Design, synthesis, biological evaluation, and docking study of 4‐isochromanone hybrids bearing N‐benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors (part II)

Abstract

A series of novel 4-isochromanone compounds bearing N-benzyl pyridinium moiety were designed and synthesized as acetylcholinesterase (AChE) inhibitors. The biological evaluation showed that most of the target compounds exhibited potent inhibitory activities against AChE. Among them, compound 1q possessed the strongest anti-AChE activity with an IC value of 0.15 nm and high AChE/BuChE selectivity (SI > 5,000). Moreover, compound 1q had low toxicity in normal nerve cells and was relatively stable in rat plasma. Together, the current finding may provide a new approach for the discovery of novel anti-Alzheimer's disease agents.

In vivo Evaluation of a Newly Synthesized Acetylcholinesterase Inhibitor in a Transgenic Drosophila Model of Alzheimer’s Disease

“…In addition to this, docking studies carried out on XJP-1 showed a dual-binding property for both the PAS and CAS of the AChE enzyme ( Wang et al, 2015 ), which may further justify the low dosage needed to slow down the amyloid aggregation, since the PAS of AChE has been linked to increased amyloid-β peptide aggregation rate ( Inestrosa et al, 1996 ). Despite not being tested in this study, XJP-1 has been predicted to have anti-inflammatory and anti-oxidant properties due to its natural product-derived structure, which may have also played a role in ameliorating the AD symptomatology in Aβ arc flies ( Wang et al, 2015 , 2018 ).…”

“…Following extensive previous in vitro studies, here we present biological evaluation of our previously reported novel AChE inhibitor (Wang et al, 2015), named XJP-1, using the Aβ arc Drosophila AD model. XJP-1 is a naturally derived product, with part of the structure derived from a compound isolated in the peel of Musa sapientum L., which has shown an excellent inhibitory activity against AChE, along with a high specificity for AChE over butyrylcholinesterase (BuChE) (Wang et al, 2015(Wang et al, , 2018. In addition to this, XJP-1 was predicted to have high BBB permeability in docking studies and no toxicity on neurotypic SH-SY5Y cells (Wang et al, 2015(Wang et al, , 2018.…”

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

“…To a solution of 2-bromo-4,5-dimethoxybenzaldehyde ( 1 ) (81.61 mmol, 1 eq) in 100 mL methanol, sodium borohydride (40.80 mmol, 0.5 eq) was slowly added at 0 °C and the mixture was stirred at the same temperature. After the completion of the reaction was detected by TLC, crushed ice was added into the mixture and stirred for another 1 h. After filtration, the filtrate was washed with cold water and collected as a white solid [ 32 ].…”

“…The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na 2 SO 4 . The organic layers were removed in vacuo to give crude colorless oil 3 [ 32 ].…”

“…We hoped that the isochromanone structure could occupy PAS as well. The benzyl piperidine fragment of donepezil is the key pharmacophore that occupies CAS, and, combined with our previous studies [ 30 , 31 , 32 ], we retained the cyclic structure of this fragment and replaced the piperidine ring with a pyridine ring. The central region of the AChE active pocket becomes narrower and consequently restricts the passage of ring structures containing larger substituents; the bottom region of the pocket becomes relatively larger and therefore contains several lateral cavities that could be further occupied to improve the affinity of a compound on AChE ( Figure 2 B).…”