CN108553460A - 芳香族酮腙噻唑化合物作为酪氨酸酶抑制剂的应用 - Google Patents

芳香族酮腙噻唑化合物作为酪氨酸酶抑制剂的应用 Download PDF

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CN108553460A
CN108553460A CN201810279721.9A CN201810279721A CN108553460A CN 108553460 A CN108553460 A CN 108553460A CN 201810279721 A CN201810279721 A CN 201810279721A CN 108553460 A CN108553460 A CN 108553460A
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aromatic ketone
tyrosinase
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刘进兵
张宇
付曦
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Abstract

本发明公开了一种芳香族酮腙噻唑类化合物在酪氨酸酶抑制剂中的应用。酪氨酸酶抑制活性检测结果表明：所合成的芳香族酮腙噻唑类化合物具有较好的酪氨酸酶抑制活性，所述芳香族酮腙噻唑衍生物的化学结构式如下述结构所示，其中R1与R2由说明书所定义。

Description

芳香族酮腙噻唑化合物作为酪氨酸酶抑制剂的应用
技术领域
本发明涉及到食品、医药、化妆品、生物杀虫剂领域，具体地，涉及芳香族酮腙噻唑类化合物作为酪氨酸酶抑制剂的应用。
背景技术
酪氨酸酶（EC 1. 14. 18. 1 , Tyrosinase）又称酚氧化酶、多酚氧化酶、儿茶酚氧化酶。通过化学和光谱学研究表明，酪氨酸酶是一种含有铜离子的金属氧化还原酶，铜离子是酪氨酸酶的活性中心。酪氨酸酶广泛存在于动植物、微生物及人体中。酪氨酸酶与黑色素的合成密切相关，黑色素可以减少紫外线对人类的伤害。然而，酪氨酸酶异常表达会导致各种皮肤病，如老年斑、黄褐斑、色斑。酪氨酸酶与昆虫的生长发育有着重要的联系，如昆虫蜕皮过程中的鞣化和伤口的愈合等。果蔬在贮藏、加工及销售过程中易发生褐变，不仅影响果蔬的价值，而且也降低了其内在品质。目前，普遍认为引起果蔬褐变主要有两方面原因：酶促褐变和非酶褐变，酪氨酸酶是与酶促褐变相关的重要酶。鉴于酪氨酸酶具有多种生物学功能，酪氨酸酶抑制剂近年来被广泛应用于食品、医药、生物杀虫剂和美容等领域，因此发现新的酪氨酸酶抑制剂也成为了国内外的研究热点。
含有噻唑结构的化合物因其生物活性的多样性引起化学工作者的广泛关注，文献报道了该类化合物具有抗癌、抗菌、抗炎及抗原虫等活性，最近报道了噻唑酮腙类化合物可以作为单胺氧化酶抑制剂和组蛋白乙酰基转移酶抑制剂。目前尚未报道关于芳香族酮腙噻唑类化合物具有抑制酪氨酸酶活性的报道，而噻唑中的硫原子可能与酪氨酸酶铜离子活性中心作用，达到抑制酪氨酸酶活性的作用，因此，研究噻唑类化合物对酪氨酸酶的抑制活性将丰富开发酪氨酸酶抑制剂的途径。
发明内容
本发明的目的是提供一种具有抑制酪氨酸酶活性的芳香族酮腙噻唑衍生物，及其在医药、化妆品、食品保鲜及生物杀虫剂领域中的应用。
本发明的另一目的是提供芳香族酮腙噻唑衍生物作为药物组合物的活性成分，以及该组合物作为酪氨酸酶抑制剂的应用。
本发明是通过以下技术方案予以实现的：
式（I）所示的芳香族酮腙噻唑衍生物：
（I）
其中
R1为4-羟基时，R2分别为氯、羟基、溴、硝基；
R1为4-溴时，R2分别为氯、羟基、溴、硝基；
式（I）所示的芳香族酮腙噻唑衍生物具体结构式如下表：
本发明提供上述芳香族酮腙噻唑衍生物的制备方法如下所示：
首先，芳香族酮在无水乙醇为溶剂的条件下，与氨基硫脲反应得到芳香族酮氨基硫脲席夫碱。然后在无水乙醇或异丙醇溶液中与特定的alfa-溴代苯乙酮反应经过后处理得到目标化合物。
本发明所涉及的芳香族酮腙噻唑衍生物可用于制备与色素相关皮肤病、黑色素瘤及帕金森病药物，还可用于制备化妆品美白剂、食品保鲜剂、生物杀虫剂。
本发明所涉及的芳香族酮腙噻唑衍生物合成方法简单，对酪氨酸酶具有较强的抑制活性，具有很好的应用前景。
具体实施方式
以下是对本发明的进一步说明，但并不是对本发明的限制。
实施例一：化合物1的合成
称取0.21g对羟基苯乙酮氨基硫脲席夫碱以及0.234g对氯α溴代苯乙酮加入到反应瓶中，再加入无水乙醇20ml，于常温下搅拌反应，反应过程通过TLC跟踪反应，反应6h后，体系无变化，抽滤，滤饼用无水乙醇洗涤，干燥。得到类白色固体0.297g。
收率86.08%. 类白色固体, 熔点：263.4-265.2oC; IR ( KBr, ν / cm-1) 3386,1617, 1490, 1196, 1171; 1H NMR (DMSO-d6, 300 MHz) δ 7.90 (d, J = 8.4Hz, 2H,ph-H), 7.64 (d, J = 7.2Hz, 2H, ph-H), 7.48 (d, J = 8.4Hz, 2H, ph-H) , 7.37(s, 1H, thiazol-H), 6.81 (d, J = 7.2Hz, 2H, ph-H), 2.26 (s, 3H, CH3); 13C NMR(DMSO-d6, 75 MHz) δ 170.0, 158.3, 147.2, 143.1, 134.5, 131.9, 129.3, 128.6,128.3, 127.2, 115.3, 104.6, 14.0; ESI-MS, m/z = 342 (M-H)-.
