含1,2,4-三唑并[3,4-b]-1,3,4-噻二唑杨梅素衍生物的设计、合成及生物活性研究

doi:10.6023/cjoc202209030

摘要/Abstract

利用活性拼接的原理, 以杨梅苷为原料, 将1,2,4-三唑并[3,4-b]-1,3,4-噻二唑引入到杨梅素结构中, 合成了一系列含三唑并噻二唑的杨梅素衍生物, 通过¹H NMR、¹³C NMR和高分辨质谱(HRMS)进行了结构表征, 并通过X单晶衍射实验确认了3-(3-((3-乙基-[1,2,4]三唑[3,4-b][1,3,4]噻二唑-6-基)硫代)丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色酮-4-酮(A5)的结构. 生物活性测试结果表明: 浓度为100 μg/mL时, 3-(3-((3-(4-(叔丁基)苯基)-[1,2,4]三唑[3,4-b][1,3,4]噻二唑-6-基)硫基)丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色酮-4-酮(A15)对柑桔溃疡病菌(Xac)的抑制率为63.3%, 优于对照药噻菌铜(57.3%); 部分化合物对烟草花叶病毒(TMV)表现出较好的抑制活性. 其中, 治疗活性方面, 化合物A5, 5,7-二甲氧基-3-(4-((3-(甲氧基甲基)-[1,2,4]三唑[3,4-b][1,3,4]噻二唑-6-基)硫代)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色酮-4-酮(A8), 5,7-二甲氧基-3-(3-((3-苯基-[1,2,4]三唑[3,4-b][1,3,4]噻二唑-6-基)硫代)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色酮-4-酮(A9), 5,7-二甲氧基-3-(4-((3-(对甲苯基)-[1,2,4]三唑[3,4-b][1,3,4]噻二唑-6-基)硫代)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色酮-4-酮(A12)的EC₅₀值分别为88.3, 139.1, 109.9, 160.1 μg/mL, 优于对照药宁南霉素(227.2 μg/mL). 保护活性方面, 5,7-二甲氧基-3-(4-((3-苯基-[1,2,4]三唑[3,4-b][1,3,4]噻二唑-6-基)硫代)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色酮-4-酮(A10), 5,7-二甲氧基-3-(4-((3-(4-甲氧基苯基)-[1,2,4]三唑[3,4-b][1,3,4]噻二唑-6-基)硫基)丁氧基)-2-(3,4,5-三甲氧基苯)-4H-色酮-4-酮(A14), 3-(3-((3-(4-(叔丁基)苯基)-[1,2,4]三唑[3,4-b][1,3,4]噻二唑-6-基)硫基)丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色酮-4-酮(A15), 3-(4-((3-(4-叔丁基)苯基)-[1,2,4]三唑[3,4-b][1,3,4]噻二唑- 6-基)硫基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色酮-4-酮(A16), 3-(4-((3-(4-氯苯基)-[1,2,4]三唑[3,4-b][1,3,4]噻二唑-6-基)硫基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色酮-4-酮(A18)的EC₅₀值分别为103.1, 107.4, 86.3, 79.2, 111.5 μg/mL, 优于对照药宁南霉素(179.2 μg/mL). 微量热涌动实验表明, 化合物A12和A16与烟草花叶病毒外壳蛋白(TMV-CP)具有较强的亲和力, 分子对接实验表明, 化合物A16与TMV-CP具有较强的相互作用.

