2-(1,3-二氧代异吲哚啉-2-基)-N-苯乙酰胺和2-(3,4-二氢异喹啉-1-基甲基)异吲哚-1,3-二酮类MOAs和ChE抑制剂的设计、合成和生物活性研究

doi:10.6023/cjoc202311027

摘要/Abstract

在本论文中,我们合成了一系列2-(1,3-二氧代异吲哚啉-2-基)-N-苯乙酰胺和2-(3,4-二氢异喹啉-1-基甲基)异吲哚-1,3-二酮衍生物并评价了它们抑制MAOs和ChE生物活性。实验结果显示,所有的化合物对单胺氧化酶具有一定的抑制活性。再分别进行MAO-A和MAO-B抑制活性研究,发现所有的化合物对MAO-B显示比较好的抑制活性, 对MAO-A显示弱的抑制活性。其中,化合物2h和3d显示最好的抑制MAO-A和MAO-B作用,对MAO的IC₅₀值分别为3.87±0.59和3.35±0.53 μM。细胞毒性实验结果显示,抑制活性比较好的化合物对L929细胞没有细胞毒性。化合物2h和3d分子对接的结果表明,化合物2h和3d与MAO-A和MAO-B之间存在明显的相互作用。另外,所有的化合物对乙酰胆碱酯酶和丁酰胆碱酯酶显示比较弱的抑制活性。

关键词: 2-(1,3-二氧代异吲哚啉-2-基)-N-苯乙酰胺, 2-(3,4-二氢异喹啉-1-基甲基)异吲哚-1,3-二酮, 单胺氧化酶, 胆碱酯酶, 细胞毒性, 分子对接

In this paper, we have synthesized a series of 2-(1,3-dioxoisoindolin-2-yl)-N-phenethylacetamide and 2-(3,4-dihydro isoquinolin-1-ylmethyl)isoindole-1,3-dionederivatives and evaluated their biological activities of MAOs and ChE inhibition. The experimental results showed that all compounds exhibited certain inhibitory activity against MAOs. Upon separate MAO-A and MAO-B activity studies, the compounds displayed better inhibition activity against MAO-B and weaker inhibition activity against MAO-A. Among these, compounds 2h and 3d exhibited the most significant inhibition of MAO-A and MAO-B, with IC₅₀ values of 3.87±0.59 and 3.35±0.53μM towards MAO, respectively. Results from cytotoxicity assays indicated that compounds with good inhibitory activity showed no cytotoxicity against L929 cells. Molecular docking of compounds 2h and 3d revealed significant interactions with both MAO-A and MAO-B. Additionally, all compounds exhibited relatively weak inhibition activity against AChE and BuChE.

Key words: 2-(1,3-dioxoisoindolin-2-yl)-N-phenethylacetamide, 2-(3,4-dihydroisoquinolin-1-ylmethyl)isoindole-1,3-dione, monoamine oxidase, cholinesterase, cytotoxicity, molecular docking

引用此文

胡懿鸣, 许嘉宇, 汤敏, 刘雅雯, 关丽萍, 金晴昊. 2-(1,3-二氧代异吲哚啉-2-基)-N-苯乙酰胺和2-(3,4-二氢异喹啉-1-基甲基)异吲哚-1,3-二酮类MOAs和ChE抑制剂的设计、合成和生物活性研究[J]. 有机化学, doi: 10.6023/cjoc202311027.

Hu Yi-ming, Xu Jia-yu, Tang Min, Liu Ya-wen, Guan Li-ping, Jin Qing-hao. Design, synthesis and biological activity studies of 2- (1,3-dioxoisoindolin- 2-yl)-N-phenethylacetamide and 2-(3,4-dihydroisoquinolin-1-ylmethyl)isoindole- 1,3-dione as MOAs and ChE inhibitors[J]. Chinese Journal of Organic Chemistry, doi: 10.6023/cjoc202311027.

