Design, Synthesis and Antioxidant Activity of Tetrahydro-β-carbolines

doi:10.6023/cjoc202301007

Abstract

Tetrahydro-β-carbolines (THBCs) are important structural units of indole alkaloids, most of which have significant biological properties, such as anti-inflammatory, antiviral, anticancer, antibacterial, and antioxidant properties. Herein, a Pictet-Spengler oxidation reaction with 3-(2-methylaminoethyl) indole and alcohols as starting materials was developed over the pincer manganese catalyst. The reaction system showed good substrate applicability, 12 kinds of THBC products were synthesized from aromatic alcohols and aliphatic alcohols with the yields of 43%~99%. The structures of the products were confirmed and characterized by ¹H NMR, ¹³C NMR, IR and HRMS. The antioxidant activity of these compounds were investigated by scavenging ABTS^＋• and DPPH•. The results showed that in the two test systems, all of those compounds had good free radical scavenging ability, indicating that those compounds are a class of potential antioxidant. Among them, 1-(4-fluoro- phenyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3c), 2-methyl-1-(naphthalen-2-yl)-2,3,4,9-tetrahydro-1H-pyrido- [3,4-b]indole (3e), 2-methyl-1-propyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(3h), 2-methyl-1-propyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole (3j) and 2-methyl-1-(2-(pyridin-3-yl)ethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3l) showed the best effect on scavenging ABTS^＋•, while 1-cyclohexyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3i) and 2-methyl- 1-(2-(thiophen-2-yl)ethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3k) were slightly weaker, followed by 2-methyl-1-phe- nyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3a), 2-methyl-1-(4-(methylthio)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]- indole (3b), 1-(furan-2-yl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3d), 2-methyl-1-(pyridin-3-yl)-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole (3f) and 2-methyl-1-(thiophen-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3g), and IC₅₀could reach 0.073 mg•mL^－1 or above. Among of the target compounds, 3a, 3c, 3e and 3h had the best effect on scavenging DPPH•, followed by 3d, 3i, 3j and 3l, and 3b, 3f and 3g had the worst effect. In conclusion, compounds 3c, 3e and 3h had good scavenging ability on ABTS^＋• and DPPH•, while compounds 3b, 3f and 3g had poor scavenging ability on 2,2'-azino- bis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS^＋•) and 1,1-diphenyl-2-picrylhydrazyl free radical (DPPH•).

Key words: tetrahydro-β-carbolines, manganese catalysis, alcohols, Pictet-Spengler reaction, antioxidation

Cite this article

Xiaoyu Zhang, Xinyan Li, Bing Cui, Zhihui Shao, Mingqin Zhao. Design, Synthesis and Antioxidant Activity of Tetrahydro-β-carbolines[J]. Chinese Journal of Organic Chemistry, 2023, 43(8): 2885-2894.

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Fig. & Tab. 9

Figure 1. Examples of natural products or drugs containing the tetrahydro-β-carbolines (THBC) scaffold

Scheme 1. Synthesis of THBCs catalyzed by Ru and Ni catalysis

Figure 2. Catalyst structure

Table 1. Effects of reaction conditions on the synthesis of the target compound 3a

Table 2. Manganese-catalyzed dehydrogenative coupling of 3-(2-methylaminiethyl) indole with various alcohols to synthesis THBCs

Scheme 2. Proposed reaction mechanism for dehydrogenative coupling of 3-(2-methylaminiethyl) indole with alcohol

Figure 3. ABTS＋? scavenging ability of of THBCs and Vc

Compound	Structure	IC₅₀/(mmol•mL^－1)
Compound	Structure	ABTS^＋•	DPPH•
3a		0.170	1.621
3b		0.192	>10
3c		0.114	1.115
3d		0.168	2.737
3e		0.115	1.115
3f		0.165	>10
3g		0.166	>10
3h		0.102	1.090
3i		0.137	8.581
3j		0.109	4.275
3k		0.126		9.476
3l		0.111		6.141
Vc		0.099		1.003

Table 3. Antioxidant activity of compounds

Figure 4. DPPH? scavenging ability of THBCs and Vc

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