiasis biology.organism_classification 3' 5'-Cyclic-AMP Phosphodiesterases PHARMACOLOGICAL VALIDATION AFRICAN TRYPANOSOMIASIS |
| Zdroj: | Bioorganic and Medicinal Chemistry, 27(18), 4013-4029. Elsevier Limited 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 and Medicinal Chemistry, vol. 27, no. 18, pp. 4013-4029 . https://doi.org/10.1016/j.bmc.2019.06.026 Bioorganic and medicinal chemistry |
| ISSN: | 1464-3391 0968-0896 |
| Popis: | 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. ispartof: BIOORGANIC & MEDICINAL CHEMISTRY vol:27 issue:18 pages:4013-4029 ispartof: location:England status: published |
| Databáze: | OpenAIRE |
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