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参考文献

[1] (a) Schmidt, U.; Schmidt J. Synthesis, 1994, 1994, 300.
(b) Ding, H.; Friestad, G. K. Synthesis 2005, 2005, 2815.
(c) Trost, B. M.; Tang, W.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 14785.
(d) Zhao, Y.-S.; Liu, Q.; Tian, P.; Tao, J.-C.; Lin, G.-Q. Org. Biomol. Chem. 2015, 13, 4174.
[2] For selected examples using homoallylic amines as intermediates, see:
(a) Ren, H.; Wulff, W. D. J. Am. Chem. Soc. 2011, 133, 5656.
(b) Silverio, D. L.; Torker, S.; Pilyugina, T.; Vieira, E. M.; Snapper, M. L.; Haeffner, F.; Hoveyda, A. H. Nature 2013, 494, 216.
(c) Zhou, X.; Li, W.; Zhou, R.; Wu, X.; Huang, Y.; Hou, W.; Li, C.; Zhang, Y.; Nie, W.; Wang, Y.; Song, H.; Liu, X.-Y.; Zheng, Z.; Xie, F.; Li, S.; Zhong, W.; Qin, Y. CCS Chem. 2021, 3, 1376.
For selected examples using homoallylic amines as catalysts and ligands, see:
(d) Jin, S.-S.; Wang, H.; Xu, M.-H. Chem. Commun. 2011, 47, 7230.
(e) Melchiorre, P. Angew. Chem. Int. Ed. 2012, 51, 9748.
(f) Dong, X.-Y.; Zhang, Y.-F.; Ma, C.-L.; Gu, Q.-S.; Wang, F.-L.; Li, Z.-L.; Jiang, S.-P.; Liu, X.-Y. Nat. Chem. 2019, 11, 1158.
[3] (a) Huo, H.-X.; Duvall, J. R.; Huang, M.-Y.; Hong, R. Org. Chem. Front. 2014, 1, 303.
(b) Blieck, R.; Taillefer, M.; Monnier, F. Chem. Rev. 2020, 120, 13545.
(c) Liu, J.; Cao, C.-G.; Sun, H.-B.; Zhang, X.; D. Niu, D. J. Am. Chem. Soc. 2016, 138, 13103.
(d) Liu, C.; Deng, C.; Yang, H.; Qian, X.; Tang, S.; Poznik, M.; Chruma, J. J. J. Org. Chem. 2019, 84, 10102.
(e) Wang, R.-Q.; Shen, C.; Cheng, X.; Wang, Z.-F.; Tao, H.-Y.; Dong, X.-Q.; Wang, C.-J. Chin. J. Chem. 2020, 38, 807.
(f) Ronchi, E.; Paradine, S. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2021, 143, 7272.
(g) Byun, S.; Farah, A. O.; Wise, H. R.; Katchmar, A.; Cheong, P. H.-Y.; Scheidt, K. A. J. Am. Chem. Soc. 2022, 144, 22850
[4] (a) Alam, R.; Diner, C.; Jonker, S.; Eriksson, L.; Szabó, K. J. Angew. Chem. Int. Ed. 2016, 55, 14417.
(b) van der Mei, F. W.; Miyamoto, H.; Silverio, D. L.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2016, 55, 4701.
(c) Zhang, H.-J.; Shi, C.-Y.; F. Zhong, F.; Yin, L. J. Am. Chem. Soc. 2017, 139, 2196.
(d) Green, J. C.; Zanghi, J. M.; Meek, S. J. J. Am. Chem. Soc. 2020, 142, 1704.
(e) Zhou, P.; Shao, X.; Malcolmson, S. J. J. Am. Chem. Soc. 2021, 143, 13999.
[5] For reviews, see:
(a) Pulis, A. P.; Yeung, K.; Procter, D. J. Chem. Sci. 2017, 8, 5240.
(b) Hemming, D.; Fritzemeier, R.; Westcott, S. A.; Santos, W. L.; Steel, P. G. Chem. Soc. Rev. 2018, 47, 7477.
(c) Talbot, F. J. T.; Dherbassy, Q.; Manna, S.; Shi, C.; Zhang, S.; Howell, G. P.; Perry, G. J. P.; Procter, D. J. Angew. Chem. Int. Ed. 2020, 59, 20278.
(d) Whyte, A.; Torelli, A.; Mirabi, B.; Zhang, A.; Lautens, M. ACS Catal. 2020, 10, 11578.
(e) Kanti Das, K.; Manna, S.; Panda, S. Chem. Commun. 2021, 57, 441.
(f) Bose, S. K.; Mao, L.; Kuehn, L.; Radius, U.; Nekvinda, J.; Santos, W. L.; Westcott, S. A.; Steel, P. G.; Marder, T. B. Chem. Rev. 2021, 121, 13238.
For examples, see:
(g) Li, X.; Liu, X.; Fu, Y.; Wang, L.; Zhou, L.; Feng, X. Chem. Eur. J. 2008, 14, 4796.
(h) Gandhi, S.; List, B. Angew. Chem. Int. Ed. 2013, 52, 2573.
(i) Meng, F.; Jang, H.; Jung, B.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2013, 52, 5046.
(j) Fujihara, T.; Sawada, A.; Yamaguchi. T.; Tani, T.; Terao, J.; Tsuji, Y. Angew. Chem. Int. Ed. 2017, 56, 1539.
