吡嗪-噻唑联芳类化合物的合成及抗氧化性能研究

doi:10.6023/cjoc202011013

摘要/Abstract

为了从吡嗪和噻唑类化合物中寻找新的抗氧化剂, 通过活性基团拼接方法, 设计合成了一系列吡嗪-噻唑联芳类化合物. 借助¹H NMR、¹³C NMR、IR和HPLC-MS等手段对目标化合物的结构进行了表征, 并通过抑制自由基引发DNA氧化反应及淬灭自由基反应体系对化合物的抗氧化活性和还原能力进行了测试. 结果表明, 在5个测试体系中, 8个目标化合物均能够有效抑制自由基引发DNA氧化反应并捕获自由基, 具有较强自由基的清除能力和还原能力, 是一类潜在的抗氧化剂. 其中, 在抑制2,2'-偶氮二异丁基脒二盐酸盐(AAPH)引发DNA氧化反应体系中, 8个化合物的有效计量因子(n)可达1.48~2.12; 在抑制HO•和还原型谷胱甘肽自由基(GS•)引发DNA氧化反应体系中, 8个化合物相对空白硫代巴比妥酸(TBARS)吸光度百分数分别为54.3%~76.1%和55.4%~68.3%; 8个化合物均能够捕获2,2'-偶氮-双-(3-乙基苯并噻唑啉-6-磺酸)二铵盐自由基(ABTS•)和二苯苦味酰肼自由基(DPPH•). 另外, 对比发现吡嗪-噻唑联芳类化合物表现出优于吡嗪-噁唑联芳类化合物的抗氧化性能.

关键词: 吡嗪-噻唑, 氧化偶联, 抗氧化, DNA, 自由基

In order to find novel pyrazine- and thiazole-based derivatives with potent antioxidant properties, eight pyrazine-thiazole bi-heteroaryl compounds were designed and prepared via active group splicing method between pyrazine-N- oxides and thiazoles. They were structurally characterized by ¹H NMR, ¹³C NMR, IR, and HPLC-MS. Antioxidant abilities of the obtained compounds were evaluated by inhibiting radicals induced oxidation of DNA and quenching radicals. The results showed that eight compounds can effectively inhibit radicals induced oxidation of DNA and quench radicals, which revealed that the compounds have strong radical scavenging properties and reduction ability, and can be potential antioxidants. The effective measurement factor (n) values of these compounds ranged from 1.48 to 2.12 in 2,2-azobis(2-amidinopropanehydro- chloride) (AAPH) induced oxidation of DNA. The absorbance percentages of eight compounds to the blank thiobarbituric acid reactive substance (TBARS percentage) were 54.3%~76.1% and 55.4%~68.3% in inhibiting HO• and glutathione radical (GS•) induced oxidation of DNA, respectively. Eight compounds can scavenge 2,2-azinobis(3-ethylbenzothiazoline-6-sul- fonate) cationic radical (ABTS•) and 2,2-diphenyl-1-picrylhydrazyl radical (DPPH•). In addition, it was found that the antioxidant activity of pyrazine-thiazole bi-heteroaryl compounds was significantly higher than that of pyrazine-oxazole bi-heteroaryl compound.

Key words: pyrazine-thiazole, oxidative cross-dehydrogenative coupling, antioxidant, DNA, free radical

引用此文

张晓平, 金桂勇, 陈芝飞, 王清福, 赵森森, 武志勇, 万帅, 席高磊, 赵旭. 吡嗪-噻唑联芳类化合物的合成及抗氧化性能研究[J]. 有机化学, 2021, 41(6): 2445-2453.

Xiaoping Zhang, Guiyong Jin, Zhifei Chen, Qingfu Wang, Sensen Zhao, Zhiyong Wu, Shuai Wan, Gaolei Xi, Xu Zhao. Synthesis and Antioxidant Properties of Pyrazine-Thiazole Bi-heteroaryl Compounds[J]. Chinese Journal of Organic Chemistry, 2021, 41(6): 2445-2453.

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图/表 8

图式1. 吡嗪-噻唑联芳类化合物的合成方法

Scheme 1. Synthetic methods of pyrazine-thiazole bi-heteroaryl compounds

Entry	Catalyst	Solvent	Time/h	T/℃	Yield/%
1	FeCl₃	Toluene	6	Reflux	31
2	FeCl₃	CH₃CN	6	Reflux	37
3	FeCl₃	CHCl₃	6	Reflux	47
4	FeCl₃	ClCH₂CH₂Cl	6	Reflux	61
5	FeCl₃	ClCH₂CH₂Cl	8	Reflux	64
6	FeCl₃	ClCH₂CH₂Cl	10	Reflux	62
7	FeCl₃	ClCH₂CH₂Cl	8	60	39
8	FeCl₃	ClCH₂CH₂Cl	8	25	Trace
9	^tBuOLi/TBAB^[13]	Xylene	24	Reflux	46
10	InCl₃	ClCH₂CH₂Cl	8	Reflux	31
11	BiCl₃	ClCH₂CH₂Cl	8	Reflux	34
12	LaCl₃	ClCH₂CH₂Cl	8	Reflux	25
13	CeCl₃	ClCH₂CH₂Cl	8	Reflux	37
14	YbCl₃	ClCH₂CH₂Cl	8	Reflux	33
15	ScCl₃	ClCH₂CH₂Cl	8	Reflux	26
16	CuCl₂	ClCH₂CH₂Cl	8	Reflux	21
17	AgCl	ClCH₂CH₂Cl	8	Reflux	12

表1. 不同反应条件对目标化合物3a合成产率的影响

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

图1. 不同浓度化合物存在下TBARS吸光度随时间的变化曲线

Figure 1. Variation of the absorbance of TBARS in various concentrations compounds

图2. 抑制期(tinh)与化合物浓度之间的关系

Figure 2. Relationships between inhibition period (tinh) and concentrations of compounds

Compd.	t_inh(min)=(n/R_i)c_compound+constant	n
3a	t_inh=0.53(±0.03)c(3a)–1.34(±0.07)	1.78(±0.08)
3b	t_inh=0.54(±0.03)c(3b)+0.59(±0.03)	1.81(±0.09)
3c	t_inh=0.57(±0.03)c(3c)–0.73(±0.04)	1.92(±0.10)
3d	t_inh=0.63(±0.03)c(3d)+0.68(±0.03)	2.12(±0.11)
3e	t_inh=0.54(±0.03)c(3e)–1.72(±0.09)	1.81(±0.09)
3f	t_inh=0.55(±0.03)c(3f)+0.96(±0.05)	1.85(±0.09)
3g	t_inh=0.61(±0.03)c(3g)–1.66(±0.08)	2.05(±0.10)
3h	t_inh=0.63(±0.03)c(3h)–0.99(±0.05)	2.12(±0.11)

表2. 化合物抑制期(tinh)与浓度(c)关系方程式以及n值

Table 2. Equations of inhibition period (tinh) and compound concentration (c), and n of compounds

图3. 化合物抑制AAPH、HO•和GS•引发DNA氧化反应活性

Figure 3. Properties of compounds in inhibiting AAPH, HO•and GS• induced oxidation of DNA.

图4. 在不同化合物存在下ABTS•和DPPH•浓度随时间的衰减曲线

Figure 4. Decay of concentrations of ABTS• and DPPH• in the presence of compounds

图5. 化合物清除ABTS•和DPPH•性能

Figure 5. Properties of compounds in scavenging ABTS• and DPPH• radicals

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