新型缩氨基硫脲类化合物的设计、合成及杀菌活性研究

doi:10.6023/cjoc202201001

摘要/Abstract

为发现新型高活性的杀菌剂候选化合物, 以天然产物肉桂醛衍生物N-α-戊基-(4-溴苯基)-亚丙烯基-N'-2',3'-O-亚异丙基-5'-O-尿苷甲酰基腙(A16)为先导, 用具有杀菌活性的硫脲基团替代先导结构中的酯基尿苷, 设计并合成了一系列缩氨基硫脲类化合物. 目标物结构均经过¹H NMR、¹³C NMR、IR、元素分析或HRMS确证. 离体抑菌活性测试结果表明, 在100 μg/mL浓度下, 部分化合物对多种病原菌表现出明显的抑菌活性. 其中, 化合物2a对黄瓜灰霉病菌(B. cinerea)、黄瓜炭疽病菌(C. orbiculare)、番茄早疫病菌(A. solani)三种病原菌的抑制率均超过80%, 化合物2p对水稻纹枯病菌(R. solani)、小麦赤霉病菌(F. graminearum)、黄瓜炭疽病菌和番茄早疫病菌的抑制率均超过90%. 进一步的精密毒力测试(EC₅₀)结果表明, 化合物2a对黄瓜灰霉病菌(EC₅₀=1.77 μg/mL)的抑制活性和化合物2p对于水稻纹枯病菌(EC₅₀=2.07 μg/mL)的抑制活性优于对照多氧霉素B. 同时, 化合物2p在40 μg/mL浓度下对几丁质合成酶的抑制活性(69%)优于对照药剂尼克霉素Z (52%）.

关键词: 缩氨基硫脲, 天然产物, 肉桂醛, 合成, 几丁质合成酶, 杀菌活性

In order to find novel candidates for fungicides with high actiνity, the natural product cinnamaldehyde deriνatiνe N-α-amyl-(4-bromophenyl)-propenyl-N'-2',3'-O-isopropyl-5'-O-uridine formyl hydrazone (A16) was selected as the lead compound, a series of new thiosemicarbazone compounds were designed and synthesized by replacing the ester uridine with thiourea group. The structures of the target compounds were confirmed by ¹HNMR, ¹³C NMR, IR, elemental analysis or HRMS. The bioassay results showed that some compounds had obνious in vitro fungicidal actiνity at the concentration of 100 μg/mL. Among them, the inhibition rates of compound 2a against B. cinerea, C. orbiculare and A. solani were more than 80%. Compound 2p showed good activity against R. solani, F. graminearum, C. orbiculare and A. solani. Furthermore, compound 2a had better inhibitory actiνity against B. cinerea (EC₅₀=1.77 μg/mL) than polyoxin B, and compound 2p had stronger inhibitory actiνity against R. solani (EC₅₀=2.07 μg/mL) than Polyoxin B (EC₅₀=15.33 μg/mL). Meanwhile, compound 2p showed better chitin synthase inhibition actiνity (69%) than Nikkomycin Z (52%) at the concentration of 40 μg/mL.

Key words: thiosemicarbazide, natural products, cinnamaldehyde, synthesis, chitin synthase, fungicidal actiνity

引用此文

石发胜, 王圣文, 徐欢, 路星星, 杨新玲, 孙腾达, 王长凯, 张晓鸣, 杨青, 凌云. 新型缩氨基硫脲类化合物的设计、合成及杀菌活性研究[J]. 有机化学, 2022, 42(7): 2106-2116.

Fasheng Shi, Shengwen Wang, Huan Xu, Xingxing Lu, Xinling Yang, Tengda Sun, Changkai Wang, Xiaoming Zhang, Qing Yang, Yun Ling. Design, Synthesis and Fungicidal Actiνity of Noνel Thiosemicarbazide Compounds[J]. Chinese Journal of Organic Chemistry, 2022, 42(7): 2106-2116.

