Alzheimer’s disease (AD) is a neurodegenerative disorder that progresses over years resulting in substantial loss of memory and higher order cognitive functions. Neurofibrillary tangles (NFTs) and amyloid plaques (Aβ) are the pathological hallmarks of AD. Tau protein is expressed in central and peripheral nervous system and is involved in stabilizing the microtubules (MTs) within the neurons. In AD, hyperphosphorylation of tau protein leads to its disassociation from the microtubule (MT) and dimerization resulting in the formation of NFTs. Two isozymes of casein kinase 1 family i.e., casein kinase 1δ (CK1δ) and casein kinase 1ε (CK1 ε) are highly overexpressed (30 and 7 fold, respectively) in Alzheimer affected brain. CK1d/e have been shown to phosphorylate tau protein at several MT binding residues inducing a dramatic decrease in tau-MT binding activity. In 3xTg-AD mice models, CK1d/e inhibition reversed hippocampal proteomic alterations in several AD associated pathways and rescued working memory deficits. In our laboratory, a series of 5,8-dihydroxy-1,4-napthoquinones were identified as CK1d/e inhibitors that also reduced tau phosphorylation. Docking studies revealed the essential features in the lead structures that were used in the design of 7-hydroxy-1H-inden-1-one new core structure. Derivatives of 7-hydroxy-1H-inden-1-one were synthesized and tested for their CK1d/e inhibition using FRET based assays. The results of the molecular modeling studies, synthesis of derivatives and the CK1d/e inhibition assays are presented here.

New derivatives of 7-hydroxy-2,3-dihydro-1H-inden-1-one as Casein kinase 1δ/e Inhibitors for treatment of Alzheimer’s disease

ACS Spring 2022

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