Design, synthesis and biological evaluation of D-ring opened galantamine analogs as multifunctional anti-Alzheimer agents

•Potent AChE/BChE inhibition activity.•Aβ42 aggregation inhibitory activity.•Nitric oxide releasing ability.•Neuroprotective effect against the Aβ-induced toxicity.•Spatial memory improving effect and good safety in vivo.

Facing the multifactorial nature of Alzheimer's disease, twelve dibenzofuran/carbazole derivatives, which can be considered as the D-ring opened analogs of galantamine, have been designed and synthesized as multifunctional anti-Alzheimer agents. In vitro tests revealed that compounds 3 and 5, which bear a nitrate moiety in the molecule, showed a potent inhibition activity towards AChE and compound 3 showed a good Aβ42 aggregation inhibitory activity. Moreover, 3 and 5 could also release a relative low concentration of NO in vitro and they did not show toxicity to neuronal cells, while exerted a neuroprotective effect against the Aβ-induced toxicity. More importantly, compound 3 showed a significant spatial memory improving effect in vivo, and a good safety in the ex vivo toxicity study.

Graphical abstractTwelve dibenzofuran/carbazole derivatives were designed and synthesized as potential multifunctional anti-Alzheimer agents.Figure optionsDownload full-size imageDownload as PowerPoint slide