Abstract
Curcumin shows a broad spectrum of activities of relevance in the treatment of Alzheimer’s disease (AD); however, it is poorly absorbed and is also chemically and metabolically unstable, leading to a very low oral bioavailability. A small library of hybrid compounds designed as curcumin analogues and incorporating the key structural fragment of piperlongumine, a natural neuroinflammation inhibitor, were synthesized by a two-step route that combines a three-component reaction between primary amines, β-ketoesters and α-haloesters and a base-promoted acylation with cinnamoyl chlorides. These compounds were predicted to have good oral absorption and CNS permeation, had good scavenging properties in the in vitro DPPH experiment and in a cellular assay based on the oxidation of dichlorofluorescin to a fluorescent species. The compounds showed low toxicity in two cellular models, were potent inductors of the Nrf2-ARE phase II antioxidant response, inhibited PHF6 peptide aggregation, closely related to Tau protein aggregation and were active against the LPS-induced inflammatory response. They also afforded neuroprotection against an oxidative insult induced by inhibition of the mitochondrial respiratory chain with the rotenone-oligomycin A combination and against Tau hyperphosphorylation induced by the phosphatase inhibitor okadaic acid. This multitarget pharmacological profile is highly promising in the development of treatments for AD and provides a good hit structure for future optimization efforts.
Highlights
Oxidative stress and protein misfolding are two major hallmarks common to several neurodegenerative diseases
Our compounds showed in general a better profile than curcumin in terms of predicted Caco-2 cell and MDCK cell permeability
This is important for Central nervous system (CNS) drug design, taking into account that MDCK cells permeability has been found to be a useful predictor of the ability of a compound to cross the blood
Summary
Oxidative stress and protein misfolding are two major hallmarks common to several neurodegenerative diseases. Its antioxidant activity is related to its two phenolic functional groups, which are able to scavenge ROS directly, and to the presence of two electrophilic positions that allow covalent binding to the Cys-151 residue of Keap1 [14]. This binding leads to Nrf translocation to the nucleus and the subsequent transcription of cytoprotective and anti-inflammatory proteins.
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