Design, Synthesis and Biological Activity Study of Chalcone Derivatives Based on the Inhibitory Activities of Monoamine Oxidase and Cholinesterase Containing Indole Ring and Benzothiophene Ring

doi:10.6023/cjoc202412024

Abstract

31 chalcone derivatives containing indole and benzothiophene rings were designed and synthesized. Their biological activities in inhibiting cholinesterase (ChE) and monoamine oxidase (MAO) were subsequently investigated. The cholinesterase test results indicated that all compounds exhibited minimal inhibitory effects on acetylcholinesterase (AChE). However, certain compounds demonstrated notable inhibitory effects on butyrylcholinesterase (BuChE), with (E)-3-(1H-indol-3-yl)-1- (m-tolyl)prop-2-en-1-one (1a) and (E)-3-(1H-indol-3-yl)-1-(2-nitrophenyl)prop-2-en-1-one (1h) showing the strongest inhibition rates of 85.55% and 76.43%, respectively. These findings from the monoamine oxidase experiments indicated that some of compounds exhibited specific inhibitory effects on monoamine oxidase. Compounds exhibiting inhibitory activity exceeding 50%, specifically (E)-1-(3,4-dimethylphenyl)-3-(1H-indol-3-yl)prop-2-en-1-one (1c), (E)-3-(1H-indol-3-yl)-1-(3-methoxy- phenyl)prop-2-en-1-one (1f), (E)-3-(1H-indol-3-yl)-1-(4-methoxyphenyl)prop-2-en-1-one (1g), (E)-1-(4-hydroxyphenyl)-3- (1H-indol-3-yl)prop-2-en-1-one (1v), and (E)-3-(benzo[b]thiophen-3-yl)-1-(4-nitrophenyl)prop-2-en-1-one (1aa), were further evaluated for their effects on MAO-A and MAO-B enzymatic activities. It was observed that compounds 1c, 1f, and 1aa displayed comparatively superior inhibitory activity against both MAO-A and MAO-B. Results from cytotoxicity assays indicated that the compounds demonstrating enhanced inhibitory activity did not exhibit cytotoxic effects on L929 cells. Additionally, the results of molecular docking of compounds 1a, 1c and 1f showed significant interaction between compounds 1a and 1f with BuChE and between compounds 1c and 1f with MAO-A and MAO-B.

Key words: indole chalcone, benzothiophene chalcone, cholinesterase, monoamine oxidase, cytotoxicity, molecular docking

Cite this article

Min Tang, Bin Zhang, Qiushi Wang, Chaohua Fang, Liwei Hu, Liping Guan. Design, Synthesis and Biological Activity Study of Chalcone Derivatives Based on the Inhibitory Activities of Monoamine Oxidase and Cholinesterase Containing Indole Ring and Benzothiophene Ring[J]. Chinese Journal of Organic Chemistry, 2025, 45(8): 2989-3003.

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Fig. & Tab. 15

Figure 1. Examples of the design of derivatives 1a~1v with inhibitory effects on MAO and ChE

Figure 2. Examples of the design of derivatives 1w~1ae with inhibitory effects on MAO and ChE

Scheme 1. Synthetic route to derivatives 1a~1ae

Figure 3. Inhibitory effects of AChE by derivatives 1a~1ae

Figure 4. Inhibitory effects of BuChE by derivatives 1a~1ae

Compound	R	IC₅₀/(µmol•L^－1)
Compound	R	BuChE
1a	3-CH₃	0.48±0.34
1f	3-OCH₃	24.56±0.12
1h	2-NO₂	47.81±0.92
1k	2-F	41.48±1.45
1l	3-F	36.38±0.23
1ab	3-OH	87.67±3.27
Tacrine	—	36.38±0.23

Table 1. Results of the IC50 test of BuChE inhibitory activity of some compounds

Figure 5. MAO inhibition activity of compounds 1a~1ae

Compound	R	Inhibition rate/%		IC₅₀/(µmol•L^－1)
Compound	R	MAO-A	MAO-B	MAO-A	MAO-B
1c	3,4-(CH₃)₂	52.46	51.11	77.85±1.36	24.96±2.33
1f	3-OCH₃	51.88	52.97	120.15±5.87	81.07±2.41
1g	4-OCH₃	46.07	48.89	53.74±0.95	104.95±3.46
1v	4-OH	30.16	32.80	49.38±1.23	>150
1aa	4-NO₂	64.37	57.22	>150	51.99±0.76
Clorgiline	—	89.35	—	47.82±2.74	—
Pargyline	—	—	87.65	—	5.40±0.21

Table 2. Inhibitory activity of compounds 1c, 1f, 1g, 1v, and 1aa against MAO-A and MAO-B

Figure 6. Effect of compounds 1a, 1f, 1h, 1k, 1l and 1ab on the proliferation of L929 cells (MTT assay)

Figure 7. Cytotoxicity of compounds 1a, 1f, 1h, 1k, 1l and 1ab on AO/EB fluorescence staining

Figure 8. (A) 3D molecular docking model of compound 1a with BuChE; (B) 2D molecular docking model of compound 1a with BuChE

Figure 9. (A) 3D molecular docking model of compound 1c with MAO-B; (B) 2D molecular docking model of compound 1c with MAO-B

Figure 10. (A) 3D molecular docking model of compound 1f with BuChE; (B) 2D molecular docking model of compound 1f with BuChE

Figure 11. (A) 3D molecular docking model of compound 1f with MAO-A; (B) 2D molecular docking model of compound 1f with MAO-A

Figure 12. (A) 3D molecular docking model of compound 1f with MAO-B; (B) 2D molecular docking model of compound 1f with MAO-B

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