CN108409683A - 脂环酮腙噻唑衍生物作为酪氨酸酶抑制剂的应用 - Google Patents

脂环酮腙噻唑衍生物作为酪氨酸酶抑制剂的应用 Download PDF

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CN108409683A
CN108409683A CN201810279719.1A CN201810279719A CN108409683A CN 108409683 A CN108409683 A CN 108409683A CN 201810279719 A CN201810279719 A CN 201810279719A CN 108409683 A CN108409683 A CN 108409683A
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alicyclic ketone
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tyrosinase
ketone hydrazone
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刘进兵
张宇
欧阳跃华
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Shaoyang University
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Abstract

本发明公开了一种具有酪氨酸酶抑制活性的脂环酮腙噻唑类衍生物。体外抑制酪氨酸酶的筛选结果表明：所合成的脂环酮腙噻唑类衍生物部分具有酪氨酸酶抑制活性。本发明所涉及的化合物制备简单，在药物、化妆品、食品保鲜及生物杀虫剂领域具有一定的应用前景。所述脂环酮腙噻唑衍生物的化学结构式如下述结构所示，其中n与R由说明书所定义。

Description

脂环酮腙噻唑衍生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，涉及脂环酮腙噻唑衍生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，广泛存在于微生物动植物以及人体中。酪氨酸酶是黑色素合成的关键限速酶，黑色素可以减少紫外线对人体的伤害，其含量与分布决定了皮肤以及毛发的颜色。然而，因酪氨酸酶活性增强引起的黑色素生成过量会导致老年斑、色斑、黄褐斑等皮肤病。同时酪氨酸酶不仅参与到哺乳动物、昆虫等的生理活动中还与食品的褐变反应密切相关。酪氨酸酶的活性决定了黑色素的含量，黑色素的含量与分布决定了动物皮肤、毛发的颜色。酪氨酸酶活性降低会导致黑色素生成量减少，引起人体色素脱失而导致白斑如白癜风、白化病等。酪氨酸酶也是昆虫赖以生存的一种重要酶，影响着昆虫的发育和防御功能，其催化合成的黑色素可以保护昆虫免受紫外线的过度辐射，并与昆虫蜕皮过程中的鞣化和伤口的愈合密切相关。此外，酪氨酸酶参与食品的褐变反应，此酶促催化反应所导致的果蔬褐变将直接影响食品的质量、营养和经济价值。酪氨酸酶抑制剂在疾病治疗、虫害防治、食品保鲜等领域具有广泛的前景。
噻唑及其衍生物因其生物活性的多样性多年来持续受到人们的关注，这类化合物在开发治疗过敏症、高血压、感染、精神分裂症、HIV感染、疼痛等领域的药物中有很好的应用，最近有文献报道了这类化合物具有较好的抗菌活性和安眠作用。经过文献调研，并未发现有关这类化合物具有酪氨酸酶抑制活性的相关报道。研究脂环酮腙噻唑衍生物的酪氨酸酶抑制活性，对拓宽开发新型高效酪氨酸酶抑制剂途径具有重要意义。
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脂环酮腙噻唑衍生物，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脂环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）所示的脂环酮腙噻唑衍生物：
式(I)
其中n=0时；R是氯、羟基、溴、硝基；n=1；时R是氯、羟基、溴、硝基；
式I所示具体化合物结构如下表：
化合物编号 化合物结构式 化合物编号 化合物结构式
1 5
2 6
3 7
4 8
本发明提供上述脂环酮腙噻唑衍生物的制备方法如下所示：
首先，脂环酮在无水乙醇为溶剂的条件下，与氨基硫脲反应得到脂环酮氨基硫脲席夫碱。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。
本发明所涉及的脂环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。
本发明所涉及的脂环酮腙噻唑衍生物合成方法简单，部分化合物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0.157g环戊酮氨基硫脲席夫碱和0.234g对氯α-溴代苯乙酮加入到反应瓶中，加入15ml异丙醇，于常温下搅拌反应，反应过程以TLC跟踪反应（乙酸乙酯：石油醚=1:2），4h后体系无变化，停止反应，抽滤，滤饼用乙醇洗涤，得到0.271g白色固体。
收率92.97%. 白色固体, 熔点：178.4-180.7oC; IR ( KBr, ν / cm-1) 2969,1611, 1492, 1093; 1H NMR (DMSO-d6, 300 MHz) δ 7.87 (d, J = 8.4Hz, 2H, ph-H),7.47 (d, J = 8.4Hz, 2H, ph-H) , 7.31 (s, 1H, thiazol-H), 2.40 (t, J = 7.2Hz,4H, 2CH2), 1.78-1.67 (m, 4H, 2CH2); 13C NMR (DMSO-d6, 75 MHz) δ 169.7, 163.2,148.4, 133.3, 129.5, 128.3, 127.2, 104.0, 32.8, 28.8, 24.5; ESI-MS, m/z = 292(M+H)+.
