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.