Synthesis and biological evaluation of chromanone-based derivatives as potential anti-neuroinflammatory agents

As a privileged scaffold, chromanone has been extensively introduced in the design of drug leads with diverse pharmacological features, particularly in the area of inflammatory diseases. Herein, the preparation of chromanone-based derivatives (4a-4i) was smoothly achieved, and their structures were characterized using 1H NMR, 13C NMR, and ESI-HRMS spectroscopy techniques. Out of them, analogue 4e exhibited the most potent inhibitory capacity against the NO release and iNOS expression, without apparent cytotoxicity. Our observations showed that 4e could dramatically prevent the translocation of NF-κB from the cytoplasm to nucleus, and decrease the production of proinflammatory cytokines TNF-α, IL-6 and IL-1β in LPS-induced BV-2 cells. Mechanistically, 4e significantly deactivated NF-κB by disturbing TLR4-mediated TAK1/NF-κB and PI3K/Akt signaling cascades. Consistent with the in vitro study, 4e could effectively mitigate the inflammation response of hippocampal tissue in LPS-induced mouse model by inhibiting microglial activation. Collectively, these results revealed 4e as a prospective neuroprotective candidate for the therapy of neuroinflammation-related disorders.