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Design, Synthesis, and Activity Study of Cinnamic Acid Derivatives as Potent Antineuroinflammatory Agents.

Neuroinflammatory cytokines are promising therapeutic targets for the treatment of Alzheimer's disease. Herein, we described our efforts toward the investigation of cinnamic acid derivatives as antineuroinflammatory agents. Intensive structural modifications led to the identification of compound 4f as the most effective antineuroinflammatory agent in vitro. The oral administration of compound 4f could reverse lipopolysaccharide (LPS)-induced memory disturbance and normalize glucose uptake and metabolism in the brains of mice. Further biological studies in vivo revealed that compound 4f was directly bound to the mitogen-activated protein kinase (MAPK) signaling pathway, resulting in suppression of its downstream signaling pathway by blocking neuroinflammatory progression. Docking studies showed that compound 4f could be inserted into the active pocket of interleukin-1β (IL-1β). Furthermore, it was confirmed that compound 4f formed hydrogen bonds with SER84 to enhance the binding affinity. Taken together, these results are of great importance in the development of cinnamic acid derivatives for the treatment of Alzheimer's disease.