基于包含吲哚环、苯并噻吩环的单胺氧化酶和胆碱酯酶抑制活性的查尔酮衍生物设计、合成及生物活性研究

doi:10.6023/cjoc202412024

摘要/Abstract

设计合成了31个含有吲哚环和苯并噻吩环的查尔酮衍生物, 并考察了其对胆碱酯酶(ChE)和单胺氧化酶(MAO)的抑制活性. 胆碱酯酶实验的结果显示, 所有化合物对乙酰胆碱酯酶(AChE)的抑制作用较弱, 部分化合物对丁酰胆碱酯酶(BuChE)的抑制效果较为显著, 其中(E)-3-(1H-吲哚-3-基)-1-(间甲苯基)丙-2-烯-1-酮(1a)和(E)-3-(1H-吲哚-3-基)-1-(2-硝基苯基)丙-2-烯-1-酮(1h)对BuChE的抑制效果最好(抑制率分别为85.55%和76.43%). 单胺氧化酶实验结果表明, 部分化合物对单胺氧化酶具有一定的抑制作用. 抑制活性超过50%的[(E)-1-(3,4-二甲基苯基)-3-(1H-吲哚-3-基)丙-2-烯-1-酮(1c), (E)-3-(1H-吲哚-3-基)-1-(3-甲氧基苯基)丙-2-烯-1-酮(1f), (E)-3-(1H-吲哚-3-基)-1-(4-甲氧基苯基)-丙-2-烯-1-酮(1g), (E)-1-(4-羟基苯基)-3-(1H-吲哚-3-基)丙-2-烯-1-酮(1v), (E)-3-(苯并[b]噻吩-3-基)-1-(4-硝基)丙-2-烯-1-酮(1aa)]的MAO-A和MAO-B酶活性被评估, 发现化合物1c, 1f, 1aa对MAO-A和MAO-B都表现出较好的抑制活性. 细胞毒性实验结果显示, 抑制活性较好的化合物对L929细胞无细胞毒性. 此外, 化合物1a、1c和1f的分子对接结果表明, 化合物1a和1f与BuChE以及化合物1c和1f与MAO-A和MAO-B之间存在显著的相互作用.

关键词: 吲哚查尔酮, 苯并噻吩查尔酮, 胆碱酯酶, 单胺氧化酶, 细胞毒性, 分子对接

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

引用此文

汤敏, 张斌, 王秋实, 方超华, 胡立威, 关丽萍. 基于包含吲哚环、苯并噻吩环的单胺氧化酶和胆碱酯酶抑制活性的查尔酮衍生物设计、合成及生物活性研究[J]. 有机化学, 2025, 45(8): 2989-3003.

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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图/表 15

图1. 具有单胺氧化酶和胆碱酯酶抑制作用的衍生物1a~1v的设计实例

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

图2. 具有单胺氧化酶和胆碱酯酶抑制作用的衍生物1w~1ae的设计实例

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

图式1. 衍生物1a~1ae合成路线

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

图3. 衍生物1a~1ae对AChE的抑制活性

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

图4. 衍生物1a~1ae对BuChE的抑制活性

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

表1. 部分化合物BuChE抑制活性的IC50测试结果

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

图5. 化合物1a~1ae的MAO抑制活性

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

表2. 化合物1c, 1f, 1g, 1v, 1aa对MAO-A、MAO-B的抑制活性

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

图6. 化合物1a, 1f, 1h, 1k, 1l和1ab对L929细胞增殖的影响(MTT法)

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

图7. 化合物1a, 1f, 1h, 1k, 1l和1ab对AO/EB荧光染色的细胞毒性

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

图8. (A) 1a与BuChE分子对接(3D); (B) 1a与BuChE分子对接(2D)

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

图9. (A) 1c与MAO-B分子对接(3D); (B) 1c与MAO-B分子对接(2D)

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

图10. (A) 1f与BuChE分子对接(3D); (B) 1f与BuChE分子对接(2D)

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

图11. (A) 1f与MAO-A分子对接(3D); (B) 1f与MAO-A分子对接(2D)