实施例二：化合物2的合成
称取0.157g环戊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，加入15ml异丙醇，于常温下搅拌反应，反应过程以TLC跟踪反应（乙酸乙酯：石油醚=1:2），10h后体系无变化，停止反应，抽滤，滤饼用乙醇洗涤，得到0.306g淡黄色色固体。
收率78.39%. 淡黄色固体, 熔点：>270oC; IR ( KBr, ν / cm-1) 3284, 3131,1618, 1343, 1174; 1H NMR (DMSO-d6, 300 MHz) δ 7.45 (d, J = 8.7Hz, 2H, ph-H),7.28 (s, 1H, thiazol-H), 6.76 (d, J = 8.7Hz, 2H, ph-H), 2.40 (t, J = 7.5Hz,4H, 2CH2), 1.80-1.68 (m, 4H, 2CH2); 13C NMR (DMSO-d6, 75 MHz) δ 167.4, 157.6,148.1, 131.3, 130.9, 129.4, 115.1, 107.7, 32.8, 29.1, 22.7; ESI-MS, m/z = 274(M+H)+.
实施例三：化合物3的合成
称取0.157g环戊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，加入15ml异丙醇，于常温下搅拌反应，反应过程以TLC跟踪反应（乙酸乙酯：石油醚=1:2），4h后体系无变化，停止反应，抽滤，滤饼用乙醇洗涤，得到0.277g白色固体。
收率82.44%. 白色固体, 熔点：186.3-189.2oC; IR ( KBr, ν / cm-1) 3063,1611, 1475, 1208; 1H NMR (DMSO-d6, 300 MHz) δ 7.80 (d, J = 8.7Hz, 2H, ph-H),7.61 (d, J = 8.7Hz, 2H, ph-H), 7.32 (s, 1H, thiazol-H), 2.40 (t, J = 7.2Hz,4H, 2CH2), 1.78-1.67 (m, 4H, 2CH2); 13C NMR (DMSO-d6, 75 MHz) δ 169.7, 163.2,133.6, 131.5, 129.8, 127.6, 120.5, 104.1, 32.8, 28.8, 24.6; ESI-MS, m/z = 336(M+H)+.
实施例四：化合物4的合成
称取0.157g环戊酮氨基硫脲席夫碱和0.244g对氯α-溴代苯乙酮加入到反应瓶中，加入15ml异丙醇，于常温下搅拌反应，反应过程以TLC跟踪反应（乙酸乙酯：石油醚=1:2），4h后体系无变化，停止反应，抽滤，滤饼用乙醇洗涤，得到0.236g黄色固体。
收率78.15%. 黄色固体, 熔点：201.1-203.2oC; IR ( KBr, ν / cm-1) 2970,1616, 1522, 1343; 1H NMR (CDCl3, 300 MHz) δ 8.37 (d, J = 9.0Hz, 2H, ph-H),7.94 (d, J = 9.0Hz, 2H, ph-H), 6.94 (s, 1H, thiazol-H), 3.65 (t, J = 7.5Hz,2H, CH2), 2.55 (t, J = 7.2Hz, 2H, CH2), 1.99-1.85 (m, 4H, 2CH2); 13C NMR(CDCl3, 75 MHz) δ 173.7, 169.1, 138.2, 132.9, 129.6, 126.5, 124.9, 104.6,33.5, 31.0, 25.1; ESI-MS, m/z = 303 (M+H)+.
实施例五：化合物5的合成
将0.171g环己酮氨基硫脲席夫碱和0.234g对氯α-溴代苯乙酮加入到反应瓶中，再加入15ml异丙醇，于常温下搅拌反应反应过程中以TLC跟踪反应（乙酸乙酯：石油醚=1:2），4h后体系无变化，停止反应，抽滤，滤饼用乙醇洗涤三次，得到白色固体0.232g。
收率75.94%. 白色固体, 熔点：172.5-175.2oC; IR ( KBr, ν / cm-1) 2931,1612, 1486, 1092, 1026; 1H NMR (DMSO-d6, 300 MHz) δ 8.35 (s, 1H, thiazol-H),8.07 (d, J = 8.7Hz, 2H, ph-H), 7.58 (d, J = 8.4Hz, 2H, ph-H), 2.28 (t, J =7.2Hz, 2H, CH2), 1.81-1.63 (m, 8H, 4CH2); 13C NMR (DMSO-d6, 75 MHz) δ 175.1,152.9, 133.0, 132.4, 128.9, 127.5, 117.3, 95.5, 34.4, 26.4, 21.7, 18.5; ESI-MS, m/z = 307 (M+H)+.
实施例六：化合物6的合成
将0.171g环己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，再加入15ml异丙醇，于常温下搅拌反应反应过程中以TLC跟踪反应（乙酸乙酯：石油醚=1:2），6h后体系无变化，停止反应，抽滤，滤饼用乙醇洗涤，得到白色固体0.212g。
