含喹唑啉酮的查尔酮衍生物的设计、合成及生物活性研究

doi:10.6023/cjoc202301020

摘要/Abstract

设计合成了25个含喹唑啉酮的查尔酮衍生物. 抗病毒生物实验结果表明, (E)-3-(4-氯苯基)-6-氟-2-((2-(4-(3-(4-甲氧基苯基)丙烯酰基)苯氧基)乙基)硫代)喹唑啉-4(3H)-酮(Z12)对烟草花叶病毒(tobacco mosaic virus, TMV)有较好的抑制活性, 治疗和保护的EC₅₀值分别为94.3和98.8 μg/mL, 优于对照药宁南霉素(ningnanmycin, NNM)的216.1和189.6 μg/mL. 透射电镜结果表明, Z12使得TMV病毒颗粒断裂, 形成长短不一的棒状结构, 微量热涌动实验(MST)的结果表明, Z12对烟草花叶病毒外壳蛋白(TMV-CP)结合的K_d值为(0.033±0.014) μmol/L, 优于宁南霉素的K_d值[(0.106±0.024) μmol/L], 说明了Z12对TMV-CP具有更强的结合力. 抑菌实验结果表明, 部分化合物对水稻白叶枯病菌(Xanthomonas oryzae pv. Oryzae, Xoo)和柑桔溃疡病菌(Xanthomonas axonopodis pv. Citri, Xac)表现出优异活性, 其中(E)-2-((2-(4-(3-(4-溴苯基)丙烯酰基)苯氧基)乙基)硫代)-3-(4-氯苯基)-6-硝基喹唑啉-4(3H)-酮(Z25)对Xoo活性最好, EC₅₀值为19.5 μg/mL, 优于叶枯唑(77.1 μg/mL)和噻菌铜(95.9 μg/mL). 扫描电镜结果表明, Z25作用后使得Xoo的细胞膜皱缩变形. 上述实验结果表明含喹唑啉酮的查尔酮衍生物是有潜力的抗病毒和抑菌药物.

关键词: 喹唑啉酮, 查尔酮, 有机合成, 抑菌, 抗病毒

Twenty-five chalcone derivatives containing quinazolinone were designed and synthesized. The results of antiviral biological experiments showed that (E)-3-(4-chlorophenyl)-6-fluoro-2-((2-(4-(3-(4-methoxyphenyl)acryloyl)phenoxy)ethyl)- thio)quinazolin-4(3H)-one (Z12) had a good inhibitory activity against tobacco mosaic virus (TMV), and the EC₅₀ values of treatment and protection were 94.3 and 98.8 μg/mL, respectively, which were better than those of ningamycin (NNM, 216.1 and 189.6 μg/mL). The results of transmission electron microscope showed that Z12 broke TMV virus particles and formed rod structures of different lengths. The results of microscale thermophoresis experiment (MST) showed that the K_d value of Z12 binding to tobacco mosaic virus coat protein (TMV-CP) was (0.033±0.014) μmol/L. The K_d value of Z12 was better than that of ningnanmycin [(0.106±0.024) μmol/L], which indicated that Z12 had stronger binding ability to TMV-CP. The antibacterial test results showed that some compounds showed excellent activity against Xanthomonas oryzae pv. Oryzae (Xoo) and Xanthomonas axonopodis pv.Citri (Xac), among which ((E)-2-((2-(4-(3-(4-bromophenyl)acryloyl)phenoxy)ethyl)thio)-3- (4-chlorophenyl)-6-nitroquinazolin-4(3H)-one (Z25) showed the best activity against Xoo. The EC₅₀ value of Xoo was 19.5 μg/mL, which was better than those of bismerthiazol (77.1 μg/mL) and thiodiazole copper (95.9 μg/mL). The results of scanning electron microscope showed that the cell membrane of Xoo was shriveled and deformed after Z25 treatment. The experimental results showed that chalcone derivatives containing quinazolinone were potential antiviral and antibacterial drugs.

Key words: quinazolinone, chalcone, organic synthesis, antibacterial, antiviral

引用此文

周然, 袁春梅, 张桃, 毛飘, 刘燚, 孟开妮, 幸惠, 薛伟. 含喹唑啉酮的查尔酮衍生物的设计、合成及生物活性研究[J]. 有机化学, 2023, 43(9): 3196-3209.

Ran Zhou, Chunmei Yuan, Tao Zhang, Piao Mao, Yi Liu, Kaini Meng, Hui Xin, Wei Xue. Design, Synthesis and Bioactivity of Chalcone Derivative Containing Quinazolinone[J]. Chinese Journal of Organic Chemistry, 2023, 43(9): 3196-3209.

