Design, Synthesis and Fungicidal Activity of Novel Piperidine Containing Cinnamaldehyde Thiosemicarbazide Derivatives

doi:10.6023/cjoc201903031

Abstract

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

Cite this article

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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Compd.	R¹	R²	瓜果腐霉病	水稻纹枯病	苹果腐烂病	油菜菌核病	水稻恶苗病
3a	H	4-Cl	96	100	99	99	68
3b	H	2-CH₃	46	78	91	47	44
3c	H	2-OCH₃	93	100	100	70	63
3d	H	4-OCH₃	94	84	95	99	100
3e	H	4-NO₂	80	85	95	66	53
3f	4-COOC₂H₅	4-Cl	92	100	78	59	49
3g	4-COOC₂H₅	2-CH₃	30	71	55	54	35
3h	4-COOC₂H₅	2-OCH₃	95	100	91	47	51
3i	4-COOC₂H₅	4-OCH₃	86	82	85	69	79
3j	4-COOC₂H₅	4-NO₂	82	88	80	51	73
3k	3-CH₃	4-Cl	83	100	98	89	60
3l	3-CH₃	2-CH₃	31	76	80	42	45
3m	3-CH₃	2-OCH₃	85	100	98	81	54
3n	3-CH₃	4-OCH₃	84	81	95	98	94
3o	3-CH₃	4-NO₂	70	81	93	77	75
3p	H	H	100	95	98	100	95
A			44	100	91	62	49
P			35	87	71	49	45
Lead compound			99	93	86	85	64
吡唑醚菌酯			47	100	100	100	79

Compd.	R¹	R²	瓜果腐霉病	水稻纹枯病	苹果腐烂病	油菜菌核病	水稻恶苗病
3a	H	4-Cl	96	100	99	99	68
3b	H	2-CH₃	46	78	91	47	44
3c	H	2-OCH₃	93	100	100	70	63
3d	H	4-OCH₃	94	84	95	99	100
3e	H	4-NO₂	80	85	95	66	53
3f	4-COOC₂H₅	4-Cl	92	100	78	59	49
3g	4-COOC₂H₅	2-CH₃	30	71	55	54	35
3h	4-COOC₂H₅	2-OCH₃	95	100	91	47	51
3i	4-COOC₂H₅	4-OCH₃	86	82	85	69	79
3j	4-COOC₂H₅	4-NO₂	82	88	80	51	73
3k	3-CH₃	4-Cl	83	100	98	89	60
3l	3-CH₃	2-CH₃	31	76	80	42	45
3m	3-CH₃	2-OCH₃	85	100	98	81	54
3n	3-CH₃	4-OCH₃	84	81	95	98	94
3o	3-CH₃	4-NO₂	70	81	93	77	75
3p	H	H	100	95	98	100	95
A			44	100	91	62	49
P			35	87	71	49	45
Lead compound			99	93	86	85	64
吡唑醚菌酯			47	100	100	100	79

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

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