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

图12. (A) 1f与MAO-B分子对接(3D); (B) 1f与MAO-B分子对接(2D)

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

参考文献 35

[1]	Ramirez, S.; Koerich, S.; Astudillo, N.; Gregorio, N. D.; Lahham, R. A.; Allison, T.; Rocha, N. P.; Wang, F.; Soto, C. Int. J. Mol. Sci. 2023, 24, 17087.
[2]	Hua, K. Y.; Zhao, W. J. Folia Neuropathol. 2023, 61, 15.
[3]	Saleem, L.; Zubbair, M. M.; Debnath, P. Heliyon 2021, 7, e08502.
[4]	Li, X. T. Metab. Brain Dis. 2022, 37, 581.
[5]	Arianna, P.; Manuela, G.; Pierpaolo, S.; Francesca, J.; Maria, D. A.; Giuseppe, S. Cell. Mol. Neurobiol. 2018, 38, 817.
[6]	Tabet, N. Age Ageing 2006, 35, 336. doi: 10.1093/ageing/afl027 pmid: 16788077
[7]	Lina, H.; Grant, S.; Katrin, B.; Sonja, M.; Simon, Y.; Klaus, H.; Jürgen, E.; Gerald, M. Pharmacol. Ther. 2007, 113, 154.
[8]	Saleh, L.Y.; Özdemir, S.; Sağlık, B. N.; Döndaş, H. A.; Altug, C. J. Mol. Struct. 2024, 1313, 138667.
[9]	Annette, M.; Klaus, H.; Marlene, K.; Matt, S.; Ralph, M.; Jürgen, E.; David, C.; Gerald, M. Adv. Drug Delivery 2008, 60, 1463.
[10]	Kim, C. R.; Choi, S. J.; Kwon, Y. K.; Kim, J. K.; Kim, Y. J.; Park, G. G. Biol. Pharm. Bull. 2016, 39, 1130.
[11]	Mirjana, B. L.; ŠGoran, H. P. R. Prog. Brain Res. 2021, 261, 379. doi: 10.1016/bs.pbr.2020.07.016 pmid: 33785136
[12]	Wang, Q. J.; Ren, H. H.; Liu, T. Q.; Zhang, X. Y. J. Affective Disord. 2024, 351, 8.
[13]	Salwierz, P.; Thapa, S.; Taghdiri, F.; Vasilevskaya, A.; Anastassiadis, C.; Wai, D. F. T. A.; Golas, C.; Tartaglia, M. C. GeroScience 2024, 46, 783. doi: 10.1007/s11357-023-01030-x pmid: 38097855
[14]	Mayeli, M.; Shafie, M.; Shiravi, M.; Parvar, T. A.; Mirsepassi, Z.; Rahiminejad, F.; Sattarpour, R.; Aghamollaii, V. Health Rep. 2024, 7, e2106.
[15]	Zhao, Y.; Qin, Y.; Hu, X.; Chen, X.; Jiang, Y. P.; Jin, X. J.; Li, G.; Li, Z. H.; Yang, J. H.; Cui, S. Y.; Zhang, Y. H. Front. Pharmacol. 2024, 15, 1406127.
[16]	Mesa, R. R.; Barquera, J. A. O. S. D. L. D.; Medellin, G.; Garza, L. A. D. L.; Torres, G. S.; Velazquez, J. O. M.; Aviles, F. S. S.; Martinez, J. Am. J. Geriat. Psychiat. 2024, 32, S102.
[17]	Fakih, N.; Fakhoury, M. J. Psychiatr. Pract. 2024, 30, 181. doi: 10.1097/PRA.0000000000000779 pmid: 38819242
[18]	Oliveira, V. M. D.; Rocha, M. N. D.; Roberto, C. H. A.; Lucio, F. N. M.; Marinho, M. M.; Marinho, E. S.; Morais, S. M. D. J. Mol. Struct. 2024, 1302, 137453.
