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=Volume 8 - 2020

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 3′,5′-cyclic nucleotide phosphodiesterases (PDEs) are validated drug targets for a large variety of 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 Trypanosoma brucei. This study provides important SAR information for the future design of effective parasite-specific PDE inhibitors.