Novel and Potent Acetylcholinesterase Inhibitors for the Treatment of Alzheimer’s Disease from Natural (±)-7,8-Dihydroxy-3-methyl-isochroman-4-one

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease that causes memory and cognitive decline as well as behavioral problems. It is a progressive and well recognized complex disease; therefore, it is very urgent to develop novel and effective anti-AD drugs. In this study, a series of novel isochroman-4-one derivatives from natural (±)-7,8-dihydroxy-3-methyl-isochroman-4-one [(±)-XJP] were designed and synthesized, and their anti-AD potential was evaluated. Among them, compound 10a [(Z)-3-acetyl-1-benzyl-4-((6,7-dimethoxy-4-oxoisochroman-3-ylidene)methyl)pyridin-1-ium bromide] possessed potent anti-acetylcholinesterase (AChE) activity as well as modest antioxidant activity. Further molecular modeling and kinetic investigations revealed that compound 10a was a dual-binding inhibitor that binds to both catalytic anionic site (CAS) and peripheral anionic site (PAS) of the enzyme AChE. In addition, compound 10a exhibited low cytotoxicity and moderate anti-Aβ aggregation efficacy. Moreover, the in silico screening suggested that these compounds could pass across the blood–brain barrier with high penetration. These findings show that compound 10a was a promising lead from a natural product with potent AChE inhibitory activity and deserves to be further developed for the prevention and treatment of AD.

Lipopolysaccharide-Induced Model of Neuroinflammation: Mechanisms of Action, Research Application and Future Directions for Its Use

“…These effects require further studies to be fully understood; nevertheless, memantine has been already used as a comparative neuroprotective agent in the LPS-induced neuroinflammation study [ 8 ]. Cholinesterase inhibitors address the deficiencies of neurotransmitter acetylcholine observed in the AD, as cholinergic transmission is crucial for cognition, learning, and memory [ 105 ]. Similarly, memantine, rivastigmine and donepezil may also exert some neuroprotective effects, shown in a study by Kim and colleagues [ 106 ], and in other, older reports [ 107 ].…”

Design, Synthesis, and Biological Evaluation of Novel Chromanone Derivatives as Multifunctional Agents for the Treatment of Alzheimer’s Disease

“…To a solution of intermediates 6-1 ∼ 6-12 (1 mmol) in 10 mL of acetonitrile, benzyl bromide (1.1 mmol) was added, and the mixture was stirred at 85 °C overnight. 42 After cooling down to room temperature, the mixture was filtered, and the solid collected from this filtration was washed with ethyl acetate for three times. The crude intermediates 7-1 ∼ 7-12 were used in the next step without purification.…”

“…Cytotoxicity assay on SH-SY5Y cells was performed as described in our previous study. 42 SH-SY5Y cells were grown in a 25 cm 2 culture flask in fresh MEM/F12 medium containing 10% fetal bovine serum, 100 U/mL penicillin, and 100 g/mL streptomycin and incubated at 37 °C with 5% CO 2 . In a 96well plate, cells were seeded at a density of 110 4 cells per well.…”

“…In order to search for novel MAO-B inhibitors, the chromanone structure has been utilized as a promising principal scaffold. − Kong et al reported a series of chromanone derivatives as MAO-B inhibitors, among which compound 5 (Figure ) showed the best MAO-B inhibitory activity (IC 50 = 8.62 nM) . Furthermore, many studies have indicated that both chromanone and synthesized analogues showed good MAO-B inhibitory activities. − Recently, we reported an isochromanone derivative (Figure ) as a potential AChE inhibitor for the treatment of AD …”

“…39−41 Recently, we reported an isochromanone derivative (Figure 3) as a potential AChE inhibitor for the treatment of AD. 42 On the basis of the evidences that AChE inhibitors are the cornerstone of treatment for AD nowadays and MAO-B inhibitors might represent an alternative approach to treat…”