关键词: 杨梅素衍生物; 1, 2, 4-三唑并[3, 4-b]-1, 3, 4-噻二唑; 生物活性; 晶体结构; 病毒蛋白

A series of myricetin derivatives containing 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole moiety were designed and synthesized using myricetin as the starting material through active splicing strategy. All target compounds were characterized by ¹H NMR, ¹³C NMR and high-resolution mass spectra (HRMS). Single crystal X-ray diffraction experiments were carried out with 3-(3-((3-ethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)thio)propoxy)-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H- chromen-4-one (A5). When the concentration was 100 μg/mL, the inhibition rate of 3-(3-((3-(4-(tert-butyl)phenyl)-[1,2,4]- triazolo[3,4-b][1,3,4]thiadiazol-6-yl)thio)propoxy)-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one (A15) agai- nst Xanthomonas axonopodis pv.citri (Xac) was 63.3%, which was better than that of the control drug thiophanate-copper (57.3%). Biological activity test results that these compounds showed good inhibitory activity against tobacco mosaic virus (TMV). Among them, in terms of therapeutic activity, the EC₅₀ values of compounds A5, 5,7-dimethoxy-3-(4-((3-(methoxy- methyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)thio)butoxy)-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one (A8), 5,7-di- methoxy-3-(3-((3-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)thio)propoxy)-2-(3,4,5-trimethoxyphenyl)-4H-chromen- 4-one (A9), and 5,7-dimethoxy-3-(4-((3-(p-tolyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)thio)butoxy)-2-(3,4,5-trimethoxy- phenyl)-4H-chromen-4-one (A12) were 88.3, 139.1, 109.9, 160.1 μg/mL, respectively, which were better than the control drug ningnanmycin (227.2 μg/mL). In terms of protective activity, the EC₅₀ values of compounds 5,7-dimethoxy-3-(4-((3-phenyl- [1,2,4]-triazolo[3,4-b][1,3,4]thiadiazol-6-yl)thio)butoxy)-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one (A10), 5,7-dimeth- oxy-3-(4-((3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)thio)butoxy)-2-(3,4,5-trimethoxyphenyl)-4H-chro- men-4-one (A14), A15, 3-(4-((3-(4-(tert-butyl)phenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)thio)butoxy)-5,7-dimeth- oxy-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one (A16), and 3-(4-((3-(4-chlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thia- diazol-6-yl)thio)butoxy)-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one (A18) were 103.1, 107.4, 86.3, 79.2, 111.5 μg/mL, respectively, which were better than the control drug ningnanmycin (179.2 μg/mL). Microscale thermophoresis (MST) indicated that compounds A12 and A16 have strong binding force to tobacco mosaic virus coat protein (TMV-CP). Molecular docking experiments showed that compound A16 has a strong interaction with TMV-CP.

Key words: myricetin derivatives; 1, 2, 4-triazolo[3, 4-b]-1, 3, 4-thiadiazole moiety; biological activity; crystal structure; viral protein

引用此文

王启帆, 张源泉, 幸丽, 周远香, 龚晨裕, 何帮灿, 张念, 吴拥军, 薛伟. 含1,2,4-三唑并[3,4-b]-1,3,4-噻二唑杨梅素衍生物的设计、合成及生物活性研究[J]. 有机化学, 2023, 43(4): 1525-1536.

Qifan Wang, Yuanquan Zhang, Li Xing, Yuanxiang Zhou, Chenyu Gong, Bangcan He, Nian Zhang, Yongjun Wu, Wei Xue. Design, Synthesis and Biological Activity of Myricetin Derivatives Containing 1,2,4-Triazolo[3,4-b]-1,3,4-thiadiazole[J]. Chinese Journal of Organic Chemistry, 2023, 43(4): 1525-1536.

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Compd.	n	R	Xac		Psa		Xoo
Compd.	n	R	100 μg/mL	50 μg/mL	100 μg/mL	50 μg/mL	100 μg/mL	50 μg/mL
A1	3	H	26.9±3.7	0.9±1.2	11.7±1.8	13.4±2.4	38.9±0.6	21.4±1.5
A2	4	H	34.5±2.7	21.6±2.3	19.3±1.9	13.6±1.5	32.9±0.2	25.5±0.6
A3	3	CH₃	31.2±0.9	14.5±1.7	19.7±1.7	14.1±2.9	25.7±0.2	16.8±0.2
A4	4	CH₃	16.4±2.6	11.8±4.3	15.7±1.3	11.9±1.0	29.2±0.9	16.3±2.4
A5	3	CH₂CH₃	17.6±2.5	11.7±2.4	17.5±0.4	12.2±0.8	28.5±0.2	20.3±0.2
A6	4	CH₂CH₃	34.9±3.2	29.2±2.0	25.6±0.6	26.1±0.8	41.4±2.7	24.1±0.2
A7	3	CH₂OCH₃	21.3±3.9	20.0±0.9	20.2±1.7	10.9±1.0	32.6±1.2	14.7±4.3
A8	4	CH₂OCH₃	40.6±2.0	39.0±3.8	18.2±3.4	15.9±1.6	33.7±0.6	22.3±0.4
A9	3	Ph	28.7±1.7	26.1±3.8	20.1±3.0	19.4±2.6	23.7±0.4	25.1±0.4
A10	4	Ph	8.9±0.3	6.5±2.7	19.3±1.6	15.4±0.9	24.3±0.8	28.5±2.3
A11	3	4-CH₃C₆H₄	37.3±2.4	31.9±1.6	31.7±1.1	30.7±0.9	26.5±0.8	25.9±1.3
A12	4	4-CH₃C₆H₄	39.1±2.8	3.3±1.7	38.4±1.2	31.0±1.6	22.7±1.7	27.1±0.7
A13	3	4-CH₃OC₆H₄	46.4±1.8	30.4±4.4	46.4±0.3	26.0±1.1	22.6±4.5	23.8±0.8
A14	4	4-CH₃C₆H₄	28.0±3.3	10.0±0.4	24.8±1.4	22.9±0.6	34.0±0.2	26.5±2.3
A15	3	4-(CH₃)₃CC₆H₄	63.3±2.8	22.4±1.5	41.6±0.4	33.9±1.2	59.9±0.9	32.0±0.7
A16	4	4-(CH₃)₃CC₆H₄	54.7±0.5	34.6±1.7	51.1±1.7	41.8±0.4	42.2±1.7	29.5±1.3
A17	3	4-ClC₆H₄	42.2±3.6	32.4±1.3	22.9±1.8	27.9±4.3	32.1±0.9	24.0±1.7
A18	4	4-ClC₆H₄	38.3±1.9	33.4±1.8	36.3±0.5	26.9±2.3	24.6±0.4	21.3±1.0
杨梅苷			20.7±0.5	18.2±0.6	13.8±4.3	12.8±1.2	13.9±1.4	8.5±1.6
叶枯唑^b			53.1±2.9	36.1±2.3	50.3±2.4	34.8±2.6	59.5±1.3	37.6±4.8
噻菌铜^b			57.3±2.5	40.1±1.4	55.9±3.5	37.8±1.3	62.3±0.6	46.8±2.0

