Development of Phthalimide-Donepezil Hybrids as Potent Multitarget- Directed Ligands for the Treatment of Alzheimer’s Disease

(E-pub Ahead of Print)

Author(s): Lintao Yu, Jian Shi, Xinfeng Cheng, Keren Wang, Shuang Liu, Wenmin Liu, Zhipei Sang*.

Journal Name: Letters in Drug Design & Discovery

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Background: Due to the complex etiology of AD, multi-target-directed ligands (MTDLs) combining two or more distinct pharmacological moieties, have been developed in both symptomatic and disease-modifying efficiencies and are considered as an effective way for the treatment of AD.

Methods: To test their biological activities including AChE/BChE inhibitory activity and MAO-A/MAO-B inhibitory activity. In addition, molecular modeling studies were performed to afford insight into the binding mode.

Results: The results displayed that compound 4c showed the best AChE inhibitory activity with IC50 value of 4.2 μM, which was supported by the kinetic study and docking study. Compound 4c was also a selective MAO-B inhibitor (IC50 = 8.2 μM). Moreover, compound 4c could cross blood-brain barrier in vitro.

Conclusion: Compound 4c deserved to further study as a potential multifunctional agent for the treatment of Alzheimer’s disease.

Keywords: Alzheimer's disease, phthalimide-donepezil hybrids, design, synthesis, AChE inhibitor, MAO-B inhibitor, blood-brain barrier, in vitro.

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Article Details

(E-pub Ahead of Print)
DOI: 10.2174/1570180817999200420120519
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