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Discovery of diaryl ether substituted tetrahydrophthalazinones as TbrPDEB1 inhibitors following structure-based virtual screening

Journal Contribution - e-publication

Several members of the 3′,5′-cyclic nucleotide phosphodiesterase (PDE) family play an essential role in cellular processes, which has labeled them as interesting targets for various diseases. The parasitic protozoan Trypanosoma brucei , causative agent of human African trypanosomiasis, contains several cyclic AMP specific PDEs from which TbrPDEB1 is validated as a drug target. The recent discovery of selective TbrPDEB1 inhibitors has increased their potential for a novel treatment for this disease. Compounds characterized by a rigid biphenyl tetrahydrophthalazinone core structure were used as starting point for the exploration of novel TbrPDEB1 inhibitors. Using a virtual screening campaign and structure-guided design, diaryl ether substituted phthalazinones were identified as novel TbrPDEB1 inhibitors with IC 50 values around 1 μM against T. brucei . This study provides important structure-activity relationship (SAR) information for the future design of effective parasite-specific PDE inhibitors.
Journal: Frontiers in Chemistry
ISSN: 2296-2646
Volume: 8
Publication year:2021
Keywords:A1 Journal article
BOF-keylabel:yes
BOF-publication weight:1
CSS-citation score:1
Authors:International
Authors from:Higher Education
Accessibility:Open