Design, Synthesis and Biological Activity of Myricetin Derivatives Containing 1,2,4-Triazolo[3,4-b]-1,3,4-thiadiazole

doi:10.6023/cjoc202209030

Abstract

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

Cite this article

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

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