Compd.	n	R	Xac		Psa		Xoo
Compd.	n	R	100 μg/mL	50 μg/mL	100 μg/mL	50 μg/mL	100 μg/mL	50 μg/mL
A1	3	H	26.9±3.7	0.9±1.2	11.7±1.8	13.4±2.4	38.9±0.6	21.4±1.5
A2	4	H	34.5±2.7	21.6±2.3	19.3±1.9	13.6±1.5	32.9±0.2	25.5±0.6
A3	3	CH₃	31.2±0.9	14.5±1.7	19.7±1.7	14.1±2.9	25.7±0.2	16.8±0.2
A4	4	CH₃	16.4±2.6	11.8±4.3	15.7±1.3	11.9±1.0	29.2±0.9	16.3±2.4
A5	3	CH₂CH₃	17.6±2.5	11.7±2.4	17.5±0.4	12.2±0.8	28.5±0.2	20.3±0.2
A6	4	CH₂CH₃	34.9±3.2	29.2±2.0	25.6±0.6	26.1±0.8	41.4±2.7	24.1±0.2
A7	3	CH₂OCH₃	21.3±3.9	20.0±0.9	20.2±1.7	10.9±1.0	32.6±1.2	14.7±4.3
A8	4	CH₂OCH₃	40.6±2.0	39.0±3.8	18.2±3.4	15.9±1.6	33.7±0.6	22.3±0.4
A9	3	Ph	28.7±1.7	26.1±3.8	20.1±3.0	19.4±2.6	23.7±0.4	25.1±0.4
A10	4	Ph	8.9±0.3	6.5±2.7	19.3±1.6	15.4±0.9	24.3±0.8	28.5±2.3
A11	3	4-CH₃C₆H₄	37.3±2.4	31.9±1.6	31.7±1.1	30.7±0.9	26.5±0.8	25.9±1.3
A12	4	4-CH₃C₆H₄	39.1±2.8	3.3±1.7	38.4±1.2	31.0±1.6	22.7±1.7	27.1±0.7
A13	3	4-CH₃OC₆H₄	46.4±1.8	30.4±4.4	46.4±0.3	26.0±1.1	22.6±4.5	23.8±0.8
A14	4	4-CH₃C₆H₄	28.0±3.3	10.0±0.4	24.8±1.4	22.9±0.6	34.0±0.2	26.5±2.3
A15	3	4-(CH₃)₃CC₆H₄	63.3±2.8	22.4±1.5	41.6±0.4	33.9±1.2	59.9±0.9	32.0±0.7
A16	4	4-(CH₃)₃CC₆H₄	54.7±0.5	34.6±1.7	51.1±1.7	41.8±0.4	42.2±1.7	29.5±1.3
A17	3	4-ClC₆H₄	42.2±3.6	32.4±1.3	22.9±1.8	27.9±4.3	32.1±0.9	24.0±1.7
A18	4	4-ClC₆H₄	38.3±1.9	33.4±1.8	36.3±0.5	26.9±2.3	24.6±0.4	21.3±1.0
杨梅苷			20.7±0.5	18.2±0.6	13.8±4.3	12.8±1.2	13.9±1.4	8.5±1.6
叶枯唑^b			53.1±2.9	36.1±2.3	50.3±2.4	34.8±2.6	59.5±1.3	37.6±4.8
噻菌铜^b			57.3±2.5	40.1±1.4	55.9±3.5	37.8±1.3	62.3±0.6	46.8±2.0