(k) Jiang, Y.; Schaus, S. E. Angew. Chem. Int. Ed. 2017, 56, 1544.
(l) Villar, L.; Orlov, N. V.; Kondratyev, N. S.; Uria, U.; Vicario, J. L.; Malkov, A. V. Chem. Euro. J. 2018, 24, 16262.
(m) Yeung, K.; Talbot, F. J. T.; Howell, G. P.; Pulis, A. P.; Procter, D. J. ACS Catal. 2019, 9, 1655.
(n) Han, J.; Zhou, W.; Zhang, P.-C.; Wang, H.; Zhang, Wu, H.-H.; Zhang, J. ACS Catal. 2019, 9, 6890.
(o) Deng, H.; Meng, Z.; Wang, S.; Zhang, Z.; Zhang, Y.; Shangguan, Y.; Yang, F.; Yuan, D.; Guo, H.; Zhang, C. Adv. Synth. Catal. 2019, 361, 3582.
(p) Pérez-Saavedra, B.; Velasco-Rubio, Á.; Rivera-Chao, E.; Varela, J. A.; Saá. C.; Fañanás-Mastral, M. J. Am. Chem. Soc. 2022, 144, 16206.
[6] Jiang, L.; Cao, P.; Wang, M.; Chen, B.; Wang, B.; Liao, J. Angew. Chem. Int. Ed. 2016, 55, 13854.
[7] Jang, H.; Romiti, F.; Torker, S.; Hoveyda, A. H. Nat. Chem. 2017, 9, 1269.
[8] Zhang, S.; Pozo, J. D.; Romiti, F.; Mu, Y.; Torker, S.; Hoveyda, A. H. Science 2019, 364, 45.
[9] Zhao, C.-Y.; Zheng, H.; Ji, D.-W.; Min, X.-T.; Hu, Y.-C.; Chen, Q.-A. Cell Rep. Phys. Sci. 2020, 1, 100067.
[10] Yeung, K.; Ruscoe, R. E.; Rae, J.; Pulis, A. P.; Procter, D. J. Angew. Chem. Int. Ed. 2016, 55, 11912.
[11] (a) Cai, Y.; Yang, X.-T.; Zhang, S.-Q.; Li, F.; Li, Y.-Q.; Ruan, L.-X.; Hong, X.; Shi, S.-L. Angew. Chem. Int. Ed. 2018, 57, 1376.
(b) Cai, Y.; Ye, X.; Liu, S.; Shi, S.-L. Angew. Chem. Int. Ed. 2019, 58, 13433.
(c) Cai, Y.; Zhang, J.-W.; Li, F.; Liu, J.-M.; Shi, S.-L. ACS Catal. 2019, 9, 1.
(d) Shen, D.; Xu, Y.; Shi, S.-L. J. Am. Chem. Soc. 2019, 141, 14938.
(e) Zhang, W.-B.; Yang, X.-T.; Ma, J.-B.; Su, Z.-M.; Shi, S.-L. J. Am. Chem. Soc. 2019, 141, 5628.
(f) Cai, Y.; Shi, S.-L. J. Am. Chem. Soc. 2021, 143, 11963.
(g) Cai, Y.; Ruan, L.-X.; Rahman A.; Shi, S.-L. Angew. Chem. Int. Ed. 2021, 60, 5262.
(h) Wang, Z.-C.; Xie, P.-P.; Xu, Y.; Hong, X.; Shi, S.-L. Angew. Chem. Int. Ed. 2021, 60, 16077.
(i) Wang, Z.-C.; Gao, J.; Cai, Y.; Ye, X.; Shi, S.-L. CCS Chem. 2022, 4, 1169.
(j) Zhang, W.-B.; Chen, G.; Shi, S.-L. J. Am. Chem. Soc. 2022, 144, 130.
(k) Ma, J.-B.; Zhao, X.; Zhang, D.; Shi, S.-L. J. Am. Chem. Soc. 2022, 144, 13643.
(l) Liu, C.-F.; Wang, Z.-C.; Luo, X.; Lu, J.; Ko, M.; Shi, S.-L.; Koh, M. J. Nat. Catal. 2022, 5, 934.
(m) Ruan, L. X.; Sun, B.; Liu, J. -M.; Shi. S.-L. Science, 2023, 379, 662.
(n) Wang, Z.-C.; Luo, X.; Zhang, J.-W. Liu, C.-F.; Koh, M. J.; Shi, S.-L. Nat. Catal. 2023, 6, 1087.
[12] (a) Fujihara, T.; Semba, K.; Terao, J.; Tsuji, Y. Catal. Sci. Technol. 2014, 4, 1699.
(b) Bin, H.-Y.; Wei, X.; Zi, J.; Zuo, Y.-J.; Wang, T.-C.; Zhong, C.-M. ACS Catal. 2015, 5, 6670.
(c) Yoshida, H. ACS Catal. 2016, 6, 1799.
(d) Chen, J.; Guo, J.; Lu, Z. Chin. J. Chem. 2018, 36, 1075.
(e) Rej, S.; Das, A.; Panda, T. K. Adv. Synth. Catal. 2021, 363, 4818.
[13] CCDC 2171104 contains the supplementary crystallographic data of this paper. These data can be obtained from The Cambridge Crystallographic Data Centre (CCDC) for free of charge.
[14] (a) Alam, R.; Das, A.; Huang, G.; Eriksson, L.; Himo, F.; Szabó, K. J. Chem. Sci. 2014, 5, 273.
(b) Rae, J.; Yeung, K.; McDouall, J. J. W.; Procter, D. J. Angew. Chem. Int. Ed. 2016, 55, 1102.
(c) Li, Z.; Zhang, L.; Nishiura, M.; Luo, G.; Luo, Y.; Hou, Z. ACS Catal. 2020, 10, 11685.
(d) Ozawa, Y.; Endo, K.; Ito, H. J. Am. Chem. Soc. 2021, 143, 13865.

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