收率73.88%. 淡黄色固体, 熔点：201.5-203.3oC; IR ( KBr, ν / cm-1) 3269,1613, 1508, 1221, 1177; 1H NMR (DMSO-d6, 300 MHz) δ 7.63 (d, J = 8.7Hz, 2H,ph-H), 7.01 (s, 1H, thiazol-H), 6.82 (d, J = 8.4Hz, 2H, ph-H), 2.46 (t, J =6.0Hz, 2H, CH2), 2.29 (t, J = 6.3Hz, 2H, CH2), 1.66-1.60 (m, 6H, 3CH2); 13C NMR(DMSO-d6, 75 MHz) δ 169.7, 157.4, 148.7, 132.6, 127.3, 115.2, 100.7, 95.3,34.7, 27.5, 26.7, 25.0; ESI-MS, m/z = 288 (M+H)+.
实施例七：化合物7的合成
将0.171g环己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，再加入15ml异丙醇，于常温下搅拌反应反应过程中以TLC跟踪反应（乙酸乙酯：石油醚=1:2），4h后体系无变化，停止反应，抽滤，滤饼用乙醇洗涤三次，得到白色固体0.257g。
收率73.43%. 白色固体, 熔点：185.4-187.9oC; IR ( KBr, ν / cm-1) 2928,1612, 1482, 1072; 1H NMR (DMSO-d6, 300 MHz) δ 8.35 (s, 1H, thiazol-H), 7.99(d, J = 8.7Hz, 2H, ph-H), 7.70 (d, J = 8.7Hz, 2H, ph-H), 2.24 (t, J = 5.1Hz,2H, CH2), 1.79-1.57 (m, 8H, 4CH2); 13C NMR (DMSO-d6, 75 MHz) δ 175.1, 152.9,132.8, 130.2, 127.8, 121.7, 117.4, 95.5, 34.4, 26.4, 24.8, 21.7; ESI-MS, m/z= 351 (M+H)+.
实施例八：化合物8的合成
将0.171g环己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，再加入15ml异丙醇，于常温下搅拌反应反应过程中以TLC跟踪反应（乙酸乙酯：石油醚=1:2），4h后体系无变化，停止反应，抽滤，滤饼用乙醇洗涤三次，得到黄色固体0.224g。
收率70.89%.黄色固体,熔点：190.3-191.7oC; IR (KBr, ν /cm-1) 2933, 1617,1523, 1341; 1H NMR (DMSO-d6, 300 MHz) δ 8.34 (d, J = 8.7Hz, 2H, ph-H), 8.17(d, J = 9.0Hz, 2H, ph-H), 7.64 (s, 1H, thiazol-H), 2.46 (t, J = 5.4Hz, 2H,CH2), 2.26 (t, J = 6.9Hz, 2H, CH2), 1.82-1.75 (m, 6H, 3CH2); 13C NMR (DMSO-d6,75 MHz) δ 175.4, 156.9, 146.4, 128.7, 126.8, 124.3, 120.7, 95.7, 34.7, 25.5,24.8, 21.7; ESI-MS, m/z = 317 (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 43.80 5 64.11
2 77.76 6 未测出
3 52.31 7 30.00
4 21.48 8 59.90
*当化合物浓度为100μmol/L时的抑制百分率。
由上表可知，脂环酮腙噻唑衍生物具有较强的酪氨酸酶抑制活性。本发明提出脂环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.式I所示脂环腙酮噻唑衍生物具有一定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；
（I）
其中
n=0时，R分别为氯、羟基、溴、硝基；
n=1时，R分别为氯、羟基、溴、硝基。
2.权利要求1的化合物具有一定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的化合物具有一定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的化合物具有一定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。
CN201810279719.1A 2018-04-01 2018-04-01 脂环酮腙噻唑衍生物作为酪氨酸酶抑制剂的应用 Withdrawn CN108409683A (zh)

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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
CN113999187A (zh) * 2021-11-30 2022-02-01 江西农业大学 一种噻唑腙衍生物及其制备方法和应用

Cited By (3)

* 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
CN113999187A (zh) * 2021-11-30 2022-02-01 江西农业大学 一种噻唑腙衍生物及其制备方法和应用

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