Structural optimization of naturally derived Ar-turmerone, as novel neuroinflammation suppressors effective in an Alzheimer mouse model

[Display omitted] •Aromatic turmerone, a monomer isolated from turmeric essential oil, as lead compound.•Structure and activity relationships of ar-turmerone was investigated.•Novel derivatives identified as neuroinflammation suppressors effective in vitro and in vivo.•Ar-turmerone derivatives protect neurons and attenuate memory impairment in AD mice. Microglia-mediated neuroinflammation plays a pivotal role in neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. The modulation of chronic and sustained inflammatory processes in the brain with small molecules presents a promising therapeutic strategy for these devastating conditions. Aromatic turmerone (ar-turmerone, ART), an active constituent of turmeric essential oil derived from the edible plant Curcuma longa, has shown substantial potential in mitigating neuroinflammatory responses and associated cognitive deficits. Building on our previous work, we sought to discover more potent neuroinflammation suppressors by designing and synthesizing a series of ar-turmerone derivatives to investigate their structure–activity relationships. Microglia-based cellular evaluations revealed that naphthyl-substituted (7c) and N-substituted amides (7a) demonstrated the most pronounced inhibitory effects against NO, TNF-α, and IL-1β release in vitro. Furthermore, in a lipopolysaccharide (LPS)-induced neuroinflammation model of Alzheimer’s disease in mice, these two compounds significantly reduced proinflammatory cytokine release, protected neurons from damage, and ameliorated memory impairments and cognitive deficits in Morris water maze tests. This structural optimization of ar-turmerone yielded highly potent anti-neuroinflammatory compounds, which may serve as promising agents for the treatment of neuroinflammation-related neurodegenerative disorders.