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Title
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Discovery of diaryl ether substituted tetrahydrophthalazinones as TbrPDEB1 inhibitors following structure-based virtual screening
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Author
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Abstract
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| 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. |
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Language
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English
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Source (journal)
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Frontiers in Chemistry
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Publication
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2021
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ISSN
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2296-2646
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DOI
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10.3389/FCHEM.2020.608030
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Volume/pages
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8
(2021)
, 10 p.
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Article Reference
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608030
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ISI
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000614422200001
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Pubmed ID
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33553105
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Medium
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E-only publicatie
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Full text (Publisher's DOI)
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Full text (open access)
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