Joubert, JacquesKapp, Erika2021-12-082021-12-082020Joubert, J., & Kapp, E. (2020). Discovery of 9-phenylacridinediones as highly selective butyrylcholinesterase inhibitors through structure-based virtual screening. Bioorganic & Medicinal Chemistry Letters ,30(9), 127075. https://doi.org/10.1016/j.bmcl.2020.1270750960-894Xhttps://doi.org/10.1016/j.bmcl.2020.127075http://hdl.handle.net/10566/7064Butyrylcholinesterase (BuChE) is considered a promising drug target as it plays an important role in the pro-gression of late stage Alzheimer’s disease (AD). Two compound libraries were selected and 64 124 aminecontaining moieties were screened using a hierarchical virtual screening protocol to discover new selectiveBuChE inhibitors. From these and subsequent docking experiments, 9-phenylacridinedione (9-PAD) was iden-tified as a promising scaffold for selective inhibition of BuChE. Selected top dock scored 9-PADs were assayedand compounds3and6exhibited potent and highly selective human BuChE inhibition (IC50: 98 nM and 142 nM,respectively). Both molecules were also predicted to show sufficient brain permeability, not have any substantialtoxicities, especially hepatotoxicity, and no significantinvitrocytotoxicity against SH-SY5Y neuroblastoma cellsat concentrations up to 100 μM. These findings indicate that 9-PAD is a promising lead structure for the de-velopment of agents able to treat late stage AD.enAlzheimer’s diseaseVirtual screeningDockingMental healthArticle