新型含咔唑环和芳环/芳稠杂环的N-酰腙衍生物的合成及蛋白酪氨酸磷酸酶1B (PTP1B)抑制活性评价

doi:10.6023/cjoc202105032

有机化学 ›› 2021, Vol. 41 ›› Issue (9): 3593-3607.DOI: 10.6023/cjoc202105032 上一篇下一篇

研究论文

新型含咔唑环和芳环/芳稠杂环的N-酰腙衍生物的合成及蛋白酪氨酸磷酸酶1B (PTP1B)抑制活性评价

李英俊^a^,^*(), 林乐弟^a, 刘季红^b, 高立信^c, 盛丽^c, 靳焜^d, 刘雪洁^a, 杨鸿境^a, 李佳^c^,^*()

a 辽宁师范大学化学化工学院辽宁大连 116029
b 大连理工大学化学分析测试中心辽宁大连 116023
c 中国科学院上海药物研究所国家新药筛选中心药物研究国家重点实验室上海 201203
d 大连理工大学精细化工国家重点实验室辽宁大连 116012

收稿日期:2021-05-17 修回日期:2021-06-21 发布日期:2021-07-12
通讯作者: 李英俊, 李佳
基金资助:
辽宁省自然科学基金(20102126)

Synthesis and Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitory Activity Evaluation of Novel N-Acylhydrazone Derivatives Containing Carbazole and Aromatic Ring/Aromatic Fused Heterocycle

Yingjun Li^a(), Ledi Lin^a, Jihong Liu^b, Lixin Gao^c, Li Sheng^c, Kun Jin^d, Xuejie Liu^a, Hongjing Yang^a, Jia Li^c()

a College of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, Liaoning 116029
b Chemistry Analysis and Inspection Center, Dalian University of Technology, Dalian, Liaoning 116023
c State Key Laboratory of Drug Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203
d State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, Liaoning 116012

Received:2021-05-17 Revised:2021-06-21 Published:2021-07-12
Contact: Yingjun Li, Jia Li
Supported by:
Natural Science Foundation of Liaoning Province(20102126)

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摘要/Abstract

为寻找高效、低毒的新型蛋白酪氨酸磷酸酶1B (PTP1B)抑制剂, 设计并合成出了一系列新型含咔唑环和芳环/芳稠杂环的N-酰腙衍生物6~8和11. 利用IR、¹H NMR、¹³C NMR和2D NMR(包括¹H-¹H COSY和NOESY)谱及元素分析确定了其结构和构型. 评价了目标化合物对PTP1B的抑制活性. 实验结果表明, 目标化合物对PTP1B均有较强的抑制活性, 除了化合物N'-[9-(2-氯噻唑-5-甲基)咔唑-3-亚甲基]-2-苯氨基乙酰肼(6a)、N'-[9-(2-氯噻唑-5-甲基)咔唑-3-亚甲基]-2-(4-甲基苯氨基)乙酰肼(6b)、N'-[9-(2-氯噻唑-5-甲基)咔唑-3-亚甲基]-2-(3-硝基苯氨基)乙酰肼(6g)和N'-[9-(2-氯噻唑-5-甲基)咔唑-3-亚甲基]-2-(4-硝基苯氨基)乙酰肼(6h)外, 其它化合物的活性均高于阳性对照药物齐墩果酸, 其中N,N'-[(9-丁基咔唑基)-3,6-二亚甲基]-2,2'-[二(4-硝基苯氨基)]双乙酰肼(11b)的活性最高, IC₅₀=(0.89±0.06) μmol/L. 利用分子对接分别研究了代表目标化合物N'-[9-(2-氯噻唑-5-甲基)咔唑-3-亚甲基]-2-(4-溴苯氨基)乙酰肼(6d)、N'-[9-(2-氯噻唑-5-甲基)咔唑-3-亚甲基]-2-((2-(1-萘氧基)甲基)苯并咪唑-1-基)乙酰肼(7f)和11b与PTP1B酶的结合模式.