实施例二：化合物2的合成
称取0.21g对羟基苯乙酮氨基硫脲席夫碱和0.215g对羟基α-溴代苯乙酮加入到反应瓶中，并加入20ml无水乙醇，于常温下搅拌反应，反应过程通过TLC跟踪，反应6h后，体系无变化，抽滤，滤饼用无水乙醇洗涤，干燥，得到0.232g类白色固体。
收率71.38%. 类白色固体, 熔点：239.5-240.7oC; IR ( KBr, ν / cm-1) 3327,3128, 1621, 1523, 1269, 1242; 1H NMR (DMSO-d6, 300 MHz) δ1H NMR (DMSO-d6, 300MHz) δ 7.84 (d, J = 8.4Hz, 2H, ph-H), 7.66 (d, J = 7.2Hz, 2H, ph-H), 7.60 (d,J = 8.4Hz, 2H, ph-H) , 7.39 (s, 1H, thiazol-H), 6.83 (d, J = 7.2Hz, 2H, ph-H), 2.28 (s, 3H, CH3); 13C NMR (DMSO-d6, 75 MHz) δ 170.1, 158.8, 147.2, 142.0,132.7, 131.0, 129.2, 127.9, 127.4, 117.8, 115.4, 106.4, 14.1; ESI-MS, m/z =324 (M-H)-.
实施例三：化合物3的合成
称取0.21g对羟基苯乙酮氨基硫脲席夫碱和0.278g对溴α-溴代苯乙酮加入到反应瓶中，并加入20ml无水乙醇，于常温下搅拌反应，反应过程通过TLC跟踪，反应6h后，体系无变化，抽滤，滤饼用无水乙醇洗涤，干燥，得到0.373g类白色固体。
收率96.13%. 类白色固体, 熔点：283.2-285.6oC; IR ( KBr, ν / cm-1) 1610,1571, 1279, 1169; 1H NMR (DMSO-d6, 300 MHz) δ 7.84 (d, J = 8.4Hz, 2H, ph-H),7.70 (d, J = 7.2Hz, 2H, ph-H), 7.51 (d, J = 8.4Hz, 2H, ph-H) , 7.08 (s, 1H,thiazol-H), 6.85 (d, J = 7.2Hz, 2H, ph-H), 2.28 (s, 3H, CH3); 13C NMR (DMSO-d6,75 MHz) δ 170.2, 158.5, 147.6, 143.8, 133.4, 131.3, 129.3, 128.4, 128.3,127.2, 115.1, 111.3, 14.0; ESI-MS, m/z = 387 (M-H)-.
实施例四：化合物4的合成
称取0.21g对羟基苯乙酮氨基硫脲席夫碱和0.244g对硝基α-溴代苯乙酮加入到反应瓶中，并加入20ml无水乙醇，于常温下搅拌反应，反应过程通过TLC跟踪，反应6h后，体系无变化，抽滤，滤饼用无水乙醇洗涤，干燥，得到0.314g黄色固体。
收率88.71%. 黄色固体, 熔点：263.4-265.8oC; IR ( KBr, ν / cm-1) 2987,1617, 1541, 1345, 1190; 1H NMR (DMSO-d6, 300 MHz) δ 8.30 (d, J = 9.0Hz, 2H,ph-H), 8.15 (d, J = 9.0Hz, 2H, ph-H), 7.71 (s, 1H, thiazol-H), 7.65 (d, J =8.7Hz, 2H, ph-H) , 6.83 (d, J = 8.7Hz, 2H, ph-H), 2.28 (s, 3H, CH3); 13C NMR(DMSO-d6, 75 MHz) δ 170.3, 158.3, 147.5, 146.1, 140.8, 131.3, 128.6, 127.2,126.3, 124.1, 115.2, 108.7, 14.0; ESI-MS, m/z = 355 (M+H)+.
实施例五：化合物5的合成
称取0.272g对溴苯乙酮氨基硫脲席夫碱和0.235g对氯α-溴代苯乙酮加入到反应瓶中，并加入20ml无水乙醇，于室温下搅拌反应，反应过程通过TLC跟踪，反应4h后，体系无变化，抽滤，滤饼用无水乙醇洗涤，干燥，得到0.312g淡黄色固体。
收率76.66%. 淡黄色固体, 熔点：247.3-248.5oC; IR ( KBr, ν / cm-1)1612,1490, 1370, 1113, 1093; 1H NMR (DMSO-d6, 300 MHz) δ 7.73 (d, J = 7.8Hz, 2H,ph-H), 7.66 (d, J = 9.0Hz, 2H, ph-H), 7.65 (d, J = 8.7Hz, 2H, ph-H), 7.07 (s,1H, thiazol-H), 6.73 (d, J = 8.7Hz, 2H, ph-H), 2.28 (s, 3H, CH3); 13C NMR(DMSO-d6, 75 MHz) δ 170.2, 157.2, 146.8, 136.8, 136.5, 130.6, 128.0, 127.2,124.9, 122.1, 115.1, 106.6, 13.9; ESI-MS, m/z = 387 (M-H)-.
