Alzheimer’s disease (ALZ) is a progressive neurodegenerative disorder in middle to older age people. It is known to have notable symptoms like short-term memory loss, and loss of intellectual abilities. Abnormal hyperphosphorylation of the tau protein (P-tau) leads to the aggregation of amyloid plaques, which is the hallmark of ALZ and several other neurodegenerative disorders. Casein kinase 1δ (CK1d) is an isozyme expressed in the brain among the seven known isozymes (α, β1, γ1, γ2, γ3, δ, and ε) that belong to Casein kinase 1 family. CK1δ plays a major role in ALZ through phosphorylation of the tau protein (associated with microtubules), leading to Neuro Fibrillary Tangle (NFT) formation. Inhibition of CK1δ has been shown to reduce NFT formation and inhibit Aβ production. Our recent studies on quinones as kinase inhibitors revealed one such compound that pharmacologically inhibited CK1δ and Pim1 kinase preferentially over CK1γ2 and 98 other human protein kinases. Our goal is to synthesize several derivatives of the lead compound 5,8-dihydroxynaphthoquinone. New novel derivatives were synthesized and preliminary in-vitro CK1δ kinase inhibition assay have shown a few compounds with good potency. Herein, we describe the synthesis and bioassay results of our study.

Synthesis of new novel CK1d inhibitors as potential therapeutics for Alzheimer’s disease

255th National Meeting (2018)

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