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Compd.	Curative activity/%	Protective activity/%	Inactivation activity/%	Compd.	Curative activity/%	Protective activity/%	Inactivation activity/%
Z1	31.5±4.6	17.9±3.4	37.5±0.8	Z19	25.1±1.1	45.8±0.7	53.1±4.2
Z2	32.3±2.7	56.3±3.0	32.3±2.7	Z20	62.5±2.9	35.5±1.3	47.6±3.2
Z3	44.8±0.4	45.8±2.5	44.8±0.4	Z21	52.3±3.5	55.7±2.4	58.5±3.3
Z4	51.2±2.2	35.8±2.5	23.0±1.9	Z22	24.7±2.7	36.9±0.9	64.7±3.9
Z5	66.9±3.2	67.4±1.1	39.8±0.2	Z23	17.9±2.3	20.1±1.7	38.1±1.6
Z6	34.7±2.1	44.1±3.4	33.6±0.8	Z24	36.6±2.5	18.9±2.3	28.1±1.2
Z7	26.2±2.1	71.1±0.9	26.2±2.1	Z25	22.2±1.8	27.7±2.9	54.1±2.8
Z8	34.6±2.6	55.9±3.1	46.8±1.8	K1	25.5±1.1	32.1±2.0	33.7±1.4
Z9	22.8±4.1	51.1±0.8	26.9±1.8	K2	35.3±2.3	27.9±1.5	42.1±1.1
Z10	45.6±3.7	63.0±1.9	45.6±3.7	K3	38.7±1.4	35.6±2.0	23.3±0.9
Z11	36.6±4.9	23.0±2.9	36.6±4.9	K4	27.3±1.2	30.1±2.3	34.5±1.5
Z12	66.6±2.9	70.4±2.7	69.5±1.3	K5	40.2±2.3	34.4±1.7	37.5±1.2
Z13	35.0±4.1	33.7±1.1	25.0±4.1	C1	33.9±1.7	24.3±2.1	35.9±1.3
Z14	32.3±1.2	34.6±2.2	61.5±1.3	C2	29.9±2.0	35.8±1.6	27.9±2.1
Z15	28.7±1.1	59.8±2.5	31.5±0.9	C3	39.9±1.6	32.2±1.4	31.1±2.0
Z16	19.8±0.8	38.9±1.0	63.4±2.9	C4	43.3±1.9	33.2±1.6	26.6±1.0
Z17	30.2±1.5	28.6±1.2	67.7±2.4	C5	28.4±1.2	36.4±1.0	38.9±2.3
Z18	22.9±2.1	32.9±2.5	38.3±2.0	NNM^b	59.7±0.7	65.4±2.4	84.1±1.3

Compd.	Curative activity/%	Protective activity/%	Inactivation activity/%	Compd.	Curative activity/%	Protective activity/%	Inactivation activity/%
Z1	31.5±4.6	17.9±3.4	37.5±0.8	Z19	25.1±1.1	45.8±0.7	53.1±4.2
Z2	32.3±2.7	56.3±3.0	32.3±2.7	Z20	62.5±2.9	35.5±1.3	47.6±3.2
Z3	44.8±0.4	45.8±2.5	44.8±0.4	Z21	52.3±3.5	55.7±2.4	58.5±3.3
Z4	51.2±2.2	35.8±2.5	23.0±1.9	Z22	24.7±2.7	36.9±0.9	64.7±3.9
Z5	66.9±3.2	67.4±1.1	39.8±0.2	Z23	17.9±2.3	20.1±1.7	38.1±1.6
Z6	34.7±2.1	44.1±3.4	33.6±0.8	Z24	36.6±2.5	18.9±2.3	28.1±1.2
Z7	26.2±2.1	71.1±0.9	26.2±2.1	Z25	22.2±1.8	27.7±2.9	54.1±2.8
Z8	34.6±2.6	55.9±3.1	46.8±1.8	K1	25.5±1.1	32.1±2.0	33.7±1.4
Z9	22.8±4.1	51.1±0.8	26.9±1.8	K2	35.3±2.3	27.9±1.5	42.1±1.1
Z10	45.6±3.7	63.0±1.9	45.6±3.7	K3	38.7±1.4	35.6±2.0	23.3±0.9
Z11	36.6±4.9	23.0±2.9	36.6±4.9	K4	27.3±1.2	30.1±2.3	34.5±1.5
Z12	66.6±2.9	70.4±2.7	69.5±1.3	K5	40.2±2.3	34.4±1.7	37.5±1.2
Z13	35.0±4.1	33.7±1.1	25.0±4.1	C1	33.9±1.7	24.3±2.1	35.9±1.3
Z14	32.3±1.2	34.6±2.2	61.5±1.3	C2	29.9±2.0	35.8±1.6	27.9±2.1
Z15	28.7±1.1	59.8±2.5	31.5±0.9	C3	39.9±1.6	32.2±1.4	31.1±2.0
Z16	19.8±0.8	38.9±1.0	63.4±2.9	C4	43.3±1.9	33.2±1.6	26.6±1.0
Z17	30.2±1.5	28.6±1.2	67.7±2.4	C5	28.4±1.2	36.4±1.0	38.9±2.3
Z18	22.9±2.1	32.9±2.5	38.3±2.0	NNM^b	59.7±0.7	65.4±2.4	84.1±1.3

