Synthesis of Naphthalimide Derivatives as Cholinesterase Inhibitors with Aggregation Induced Emission Properties

doi:10.6023/cjoc202107064

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by impaired cognitive and memory function, which seriously affects the quality of life of the elderly. At present, the main drugs for the treatment of AD are cholinesterase inhibitors, such as donepezil and rivastigmine. In this paper, a series of novel naphthimide derivatives were designed, synthesized and evaluated based on the structure of donepezil. The results showed that all of the tested compounds were acetylcholinesterase (AChE) selective inhibitors, 2-((1-(3-methoxybenzyl)piperidin-4-yl)methyl)-1H-benzo[de]isoquinoline- 1,3(2H)-dione (4k) exhibited the strongest inhibition to AChE with an IC₅₀ value of 4.43 μmol/L, which was better than the control rivastigmine. Kinetic and molecular modeling studies indicated that 4k targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4k didn’t show obvious cytotoxicity against SH-SY5Y and PC12 cell lines. Besides, these compounds exhibited typical aggregation induced emissions (AIE) properties, which might be controlled by mechanism of restriction of intramolecular rotations.

Key words: naphthalimide, cholinesterase, aggregation induced emission

Cite this article

Yongmei Zhao, Yeshu Mu, Wen Luo, Zhiyong Tian. Synthesis of Naphthalimide Derivatives as Cholinesterase Inhibitors with Aggregation Induced Emission Properties[J]. Chinese Journal of Organic Chemistry, 2022, 42(3): 819-829.

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Fig. & Tab. 12

Figure 1. Chemical structures of donepezil and naphthalimide derivatives

Scheme 1. Synthesis of the target compounds Reagents and conditions: (a) 1-Boc-4-(aminomethyl)piperidine, EtOH, reflux, 5 h; (b) HCl, EtOH, r.t.,12 h; (c) Benzyl bromide, CH3CN, 60 ℃, 6 h

Compd.	R¹		IC₅₀/(μmol•L^–1) for AChE^a	IC₅₀/(μmol•L^–1) for BChE^b	SI^c
4a	H		18.43±1.96	>100	<0.18
4b	H		12.28±1.79	>100	<0.12
4c	H		9.15±0.55	>100	<0.09
4d	H		11.19±1.13	>100	<0.11
4e	H		4.66±0.54	>100	<0.05
4f	H		12.98±1.78	>100	<0.13
4g	H		8.86±1.05	>100	<0.09
4h	H		7.43±0.71	>100	<0.07
4i	H		12.72±1.92	>100	<0.13
4j	H		11.57±1.06	>100	<0.12
4k	H		4.43±0.45	>100	<0.04
5a	Br		17.14±1.69	>100	<0.17
5b	Br		14.52±0.75	>100	<0.15
5c	Br		9.58±0.81	41.36±2.23	0.23
5d	Br		14.30±1.30	>100	<0.14
Riv.^d	—	—	7.25±0.34	1.85±0.21	3.92
Dpz.^e	—	—	0.027±0.003	1.155±0.03	0.023

Table 1. In vitro ChEs inhibitory activity of the target compounds

Figure 2. Docking model of 4k with 1EVE (A) and 3D model of 1EVE (B)

Figure 3. Lineweaver-Burk plots for compound 4k with TcAChE

Figure 4. Absorption (A) and FL spectra (B, λex=340 nm, slit: 2.5/5 nm) of 4k (20 µmol/L) in different solvents

Figure 5. Absorption (A) and FL spectra (B, λex=340 nm, slit: 2.5/5 nm) of 4k (20 µmol/L) in THF/water mixtures

Figure 6. Changes of FL peak intensities at 394 nm vs the water fraction in the THF/water mixtures Inset: FL photographs under the illumination of a UV lamp (365 nm)

Figure 7. Tyndall effect of 4k (20 μmol/L) in different fraction THF/water mixtures (fw: 0%, 20%, 40%, 60%, 80%, 100%)

Figure 8. Photograph of different concentrations of 4k in THF under UV lamp (365 nm) Left to right: 1 µmol/L, 10 µmol/L, 100 µmol/L, 1 mmol/L, 10 mmol/L, 100 mmol/L, 125 mmol/L

Figure 9. Absorption (A) and FL spectra (B, λex=340 nm, slit: 2.5/5 nm) of 4k (20 µmol/L) in MeOH/glycerin mixtures

Figure 10. Effect of compound 4k on viability of SH-SY5Y and PC12 cell lines

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