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Synthesis and evaluation of paeonol derivatives as potential multifunctional agents for the treatment of Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder characterized by memory loss, language impairment, personality changes and intellectual decline. Taking into account the key pathological features of AD, such as low levels of acetylcholine, beta-amyloid (A?) aggregation, oxidative stress and dyshomeostasis of biometals, a new series of paeonol derivatives 5a-5d merging three different functions, i.e., antioxidant, anti-acetylcholinesterase (AChE) activity, metal chelating agents for AD treatment have been synthesized and characterized. Biological assays revealed that compared with paeonol (309.7 ?M), 5a-5d had a lower DPPH IC50 value (142.8-191.6 ?M). 5a-5d could significantly inhibit hydrogen peroxide-induced neuronal PC12 cell death assessed by MTT assay in the concentration range of 5-40 ?M. AChE activity was effectively inhibited by 5a-5d, with IC50 values in the range of 0.61-7.04 ?M. 5a-5d also exhibited good metal-chelating ability. All the above results suggested that paeonol derivatives may be promising multifunctional agents for AD treatment.

SUBMITTER: Zhou A

PROVIDER: S-EPMC6272137 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Synthesis and evaluation of paeonol derivatives as potential multifunctional agents for the treatment of Alzheimer's disease.

Zhou An A Wu Hongfei H Pan Jian J Wang Xuncui X Li Jiaming J Wu Zeyu Z Hui Ailing A

Molecules (Basel, Switzerland) 20150114 1

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder characterized by memory loss, language impairment, personality changes and intellectual decline. Taking into account the key pathological features of AD, such as low levels of acetylcholine, beta-amyloid (Aβ) aggregation, oxidative stress and dyshomeostasis of biometals, a new series of paeonol derivatives 5a-5d merging three different functions, i.e., antioxidant, anti-acetylcholinesterase (AChE) activity, metal chelatin ...[more]

PMID: 25594344

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Project description:A series of indole derivatives was designed and synthesised to improve on activity and circumvent pharmacokinetic limitations experienced with the structurally related compound, ladostigil. The compounds consisted of a propargylamine moiety (a known MAO inhibitor and neuroprotector) at the N1 position and a ChE inhibiting diethyl-carbamate/urea moiety at the 5 or 6 position of the indole ring. In order to prevent or slow down the in vivo hydrolysis and deactivation associated with the carbamate function of ladostigil, a urea moeity was incorporated into selected compounds to obtain more metabolically stable structures. The majority of the synthesised compounds showed improved MAO-A inhibitory activity compared to ladostigil. The compounds possessing the propargylamine moiety showed good MAO-B inhibitory activity with 6 and 8 portraying IC50 values between 14-20 fold better than ladostigil. The ChE assay results indicated that the compounds have non-selective inhibitory activities on eeAChE and eqBuChE regardless of the type or position of substitution (IC50: 2-5 ?M). MAO-A and MAO-B docking results showed that the propargylamine moiety was positioned in close proximity to the FAD cofactor suggesting that the good inhibitory activity may be attributed to the propargylamine moiety and irreversible inhibition as confirmed in the reversibility studies. Docking results also indicated that the compounds have interactions with important amino acids in the AChE and BuChE catalytic sites. Compound 6 was the most potent multifunctional agent showing better inhibitory activity than ladostigil in vitro on all enzymes tested (hMAO-A IC50 = 4.31 ?M, hMAO-B IC50 = 2.62 ?M, eeAChE IC50 = 3.70 ?M, eqBuChE IC50 = 2.82 ?M). Chemical stability tests confirmed the diethyl-urea containing compound 6 to be more stable than its diethyl-carbamate containing counterpart compound 8. Compound 6 also exerted significant neuroprotection (52.62% at 1 ?M) against MPP+ insult to SH-SY5Y neural cells and has good in silico predicted ADMET properties. The favourable neuronal enzyme inhibitory activity, likely improved pharmacokinetic properties in vivo and the potent neuroprotective ability of compound 6 make it a promising compound for further development.

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Synthesis and evaluation of paeonol derivatives as potential multifunctional agents for the treatment of Alzheimer's disease.

Publications

Synthesis and evaluation of paeonol derivatives as potential multifunctional agents for the treatment of Alzheimer's disease.

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