Xie_2021_Bioorg.Chem_109_104710

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+)-Abeta complexes, alleviated the Zn(2+) induced neurotoxicity and inhibited the production of ROS catalyzed by Zn(2+) in Abeta42 transgenic C. elegans. Furthermore, compound 10 also inhibited the expressions of pro-inflammatory cytokines, such as NO, TNF-alpha, IL-6 and IL-1beta, induced by Zn(2+) + Abeta(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.