实施例六：化合物6的合成
称取0.272g对溴苯乙酮氨基硫脲席夫碱和0.216g对羟基α-溴代苯乙酮加入到反应瓶中，并加入20ml无水乙醇，于室温下搅拌反应，反应过程通过TLC跟踪，反应8h后，体系无变化，抽滤，滤饼用无水乙醇洗涤，干燥，得到0.239g黄色固体。
收率61.59%. 黄色固体, 熔点：282.3-283.1oC; IR ( KBr, ν / cm-1)3126,1606,
1509, 1397, 1271, 1080; 1H NMR (DMSO-d6, 300 MHz) δ 7.91 (d, J = 8.7Hz,2H, ph-H), 7.74 (d, J = 8.7Hz, 2H, ph-H), 7.64 (d, J = 8.7Hz, 2H, ph-H), 7.49(d, J = 8.7Hz, 2H, ph-H), 7.42 (s, 1H, thiazol-H), 2.30 (s, 3H, CH3); 13C NMR(DMSO-d6, 75 MHz) δ 169.7, 168.5, 145.5, 137.0, 133.5, 131.9, 129.5, 128.6,128.4, 127.7, 122.1, 105.0, 13.8; ESI-MS, m/z = 405 (M-H)-.
实施例七：化合物7的合成
称取0.272g对溴苯乙酮氨基硫脲席夫碱和0.276g对溴α-溴代苯乙酮加入到反应瓶中，并加入20ml无水乙醇，于室温下搅拌反应，反应过程通过TLC跟踪，反应8h后，体系无变化，抽滤，滤饼用无水乙醇洗涤，干燥，得到0.384g淡黄色固体。
收率85.14%. 淡黄色固体, 熔点：247.7-249.3oC; IR ( KBr, ν / cm-1)1623,1487, 1398, 1110, 1073; 1H NMR (DMSO-d6, 300 MHz) δ 7.86 (d, J = 8.7Hz, 2H,ph-H), 7.74 (d, J = 8.7Hz, 2H, ph-H), 7.64-7.60 (m, 4H, ph-H), 7.43 (s, 1H,thiazol-H), 2.30 (s, 3H, CH3); 13C NMR (DMSO-d6, 75 MHz) δ169.7, 168.5, 145.5,137.0, 133.8, 131.3, 129.8, 127.6, 122.1, 121.4, 120.5, 105.1, 14.0; ESI-MS,m/z = 450 (M-H)-.
实施例八：化合物8的合成
称取0.272g对溴苯乙酮氨基硫脲席夫碱和0.245g对硝基α-溴代苯乙酮加入到反应瓶中，并加入20ml无水乙醇，于室温下搅拌反应，反应过程通过TLC跟踪，反应5h后，体系无变化，抽滤，滤饼用无水乙醇洗涤，干燥，得到0.388g淡黄色固体。
收率93.05%.淡黄色固体, 熔点： 245.1-247.7oC; IR ( KBr, ν / cm-1) 1617,1600, 1514, 1343, 1081; 1H NMR (DMSO-d6, 300 MHz) δ 7.70-7.61 (m, 4H, ph-H),7.46-7.43 (m, 2H, ph-H), 7.08 (s, 1H, thiazol-H), 6.81 (d, J = 8.7Hz, 2H, ph-H), 2.30 (s, 3H, CH3); 13C NMR (DMSO-d6, 75 MHz) δ 169.9, 168.6, 157.1, 137.0,133.6, 130.7, 129.8, 126.9, 125.4, 124.9, 115.3, 100.9, 13.8; ESI-MS, m/z =418 (M+H)+.
实施例九：酪氨酸酶抑制活性测试
在总计1000 μL的测试体系中加入940-950μL 0.1mol/L pH6.8磷酸盐缓冲液，10 μL样品溶液（10 μL样品作对照，以去除样品的颜色对实验的影响），10-20μL酶液，25℃孵化10min，加入30μL DOPA溶液，475nm进行时间扫描，记录一分钟的OD值。改变样品溶液的剂量，分别测试酶催化活性。可以通过稀释的方式改变样品的浓度。以没有加入样品的酶催化活性OD/min值为100%，用抑制百分数（指被抑制而失去活力的百分数）表示不同浓度样品对酶的抑制活性。抑制率的计算公式如下：
抑制率（%）= [(B-S)/B]×100
其中B为空白吸光度，S为样品吸光度。
由上述方法得到目标产物的活性如下表：
化合物编号 抑制活性* 化合物编号 抑制活性*
1 37.02 5 63.91
2 60.48 6 32.29
3 71.28 7 50.08
4 50.82 8 84.53
*当化合物浓度为100μmol/L时的抑制百分率。
由上表可知，芳香族酮腙噻唑衍生物具有较强的酪氨酸酶抑制活性。本发明提出芳香族酮腙噻唑衍生物对酪氨酸酶抑制活性好，具有较好的应用前景。
上列详细说明是针对本发明可行实施例的具体说明，但并非限制本发明的专利范围，凡未脱离本专利所为的等效实施或变更，均应包含于本案的发明保护范围内。