[19]	Meghan, P.; Zhi, L.; Bing, Q.; Grace, T.; Matthew, U.; Reed, O.; Rebecca, D.; Julia, V.; Sheyum, S.; Nissim, I.; María, D. L. P. F.; Mimi, S. H. Sci. Rep. 2023, 13, 10411.
[20]	Flavia, R.; Claudio, C.; Andrea, S.; Niccolò, S.; Alessandro, V.; Nicolas, Z.; Michele, F.; Ken, G.; Ignazio, C. C.; Vincent, V. D. E.; Stephen, S.; Felice, L.; Andrea, D. B. Eur. Neuropsychopharmacol. 2023, 72, 60.
[21]	Ji, Y.; Yang, C. Y.; Pang, X. R.; Yan, Y. B.; Wu, Y.; Geng, Z.; Hu, W. J.; Hu, P. P.; Wu, X. Q.; Wang, K. Neural Regener. Res. 2024, 20, 326.
[22]	Kupershmidt, L.; Youdim, M. B. H. Cell 2023, 12, 763.
[23]	Min, P. S.; Hyun, L. S.; Yan, Z. H.; Jeongtae, K.; Young, J. J.; Jin, C. Y.; Soyeon, J.; Soyeong, S.; Kyungsook, J.; Hee, J. J. Front. Neurosci. 2023, 17, 1108371.
[24]	Daniela, M.; Sara, M.; Benjamin, M.; Joseph, B. J.; František, D. Front. Pharmacol. 2023, 14, 1196413.
[25]	Sang, Z. P.; Wang, K. R.; Wang, H. F.; Wang, H. J.; Ma, Q. W.; Han, X.; Ye, M. Y.; Yu, L. T.; Liu, W. M. Bioorg. Med. Chem. Lett. 2017, 27, 5046.
[26]	Asif, H.; Al, B. K.; Jawaid, A. M.; Alam, K. S. J. Mol. Struct. 2021.
[27]	Macklin, J. L.; Schwans, P. J. Bioorg. Med. Chem. Lett. 2020, 30, 127213.
[28]	Singh, A.; Sharma, S.; Arora, S.; Attri, S.; Kaur, P.; Gulati, H. K.; Bhagat, K.; Kumar, N.; Singh, H.; Singh, J. V.; Bedi, P. M. S. Bioorg. Med. Chem. Lett. 2020, 30, 127477.
[29]	Rialette, H.; Petzer, J. P.; Anél, P. Bioorg. Med. Chem. Lett. 2022, 77, 129038.
[30]	Jawed, A. M.; Amena, A.; Abuzer, A.; Arunkumar, T.; Bakht, M. A.; Mohammad, Y.; Salahuddin, A. ACS Omega 2022, 7, 38207.
[31]	Munir, S.; Shahid, A.; Aslam, B.; Ashfaq, U. A.; Akash, M. S. H.; Ali, M. A.; Almatroudi, A.; Allemailem, K. S.; Rajoka, M. S. R.; Khurshid, M.; Baloch, Z. J. Evidence-Based Complementary Altern. Med. 2020, 2020, 8836983.
[32]	Funahashi, R.; Matsuura, F.; Ninomiya, M.; Okabe, S.; Takashima, S.; Tanaka, K.; Nishina, A.; Koketsu, M. Bioorg. Chem. 2024, 145, 107229.
[33]	Liu, W. H.; Zhao, D. H.; He, Z. W.; Hu, Y. M.; Zhu, Y. X.; Zhang, L. J.; Jin, L. H.; Guan, L. P.; Wang, S. H. Molecules 2022, 27, 9062.
[34]	Tan, Q. W.; He, L. Y.; Zhang, S. S.; He, Z. W.; Liu, W. H.; Zhang, L.; Guan, L. P.; Wang, S. H. Chem. Biodiversity 2022, 19, e202100610.
[35]	Guan, L. P.; He, Z. W.; Jiang, K. L.; Sun, X. H.; Tang, M.; Liu, Y. W.; Wu, D. Chem. Biodiversity 2023, 20, e202301271.