Synthesis and biological evaluation of novel 8- substituted sampangine derivatives as potent inhibitor of Zn2+-Aβ complex mediated toxicity, oxidative stress and inflammation

A series of 8-substituted sampangine derivatives have been designed, synthesized and tested for their ability to inhibit cholinesterase and penetrate the blood–brain barrier. Their chelating ability toward Zn 2+ and other biologically relevant metal ions was also demonstrated by isothermal titration calorimetry. The new derivatives exhibited high acetylcholinesterase inhibitory activity, high blood–brain barrier penetration ability and high chelating selectivity for Zn 2+ . Moreover, compound 10 with the strongest binding affinity to Zn 2+ was selected for further research. Western blotting analysis, transmission electron microscopy, DCFH-DA assay and paralysis experiment indicated that compound 10 suppressed the formation of Zn 2+ -Aβ complexes, alleviated the Zn 2+ induced neurotoxicity and inhibited the production of ROS catalyzed by Zn 2+ in Aβ42 transgenic C. elegans . Furthermore, compound 10 also inhibited the expressions of pro-inflammatory cytokines, such as NO, TNF-α, IL-6 and IL-1β, induced by Zn 2+ + Aβ 1-42 in BV2 microglial cells. In general, this work provided new insights into the design and development of potent metal-chelating agents for Alzheimer’s disease treatment.