1,4,5,6-Tetrahydrobenzo[2,3]oxepino[4,5-d]pyrimidine derivatives as anti-neuroinflammatory agents: Design, synthesis, and preliminary biological evaluation.

Neuroinflammation has been identified as a causative factor of multiple neurological diseases. Microglia cells are the primary immune cells that regulate the neuroinflammation response. Hence, twenty-six 1,4,5,6-tetrahydrobenzo[2,3]oxepino[4,5-d]pyrimidine derivatives (BPMs) as anti-inflammatory molecules were designed and synthesized through two-step structural modification on the basis of the structure of the initial hit DL-1 from an in-house chemical library. The most potent compound 10a, modified with piperidine and benzamidine hydrochloride, was identified as the optimal candidate with strong anti-neuroinflammatory efficacies with no evident cellular cytotoxicity. Treatment with 10a efficiently attenuated LPS-induced neuroinflammation in microglia, as evidenced by reduced levels of inflammatory mediators, including ROS, NO, IL-1β, IL-6, TNF-α, and IL-18. Mechanistic studies demonstrated that 10a inhibits the NF-κB/NLRP3 pathway by suppressing phosphorylation of p65 and IκBα and decreasing NLRP3 protein expression. These results provide a promising strategy and good starting point for the development of a therapeutic candidate for neuroinflammation-related diseases.