关键词: PTP1B抑制剂, 咔唑, N-酰腙, 合成, 分子对接

In order to find more efficient and low toxicity protein tyrosine phosphatase 1B (PTP1B) inhibitors, a series of novel N-acylhydrazone derivatives containing carbazole and aromatic ring/aromatic fused heterocycle 6~8 and 11 were designed and synthesized. Their structures and configurations were confirmed by IR, ¹H NMR, ¹³C NMR, two-dimensional NMR spectra (including ¹H-¹H COSY and NOESY) and elemental analysis. The inhibitory activities of all the target compounds against PTP1B were evaluated. The experimental results indicated that all the target compounds had potent inhibitory activity against PTP1B, and the activities were higher than the control drug oleanolic acid except for N'-[9-(2-chlorothiazole-5-methyl)carbazole-3-methylene]-2-phenylaminoacethydrazide (6a), N'-[9-(2-chlorothiazole-5-methyl)carbazole-3-methylene]- 2-(4-methylphenylamino)acethydrazide (6b), N'-[9-(2-chlorothiazole-5-methyl)carbazole-3-methylene]-2-(3-nitrophenylamino)acethydrazide (6g) and N'-[9-(2-chlorothiazole-5-methyl)carbazole-3-methylene)-2-(4-nitrophenylamino) acethydrazide (6h). Among them, N,N'-[(9-butylcarbazolyl)-3,6-dimethylene]-2,2'-[di(4-nitrophenylamino)]bisacetohydrazide (11b) had the highest inhibitory activity against PTP1B with IC₅₀ of (0.89±0.06) μmol/L. Molecular docking was used to study the bind of the representative target compounds N'-[9-(2-chlorothiazole-5-methyl)carbazole-3-methylene]-2-(4-bromophenylamino)acethydrazide (6d), N'-[9-(2-chlorothiazole-5-methyl)carbazole-3-methylene)-2-((2-(1-naphthyloxy)methyl)benzimidazol-1-yl)- acethydrazide (7f) and 11b with PTP1B enzyme, respectively.

Key words: PTP1B inhibitor, carbazole, N-actylhydrazone, synthesis, molecular docking

引用此文

李英俊, 林乐弟, 刘季红, 高立信, 盛丽, 靳焜, 刘雪洁, 杨鸿境, 李佳. 新型含咔唑环和芳环/芳稠杂环的N-酰腙衍生物的合成及蛋白酪氨酸磷酸酶1B (PTP1B)抑制活性评价[J]. 有机化学, 2021, 41(9): 3593-3607.

Yingjun Li, Ledi Lin, Jihong Liu, Lixin Gao, Li Sheng, Kun Jin, Xuejie Liu, Hongjing Yang, Jia Li. Synthesis and Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitory Activity Evaluation of Novel N-Acylhydrazone Derivatives Containing Carbazole and Aromatic Ring/Aromatic Fused Heterocycle[J]. Chinese Journal of Organic Chemistry, 2021, 41(9): 3593-3607.

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Position	δ_H		¹H-¹H COSY A (B)	NOESY A (B)
Position	A	B	¹H-¹H COSY A (B)	NOESY A (B)
1 (1')	7.86 (d, J=8.5 Hz)	—^a	H-2 (—)	/
2 (2')	7.93 (dd, J=8.8, 1.3 Hz)	7.86	H-1, 4	H-9/H-9'
3 (3')	/^b	/	/	/
4 (4')	8.50 (d, J=1.0 Hz)	8.47	H-2 (H-2')	/
5 (5')	8.24 (d, J=8.0 Hz)	8.23 (d, J=8.0 Hz)	H-6 (—)	/
6 (6')	7.29 (t, J=7.5 Hz)	—	H-5, 7 (—)	/
7 (7')	7.53 (td, J=7.8, 1.0 Hz)	—	H-6, 8 (—)	/
8 (8')	7.83 (d, J=8.5 Hz)	—	H-7 (—)	H-13 (—)
9 (9')	8.20	8.37	/	H-2/H-2'/H-10/H-10'
10 (10')	11.74	11.80	/	H-9/H-9'/H-11/H-11'
11 (11')	5.68	5.17	/	H-10/H-10'/H-15 (—)
12 (12')	5.44	—	/	H-19 (—)
13 (13')	5.95	5.94	/	H-8 (—)/H-14 (—)
14 (14')	7.88	—	/	H-13 (—)
15 (15')	7.614 (d, J=7.5 Hz)	7.606 (d, J=7.5 Hz)	H-16 (—)	H-11 (—)
16 (16')	7.27 (t, J=7.0 Hz)	—	H-15, 17 (—)	/
17 (17')	7.24 (td, J=7.5, 1.0 Hz)	—	H-16, 18 (—)	/
18 (18')	7.69 (d, J=7.5 Hz)	—	H-17 (—)	/
19 (19')	7.10 (d, J=9.5 Hz)	—	H-20 (—)	H-12 (—)
20 (20')	7.26 (d, J=9.0 Hz)	—	H-19 (—)	/

