AUTHOR=de Heuvel Erik , Kooistra Albert J. , Edink Ewald , van Klaveren Sjors , Stuijt Jeffrey , van der Meer Tiffany , Sadek Payman , Mabille Dorien , Caljon Guy , Maes Louis , Siderius Marco , de Esch Iwan J. P. , Sterk Geert Jan , Leurs Rob TITLE=Discovery of Diaryl Ether Substituted Tetrahydrophthalazinones as TbrPDEB1 Inhibitors Following Structure-Based Virtual Screening JOURNAL=Frontiers in Chemistry VOLUME=8 YEAR=2021 URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2020.608030 DOI=10.3389/fchem.2020.608030 ISSN=2296-2646 ABSTRACT=

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 IC50 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.