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• Compound 9d with memantine as a cap structure exhibits balanced anti-NMDAR and HDAC activity. • The structural activity relationship is explained in detail. • HDAC inhibitors of isohydroxamic showed a strong protective effect against hydrogen peroxide damage. Histone deacetylases (HDACs) have been indicated important roles in neurodegenerative disorders including Alzheimer's disease (AD). Herein, a series of novel compounds that contain a memantine moiety were designed to target HDACs and N -methyl- d -aspartate receptor (NMDAR) which are related to the treatment of AD. Biological characterization established that compound 9d exhibited a balanced inhibitory activity on NMDAR and HDACs. This compound is relatively selective to HDAC6 with IC 50 of 0.18 μM and also maintains comparable activity on NMDAR (K i = 0.59 μM) as memantine. Functionally, treatment with 9d increased the level of AcTubulin in MV4-11 cells and rescued PC-12 cells from H 2 O 2 -induced cytotoxicity with EC 50 of 0.94 μM. Studies in mice also demonstrated that compound 9d efficiently penetrates the blood brain barrier to reach the brain tissue. Collectively, the results strongly encourage further development of 9d as a potential therapeutic agent for AD. [ABSTRACT FROM AUTHOR]

• Twenty-eight derivatives were designed, synthesized, and biologically evaluated. • Some compounds were found to potently inhibit both AChE and HDAC. • Compounds exhibited potential Cu2+ chelating properties, and HDAC isoform inhibition selectivity. • Compound A10 could serve as apromising candidate analogs as AD therapeutics. In order to develop multitarget-directed ligands as potential treatments for Alzheimer's disease, twenty-eight new tacrine-hydroxamate derivatives were designed, synthesized, and biologically evaluated. As expected, most of the compounds exhibited inhibitory activities against cholinesterases (ChEs) and histone deacetylase (HDACs). Among the tested compounds, A10 showed not only potent and selective inhibition on AChE at sub-nanomolar potency (AChE IC50 = 0.12 nM, BChE IC50 = 361.52 nM) but also potent inhibition on HDAC (IC 50 = 0.23 nM). Moreover, A10 exhibited inhibitory activity on Aβ 1-42 self-aggregation as well as disaggregation activity on pre-formed Aβ fibrils. Furthermore, A10 exhibited antioxidant activity and metal chelating properties. Further mechanistic studies demonstrated that A10 is a pan-inhibitor of HDACs and a mixed-type inhibitor for AChE. It shown that A10 is a BBB penetrant by online prediction. Taken together, the results indicate that A10 can serve as a lead compound to develop promising candidate analogs as AD therapeutics. [ABSTRACT FROM AUTHOR]