新型哌啶基肉桂醛缩氨基硫脲衍生物的设计、合成及抑菌活性研究

doi:10.6023/cjoc201903031

摘要/Abstract

为了发现高活性杀菌剂先导化合物, 利用骨架跃迁原理, 以哌啶基苯甲醛缩氨基硫脲为先导化合物, 设计并合成了一系列未见文献报道的肉桂醛缩氨基硫脲类衍生物. 化合物结构经过 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, 一些化合物对多种病原真菌表现出优异的杀菌活性. 在50 μg/mL浓度下, N'-[(1E, 2E)-3-(4-氯苯基)烯丙基]哌啶-1-硫代酰肼(3a)和N'-((1E,2E)-3-苯基烯丙基)哌啶-1-硫代酰肼(3p)对苹果腐烂病菌、油菜菌核病菌菌、瓜果腐霉病菌和水稻纹枯病菌的离体抑菌活性均在95%以上. EC₅₀测试结果表明, 化合物3a, 3p对这4种病原真菌EC₅₀均在10 μg/mL以内, 表现出广谱的杀菌活性. 初步构效关系分析表明, 将苯甲醛骨架替换为具有杀菌活性的肉桂醛骨架结构, 有利于活性的提高.

关键词: 天然产物, 肉桂醛, 缩氨基硫脲, 合成, 杀菌活性

In order to find new lead compound with higher fungicidal activity, a series of novel cinnamaldehyde thio- semicarbazone derivatives were designed and synthesized according to scaffold hopping strategy, based on the lead of the thiosemicarbazide derivatives containing piperidine discovered in our preliminary studies. Their structures were confirmed by ¹H NMR, ¹³C NMR, IR, elemental analysis or HRMS. The bioassay results indicated that some compounds exhibited excellent fungicidal activities. In particular, N'-((1E,2E)-3-(4-chlorophenyl)allylidene)piperidine-1-carbothiohydrazide (3a) and N'-((1E, 2E)-3-phenylallylidene)piperidine-1-carbothiohydrazide (3p) showed above 95% inhibitory rate against Cytospora sp, S. sclerotiorum, P. aphanidermatum and T. cucumeris at 50 μg/mL with EC₅₀ values lower than 10 μg/mL. The preliminary structure-activity relationship indicated that cinnamaldehyde contributes more to the bioactivity than benzaldehyde.

Key words: natural product, cinnamyl aldehyde, thiosemicarbazide, synthesis, fungicidal activity

引用此文

张学博, 马航宇, 孙腾达, 雷鹏, 杨新玲, 张晓鸣, 凌云. 新型哌啶基肉桂醛缩氨基硫脲衍生物的设计、合成及抑菌活性研究[J]. 有机化学, 2019, 39(10): 2965-2972.

Zhang, Xuebo, Ma, Hangyu, Sun, Tengda, Lei, Peng, Yang, Xinling, Zhang, Xiaoming, Ling, Yun. Design, Synthesis and Fungicidal Activity of Novel Piperidine Containing Cinnamaldehyde Thiosemicarbazide Derivatives[J]. Chinese Journal of Organic Chemistry, 2019, 39(10): 2965-2972.

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参考文献 19

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Compd.	EC₅₀/(μg?mL^–1)	线性方程	R²
3a	5.53	y=2.2927x+3.2971	0.98
3b	15.17	y=2.2541x+2.3389	0.97
3c	8.56	y=1.7871x+3.3347	0.98
3d	6.09	y=1.6526x+3.7034	0.98
3e	17.60	y=0.9497x+3.8172	0.95
3f	16.62	y=1.3833x+3.3123	0.99
3h	14.23	y=1.3574x+3.4357	0.97
3i	51.81	y=0.8067x+3.6170	0.97
3j	24.72	y=1.2658x+3.2367	0.91
3k	5.22	y=1.8442x+3.6777	0.98
3l	8.64	y=1.8229x+3.2947	0.99
3m	6.04	y=1.4877x+3.8395	0.98
3n	33.53	y=0.9639x+3.5296	0.98
3o	19.95	y=0.9814x+3.7242	0.93
3p	5.20	y=2.0812x+3.5097	0.96
Lead compound	6.58	y=1.8537x+3.4834	0.98
A	5.70	y=1.3559x+3.9746	0.99
P	16.70	y=1.0628x+3.7005	0.96
嘧菌酯	0.01	y=0.7677x+6.4285	0.94
吡唑醚菌酯	0.01	y=1.2443x+7.4561	0.96