Claims (4)

1.下式所示芳香族酮腙噻唑衍生物具有较强的抑制酪氨酸酶活性的作用，可用于制备具有抑制酪氨酸酶作用的药物；
其中R1为4-羟基时，R2分别为氯、羟基、溴、硝基；R1为4-溴时，R2分别为氯、羟基、溴、硝基。
2.权利要求1的化合物具有较强的抑制酪氨酸酶活性的作用，可用于制备具有抑制酪氨酸酶作用的美白化妆品。
3.权利要求1的化合物具有较强的抑制酪氨酸酶活性的作用，可用于制备具有抑制酪氨酸酶作用的食品保鲜剂。
4.权利要求1的化合物具有较强的抑制酪氨酸酶活性的作用，可用于制备具有抑制酪氨酸酶作用的生物杀虫剂。
CN201810279721.9A 2018-04-01 2018-04-01 芳香族酮腙噻唑化合物作为酪氨酸酶抑制剂的应用 Withdrawn CN108553460A (zh)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
CN113880786A (zh) * 2021-10-16 2022-01-04 江西农业大学 一种莰烯醛基噻唑腙类衍生物的合成方法及其抗氧化应用

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113880786A (zh) * 2021-10-16 2022-01-04 江西农业大学 一种莰烯醛基噻唑腙类衍生物的合成方法及其抗氧化应用
CN113880786B (zh) * 2021-10-16 2023-03-03 江西农业大学 一种莰烯醛基噻唑腙类衍生物的合成方法及其抗氧化应用

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