Design, synthesis and evaluation of novel bivalent β-carboline derivatives as multifunctional agents for the treatment of Alzheimer's disease

Publication date: Available online 14 June 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Yifan Zhao, Feng Ye, Jian Xu, Qinghong Liao, Lei Chen, Weijia Zhang, Haopeng Sun, Wenyuan Liu, Feng Feng, Wei Qu
To develop potent multi-target ligands against Alzheimer's disease (AD), a series of novel bivalent β-carboline derivatives were designed, synthesized, and evaluated. In vitro studies revealed these compounds exhibited good multifunctional activities. In particular, compounds 8f and 8g showed the good selectivity potency on BuChE inhibition (IC50 = 1.7 and 2.7 μM, respectively), Aβ1-42 disaggregation and neuroprotection. Compared with the positive control resveratrol, 8f and 8g showed better activity in inhibiting Aβ1-42 aggregation, with inhibitory rate 82.7% and 85.7% at 25 μM, respectively. Moreover, compounds 8e, 8f and 8g displayed excellent neuroprotective activity by ameliorating the impairment induced by H2O2, okadaic acid (OA) and Aβ1-42 without cytotoxicity in SH-SY5Y cells. Thus, the present study evidently showed that compounds 8f and 8g are potent multi-functional agents against AD and might serve as promising lead candidates for further development.

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