A series of novel trienomycin A (TA)-mimetic compounds (5a-p) have been designed, synthesized, and evaluated for their in vitro anti-neuroinflammatory and neuroprotective activities. Among them, compounds 5h, 5n, and 5o exhibits relatively strong NO inhibitory activity in LPS-activated BV-2 cells with the EC<sub>50</sub> values of 12.4, 17.3, and 8.9 μM, respectively. Moreover, 5h showed evidently neuroprotective effect against H<sub>2</sub>O<sub>2</sub>-induced PC-12 cells without cytotoxicity at 20 μM. Overall, these compounds can provide a better understanding of the structure-activity relationship of TA and furnish research ideas for anti-neuroinflammatory and neuroprotective agents.