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Compd.	R¹	R²	水稻纹枯病菌	黄瓜灰霉病菌	小麦赤霉病菌	黄瓜炭疽病菌	番茄早疫病菌	马铃薯晚疫病菌
2a	H	CH₃	35	85	62	86	83	69
2b	H	CH₂CH₃	0	82	58	78	87	57
2c	H	(CH₂)₂CH₃	0	81	62	64	66	48
2d	H	(CH₂)₃CH₃	0	72	52	61	48	48
2e	H	(CH₂)₄CH₃	0	72	51	62	45	50
2f	H	(CH₂)₅CH₃	0	59	46	71	62	60
2g	H	(CH₂)₆CH₃	0	59	54	67	38	42
2h	H	(CH₂)₇CH₃	0	51	48	38	0	57
2i	H	(CH₂)₈CH₃	0	46	54	33	0	0
2j	2-Cl	CH₂CH₃	0	59	54	43	34	58
2k	4-Cl	CH₂CH₃	52	89	69	65	44	40
2l	2-Br	CH₂CH₃	35	63	57	49	64	72
2m	4-Br	CH₂CH₃	0	76	42	52	40	38
2n	2-Me	CH₂CH₃	43	71	57	58	53	82
2o	4-Me	CH₂CH₃	0	72	46	65	50	47
2p	2-OMe	CH₂CH₃	96	85	92	100	100	82
2q	4-OMe	CH₂CH₃	39	79	62	67	71	69
2r	4-Cl	(CH₂)₂CH₃	43	89	72	59	50	63
2s	4-F	(CH₂)₄CH₃	0	64	62	77	58	67
2t	4-Br	(CH₂)₄CH₃	30	83	73	66	58	65
2u	4-Cl	(CH₂)₅CH₃	70	64	67	74	47	58
2v	4-Me	(CH₂)₅CH₃	26	63	66	71	63	71
2w	4-NO₂	CH₂CH₃	0	0	0	36	0	0
2x	4-NO₂	(CH₂)₄CH₃	30	77	68	27	0	0
A16			0	48	50	45	51	—
多氧霉素B			63	83	57	63	77	70

Compd.	R¹	R²	水稻纹枯病菌	黄瓜灰霉病菌	小麦赤霉病菌	黄瓜炭疽病菌	番茄早疫病菌	马铃薯晚疫病菌
2a	H	CH₃	35	85	62	86	83	69
2b	H	CH₂CH₃	0	82	58	78	87	57
2c	H	(CH₂)₂CH₃	0	81	62	64	66	48
2d	H	(CH₂)₃CH₃	0	72	52	61	48	48
2e	H	(CH₂)₄CH₃	0	72	51	62	45	50
2f	H	(CH₂)₅CH₃	0	59	46	71	62	60
2g	H	(CH₂)₆CH₃	0	59	54	67	38	42
2h	H	(CH₂)₇CH₃	0	51	48	38	0	57
2i	H	(CH₂)₈CH₃	0	46	54	33	0	0
2j	2-Cl	CH₂CH₃	0	59	54	43	34	58
2k	4-Cl	CH₂CH₃	52	89	69	65	44	40
2l	2-Br	CH₂CH₃	35	63	57	49	64	72
2m	4-Br	CH₂CH₃	0	76	42	52	40	38
2n	2-Me	CH₂CH₃	43	71	57	58	53	82
2o	4-Me	CH₂CH₃	0	72	46	65	50	47
2p	2-OMe	CH₂CH₃	96	85	92	100	100	82
2q	4-OMe	CH₂CH₃	39	79	62	67	71	69
2r	4-Cl	(CH₂)₂CH₃	43	89	72	59	50	63
2s	4-F	(CH₂)₄CH₃	0	64	62	77	58	67
2t	4-Br	(CH₂)₄CH₃	30	83	73	66	58	65
2u	4-Cl	(CH₂)₅CH₃	70	64	67	74	47	58
2v	4-Me	(CH₂)₅CH₃	26	63	66	71	63	71
2w	4-NO₂	CH₂CH₃	0	0	0	36	0	0
2x	4-NO₂	(CH₂)₄CH₃	30	77	68	27	0	0
A16			0	48	50	45	51	—
多氧霉素B			63	83	57	63	77	70

测试菌种	Compd.	EC₅₀/(μg•L^–1)	Y曲线	r
水稻纹枯病菌	2p	2.07	Y=0.755X+4.761	0.9762
水稻纹枯病菌	多氧霉素B	15.33	Y=1.941X+2.699	0.9980
黄瓜灰霉病菌	2a	1.77	Y=0.897X+4.777	0.9990
	2p	18.85	Y=0.806X+3.972	0.9935
	多氧霉素B	3.08	Y=1.033X+4.496	0.9670
小麦赤霉病菌	2p	26.49	Y=1.107X+3.417	0.9864
小麦赤霉病菌	多氧霉素B	44.66	Y=1.091X+3.200	0.9985

测试菌种	Compd.	EC₅₀/(μg•L^–1)	Y曲线	r
水稻纹枯病菌	2p	2.07	Y=0.755X+4.761	0.9762
水稻纹枯病菌	多氧霉素B	15.33	Y=1.941X+2.699	0.9980
黄瓜灰霉病菌	2a	1.77	Y=0.897X+4.777	0.9990
	2p	18.85	Y=0.806X+3.972	0.9935
	多氧霉素B	3.08	Y=1.033X+4.496	0.9670
小麦赤霉病菌	2p	26.49	Y=1.107X+3.417	0.9864
小麦赤霉病菌	多氧霉素B	44.66	Y=1.091X+3.200	0.9985

Compd.	R¹	R²	抑制效果/%
Compd.	R¹	R²	40 μg•mL^–1	100 μg•mL^–1
2a	H	CH₃	37	67
2p	2-OMe	CH₂CH₃	69	80
2t	4-Br	(CH₂)₄CH₃	58	83
A16			47	79
尼克霉素Z			52	86