New isoconessimine derivatives were synthesized from conessine （1） and evaluated as acetylcholinesterase （ACHE） inhibitors. The derivatives were prepared via two reaction steps, N-demethylation and nuc]eophilic su...New isoconessimine derivatives were synthesized from conessine （1） and evaluated as acetylcholinesterase （ACHE） inhibitors. The derivatives were prepared via two reaction steps, N-demethylation and nuc]eophilic substi- tution. All of the synthesized derivatives exhibited more potential anti-acetylcholinesterase activities than conessine （1） （IC50=16μmol·L^-1） and isoconessimine （2） （IC50〉300 μmol·L ^-1）. Compound 7b （3fl-[methyl-[2-（4-nitro- phenoxy）ethyl]amino]con-5-enine） showed the most potent inhibitory activity with an IC50 of 110 μmol/L which is close to that of reference compound huperzine A （IC50= 70 μmol/L）. The mode of AChE inhibition by 7h was re- versible and non-competitive. In addition, molecular modeling was performed to explore the binding mode of in- hibitor 7b at the active site of AChE and the results showed that 7b could be docked into the acetylcholinesterase active site and compound 7h had hydrophobic interactions with Trp279 and Leu282.展开更多
基金The authors are grateful to the National Natural Science Foundation of China，the Excellent Young Teachers Program of Lanzhou University of Technology，Zhejiang Provincial Natural Science Foundation of China，the open fund of the Key Laboratory of the New Animal Drug Project of Gansu Province and the Key Laboratory of Veterinary Pharmaceutical Development of the Ministry of Agriculture
文摘New isoconessimine derivatives were synthesized from conessine （1） and evaluated as acetylcholinesterase （ACHE） inhibitors. The derivatives were prepared via two reaction steps, N-demethylation and nuc]eophilic substi- tution. All of the synthesized derivatives exhibited more potential anti-acetylcholinesterase activities than conessine （1） （IC50=16μmol·L^-1） and isoconessimine （2） （IC50〉300 μmol·L ^-1）. Compound 7b （3fl-[methyl-[2-（4-nitro- phenoxy）ethyl]amino]con-5-enine） showed the most potent inhibitory activity with an IC50 of 110 μmol/L which is close to that of reference compound huperzine A （IC50= 70 μmol/L）. The mode of AChE inhibition by 7h was re- versible and non-competitive. In addition, molecular modeling was performed to explore the binding mode of in- hibitor 7b at the active site of AChE and the results showed that 7b could be docked into the acetylcholinesterase active site and compound 7h had hydrophobic interactions with Trp279 and Leu282.