Compound	n	R	Curative activity/%	Protective activity/%	Inactivative activity/%
A1	3	H	50.6±4.8	61.5±1.4	65.3±3.9
A2	4	H	66.5±1.8	62.3±3.5	54.8±0.8
A3	3	CH₃	50.7±1.9	49.7±2.4	61.0±2.9
A4	4	CH₃	54.2±3.6	55.6±4.7	47.8±1.2
A5	3	CH₂CH₃	73.6±4.1	66.4±1.7	41.4±2.8
A6	4	CH₂CH₃	66.5±2.5	66.9±2.4	57.4±4.7
A7	3	CH₂OCH₃	60.8±2.4	42.2±3.3	58.8±4.2
A8	4	CH₂OCH₃	67.8±2.1	53.5±1.4	56.9±1.6
A9	3	Ph	71.7±4.7	54.9±3.9	51.6±1.5
A10	4	Ph	50.7±4.2	72.1±3.8	57.8±3.9
A11	3	4-CH₃C₆H₄	44.4±4.6	60.4±2.8	70.5±3.7
A12	4	4-CH₃C₆H₄	64.1±1.8	62.2±2.9	78.1±3.8
A13	3	4-CH₃OC₆H₄	45.2±2.9	48.0±3.4	35.1±3.4
A14	4	4-CH₃OC₆H₄	53.3±2.5	67.3±3.3	36.0±2.8
A15	3	4-(CH₃)₃CC₆H₄	54.3±4.0	69.8±3.7	72.2±3.5
A16	4	4-(CH₃)₃CC₆H₄	60.1±3.3	73.8±3.7	77.9±4.1
A17	3	4-ClC₆H₄	53.5±4.1	60.7±0.7	53.4±4.5
A18	4	4-ClC₆H₄	59.2±3.9	67.3±3.0	74.8±3.2
杨梅苷^b			33.7±3.5	44.5±2.8	32.4±4.3
Ningnanmycin^c			57.5±1.6	62.8±0.4	84.9±2.4

Compound	n	R	Curative activity/%	Protective activity/%	Inactivative activity/%
A1	3	H	50.6±4.8	61.5±1.4	65.3±3.9
A2	4	H	66.5±1.8	62.3±3.5	54.8±0.8
A3	3	CH₃	50.7±1.9	49.7±2.4	61.0±2.9
A4	4	CH₃	54.2±3.6	55.6±4.7	47.8±1.2
A5	3	CH₂CH₃	73.6±4.1	66.4±1.7	41.4±2.8
A6	4	CH₂CH₃	66.5±2.5	66.9±2.4	57.4±4.7
A7	3	CH₂OCH₃	60.8±2.4	42.2±3.3	58.8±4.2
A8	4	CH₂OCH₃	67.8±2.1	53.5±1.4	56.9±1.6
A9	3	Ph	71.7±4.7	54.9±3.9	51.6±1.5
A10	4	Ph	50.7±4.2	72.1±3.8	57.8±3.9
A11	3	4-CH₃C₆H₄	44.4±4.6	60.4±2.8	70.5±3.7
A12	4	4-CH₃C₆H₄	64.1±1.8	62.2±2.9	78.1±3.8
A13	3	4-CH₃OC₆H₄	45.2±2.9	48.0±3.4	35.1±3.4
A14	4	4-CH₃OC₆H₄	53.3±2.5	67.3±3.3	36.0±2.8
A15	3	4-(CH₃)₃CC₆H₄	54.3±4.0	69.8±3.7	72.2±3.5
A16	4	4-(CH₃)₃CC₆H₄	60.1±3.3	73.8±3.7	77.9±4.1
A17	3	4-ClC₆H₄	53.5±4.1	60.7±0.7	53.4±4.5
A18	4	4-ClC₆H₄	59.2±3.9	67.3±3.0	74.8±3.2
杨梅苷^b			33.7±3.5	44.5±2.8	32.4±4.3
Ningnanmycin^c			57.5±1.6	62.8±0.4	84.9±2.4

Compound	n	R	Regression equation	r	EC₅₀/(μg•mL^－1)
A2	4	H	y=0.7824x＋3.2698	0.9869	162.7
A5	3	CH₂CH₃	y=0.685x＋3.6671	0.9851	88.3
A6	4	CH₂CH₃	y=0.3793x＋3.9502	0.9627	585.8
A8	4	CH₂OCH₃	y=0.8048x＋3.2751	0.9909	139.1
A9	3	Ph	y=0.746x＋3.4774	0.9677	109.9
A12	4	4-CH₃C₆H₄	y=0.7368x＋3.3759	0.9900	160.1
A16	4	4-(CH₃)₃CC₆H₄	y=0.6697x＋3.4492	0.9940	206.9
Ningnanmycin^b			y=0.5854x＋3.6206	0.9879	227.2