Compd.	EC₅₀/(μg?mL^–1)	线性方程	R²
3a	5.53	y=2.2927x+3.2971	0.98
3b	15.17	y=2.2541x+2.3389	0.97
3c	8.56	y=1.7871x+3.3347	0.98
3d	6.09	y=1.6526x+3.7034	0.98
3e	17.60	y=0.9497x+3.8172	0.95
3f	16.62	y=1.3833x+3.3123	0.99
3h	14.23	y=1.3574x+3.4357	0.97
3i	51.81	y=0.8067x+3.6170	0.97
3j	24.72	y=1.2658x+3.2367	0.91
3k	5.22	y=1.8442x+3.6777	0.98
3l	8.64	y=1.8229x+3.2947	0.99
3m	6.04	y=1.4877x+3.8395	0.98
3n	33.53	y=0.9639x+3.5296	0.98
3o	19.95	y=0.9814x+3.7242	0.93
3p	5.20	y=2.0812x+3.5097	0.96
Lead compound	6.58	y=1.8537x+3.4834	0.98
A	5.70	y=1.3559x+3.9746	0.99
P	16.70	y=1.0628x+3.7005	0.96
嘧菌酯	0.01	y=0.7677x+6.4285	0.94
吡唑醚菌酯	0.01	y=1.2443x+7.4561	0.96

Compd.	EC₅₀/(μg?mL^–1)	线性方程	R²
3a	2.35	y=1.3663x+4.4942	0.96
3c	2.20	y=0.9405x+4.6784	0.95
3d	6.17	y=1.1077x+4.1249	0.97
3e	6.80	y=1.1765x+4.0206	0.99
3f	4.04	y=1.4348x+4.1311	0.97
3h	3.66	y=1.2256x+4.3109	0.98
3i	7.77	y=1.2411x+3.8950	0.95
3j	8.60	y=1.5194x+3.5798	0.99
3k	1.22	y=0.9178x+4.9219	0.95
3m	1.46	y=1.1335x+4.8152	0.99
3n	10.49	y=1.1615x+3.8146	0.94
3o	10.22	y=1.2466x+3.7418	0.95
3p	1.02	y=0.9761x+4.9881	0.98
Lead compound	5.60	y=0.6868x+4.4864	0.91
A	3.12	y=1.3133x+4.3346	0.92
P	5.60	y=0.9895x+4.2629	0.91
吡唑醚菌酯	0.03	y=0.7435x+6.1470	0.99

Compd.	EC₅₀/(μg?mL^–1)	线性方程	R²
3a	2.35	y=1.3663x+4.4942	0.96
3c	2.20	y=0.9405x+4.6784	0.95
3d	6.17	y=1.1077x+4.1249	0.97
3e	6.80	y=1.1765x+4.0206	0.99
3f	4.04	y=1.4348x+4.1311	0.97
3h	3.66	y=1.2256x+4.3109	0.98
3i	7.77	y=1.2411x+3.8950	0.95
3j	8.60	y=1.5194x+3.5798	0.99
3k	1.22	y=0.9178x+4.9219	0.95
3m	1.46	y=1.1335x+4.8152	0.99
3n	10.49	y=1.1615x+3.8146	0.94
3o	10.22	y=1.2466x+3.7418	0.95
3p	1.02	y=0.9761x+4.9881	0.98
Lead compound	5.60	y=0.6868x+4.4864	0.91
A	3.12	y=1.3133x+4.3346	0.92
P	5.60	y=0.9895x+4.2629	0.91
吡唑醚菌酯	0.03	y=0.7435x+6.1470	0.99

Compd.	EC₅₀/(μg?mL^–1)	线性方程	R²
3a	4.94	y=0.8204x+4.4318	0.91
3d	7.41	y=2.1292x+3.1484	0.91
3k	7.55	y=1.0553x+4.0749	0.99
3m	9.57	y=1.3686x+3.6580	0.94
3n	47.43	y=1.1461x+3.0791	0.91
3p	5.10	y=2.8944x+2.9508	0.94
Lead compound	12.61	y=0.7568x+4.1669	0.94
A	24.21	y=1.1892x+3.3541	0.98
P	60.40	y=1.0606x+3.1111	0.92
嘧菌酯	5.17	y=0.5026x+4.6425	0.91