	Compd.	R¹	R²	Regression equation	r	EC₅₀/(μg•mL^–1)
Curative	Z5	4-Br	Br	y=0.9764x+2.7880	0.9798	184.3
	Z12	4-OCH₃	F	y=0.8768x+3.2688	0.9961	94.3
	Z20	4-Br	OCH₃	y=0.9034x+2.9644	0.9973	179.2
	NNM^b	—	—	y=0.9338x+2.8199	0.9915	216.1
Protection	Z5	4-Br	Br	y=0.8797x+3.0150	0.9961	180.1
	Z7	4-OCH₃	CH₃	y=0.8934x+3.0322	0.9779	159.4
	Z12	4-OCH₃	F	y=0.7942x+3.4156	0.9902	98.8
	NNM	—	—	y=1.0142x+2.6898	0.9928	189.6

	Compd.	R¹	R²	Regression equation	r	EC₅₀/(μg•mL^–1)
Curative	Z5	4-Br	Br	y=0.9764x+2.7880	0.9798	184.3
	Z12	4-OCH₃	F	y=0.8768x+3.2688	0.9961	94.3
	Z20	4-Br	OCH₃	y=0.9034x+2.9644	0.9973	179.2
	NNM^b	—	—	y=0.9338x+2.8199	0.9915	216.1
Protection	Z5	4-Br	Br	y=0.8797x+3.0150	0.9961	180.1
	Z7	4-OCH₃	CH₃	y=0.8934x+3.0322	0.9779	159.4
	Z12	4-OCH₃	F	y=0.7942x+3.4156	0.9902	98.8
	NNM	—	—	y=1.0142x+2.6898	0.9928	189.6

Compd.	Xac		Psa		Xoo
Compd.	100 µg/mL	50 µg/mL	100 µg/mL	50 µg/mL	100 µg/mL	50 µg/mL
Z1	25.1±1.1	21.2±1.2	35.4±2.4	22.7±2.2	25.4±2.4	12.7±0.5
Z2	38.2±0.8	23.5±0.8	47.9±2.0	34.7±2.7	27.9±2.0	14.7±2.7
Z3	23.9±5.4	18.4±0.9	52.9±4.8	44.9±2.3	32.9±4.8	10.9±2.3
Z4	22.9±0.5	21.7±5.7	50.5±2.4	39.9±2.5	30.5±2.4	19.9±2.5
Z5	43.5±2.7	31.3±1.7	25.4±5.4	12.7±1.2	45.4±1.4	22.7±1.2
Z6	30.1±1.6	27.1±2.4	37.9±2.0	24.7±2.7	27.9±2.0	14.7±2.7
Z7	24.5±1.2	12.4±8.2	61.8±5.7	44.5±3.6	11.8±2.7	—
Z8	38.5±1.9	22.4±2.3	38.8±3.5	24.0±5.6	28.8±3.5	14.0±0.6
Z9	36.7±1.8	33.6±0.8	28.0±2.6	11.2±3.0	28.0±2.6	11.2±3.0
Z10	26.0±2.5	15.7±3.8	13.9±3.0	7.5±0.9	33.9±3.0	17.5±3.9
Z11	37.7±1.8	26.4±1.8	27.3±1.1	11.2±4.3	27.3±3.1	11.2±4.3
Z12	45.8±4.9	24.3±1.9	37.5±3.9	22.5±3.9	27.5±3.9	14.5±3.9
Z13	57.8±2.1	35.7±2.1	27.4±4.3	15.1±4.6	27.4±4.3	15.1±2.1
Z14	33.8±1.8	21.9±1.8	49.0±4.2	32.3±1.2	59.0±4.2	32.3±1.2
Z15	32.1±1.6	21.5±1.6	27.2±4.6	15.1±1.2	27.2±4.6	16.1±1.6
Z16	42.6±3.3	21.2±3.5	15.6±4.2	9.1±0.2	35.6±4.2	23.1±1.2
Z17	35.6±1.8	23.1±2.2	36.5±1.0	25.2±2.1	61.5±1.0	45.2±2.1
Z18	33.1±3.8	20.7±0.3	35.4±3.3	28.8±4.3	25.4±3.3	13.8±4.3
Z19	35.7±2.7	15.5±2.5	29.2±4.6	13.2±2.6	29.2±4.6	12.2±4.6
Z20	59.7±2.6	27.3±0.5	32.2±0.8	21.6±0.6	22.2±0.8	11.6±3.6
Z21	21.2±.5	11.1±2.2	25.2±0.6	11.5±1.6	35.2±0.6	17.5±1.6
Z22	23.3±1.4	15.6±1.3	35.8±0.1	21.6±2.1	45.8±0.1	21.6±3.1
Z23	38.9±2.6	27.1±1.5	42.1±1.2	31.0±1.0	32.1±3.2	18.0±2.0
Z24	32.2±3.3	16.7±0.6	36.1±2.3	29.3±5.4	26.1±2.3	19.3±1.4
Z25	57.5±2.7	45.4±0.3	37.2±0.9	27.5±3.2	67.2±0.9	57.2±3.2
TC^b	52.2±0.5	46.1±1.8	52.1±3.4	42.2±3.9	55.4±3.4	42.7±1.2
BT^b	47.7±1.0	33.0±2.6	49.2±3.0	36.3±1.8	50.9±2.0	36.9±2.7