Position	δ_H		¹H-¹H COSY A (B)	NOESY A (B)
Position	A	B	¹H-¹H COSY A (B)	NOESY A (B)
1 (1')	7.86 (d, J=8.5 Hz)	—^a	H-2 (—)	/
2 (2')	7.93 (dd, J=8.8, 1.3 Hz)	7.86	H-1, 4	H-9/H-9'
3 (3')	/^b	/	/	/
4 (4')	8.50 (d, J=1.0 Hz)	8.47	H-2 (H-2')	/
5 (5')	8.24 (d, J=8.0 Hz)	8.23 (d, J=8.0 Hz)	H-6 (—)	/
6 (6')	7.29 (t, J=7.5 Hz)	—	H-5, 7 (—)	/
7 (7')	7.53 (td, J=7.8, 1.0 Hz)	—	H-6, 8 (—)	/
8 (8')	7.83 (d, J=8.5 Hz)	—	H-7 (—)	H-13 (—)
9 (9')	8.20	8.37	/	H-2/H-2'/H-10/H-10'
10 (10')	11.74	11.80	/	H-9/H-9'/H-11/H-11'
11 (11')	5.68	5.17	/	H-10/H-10'/H-15 (—)
12 (12')	5.44	—	/	H-19 (—)
13 (13')	5.95	5.94	/	H-8 (—)/H-14 (—)
14 (14')	7.88	—	/	H-13 (—)
15 (15')	7.614 (d, J=7.5 Hz)	7.606 (d, J=7.5 Hz)	H-16 (—)	H-11 (—)
16 (16')	7.27 (t, J=7.0 Hz)	—	H-15, 17 (—)	/
17 (17')	7.24 (td, J=7.5, 1.0 Hz)	—	H-16, 18 (—)	/
18 (18')	7.69 (d, J=7.5 Hz)	—	H-17 (—)	/
19 (19')	7.10 (d, J=9.5 Hz)	—	H-20 (—)	H-12 (—)
20 (20')	7.26 (d, J=9.0 Hz)	—	H-19 (—)	/

Compd.	Ar/Ar'	IC₅₀/(μmol•L^–1)	Compd.	Ar/Ar'	IC₅₀/(μmol•L^–1)
6a	C₆H₅	6.14±0.00	7a	4-CH₃C₆H₄	1.91±0.32
6b	4-CH₃C₆H₄	3.05±0.96	7b	2,4-(CH₃)₂C₆H₃	2.40±0.17
6c	4-CH₃OC₆H₄	2.26±0.32	7c	4-CH₃OC₆H₄	2.46±0.27
6d	4-BrC₆H₄	2.01±0.16	7d	4-ClC₆H₄	1.92±0.47
6e	3-ClC₆H₄	2.44±0.35	7e	3-O₂NC₆H₄	2.35±0.25
6f	4-ClC₆H₄	2.91±0.67	7f	1-C₁₀H₇	1.83±0.11
6g	3-O₂NC₆H₄	3.53±0.21	8		2.71±0.60
6h	4-O₂NC₆H₄	3.29±0.39	11a	3-O₂NC₆H₄	0.98±0.00
OA		2.93±0.92	11b	4-O₂NC₆H₄	0.89±0.06

Compd.	Ar/Ar'	IC₅₀/(μmol•L^–1)	Compd.	Ar/Ar'	IC₅₀/(μmol•L^–1)
6a	C₆H₅	6.14±0.00	7a	4-CH₃C₆H₄	1.91±0.32
6b	4-CH₃C₆H₄	3.05±0.96	7b	2,4-(CH₃)₂C₆H₃	2.40±0.17
6c	4-CH₃OC₆H₄	2.26±0.32	7c	4-CH₃OC₆H₄	2.46±0.27
6d	4-BrC₆H₄	2.01±0.16	7d	4-ClC₆H₄	1.92±0.47
6e	3-ClC₆H₄	2.44±0.35	7e	3-O₂NC₆H₄	2.35±0.25
6f	4-ClC₆H₄	2.91±0.67	7f	1-C₁₀H₇	1.83±0.11
6g	3-O₂NC₆H₄	3.53±0.21	8		2.71±0.60
6h	4-O₂NC₆H₄	3.29±0.39	11a	3-O₂NC₆H₄	0.98±0.00
OA		2.93±0.92	11b	4-O₂NC₆H₄	0.89±0.06

新型含咔唑环和芳环/芳稠杂环的N-酰腙衍生物的合成及蛋白酪氨酸磷酸酶1B (PTP1B)抑制活性评价

Synthesis and Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitory Activity Evaluation of Novel N-Acylhydrazone Derivatives Containing Carbazole and Aromatic Ring/Aromatic Fused Heterocycle

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