含天然蒎烯结构的4-酰基-3-氨基-1,2,4-三唑-硫醚衍生物的合成、抑菌活性、三维定量构效关系及分子对接研究

doi:10.6023/cjoc202108031

摘要/Abstract

为了探寻以天然可再生资源为基础的生物活性分子, 设计并合成了24个新型含天然蒎烯结构的4-酰基-3-氨基- 1,2,4-三唑-硫醚衍生物, 通过IR, ¹H NMR, ¹³C NMR, ESI-MS和元素分析对所有目标化合物的结构进行了表征. 初步的离体抑菌活性测试结果表明, 在质量浓度为50 μg/mL时, 目标化合物对测试的8种植物病原菌表现出一定的抑菌活性, 其中有4个化合物对苹果轮纹病菌有优良的抑菌活性, 远优于阳性对照百菌清; 2个化合物对花生褐斑病菌有良好的抑制活性, 远优于阳性对照百菌清. 使用比较分子力场分析法(CoMFA)对目标化合物的抗苹果轮纹病菌活性进行了初步的三维定量构效关系(3D-QSAR)分析, 建立了一个合理的3D-QSAR模型(r²=0.961, q²=0.613). 此外, 分子对接结果表明, 目标化合物诺卜醇基4-(4'-氟苯甲酰基)-3-氨基-1,2,4-三唑-硫醚(5k)在琥珀酸脱氢酶(SDH)活性口袋的结合模式与商品杀菌剂萎锈灵相似.

关键词: β-蒎烯, 诺卜醇, 1,2,4-三唑-硫醚, 3D-QSAR, 分子对接, 抑菌活性

Twenty-four 4-acyl-3-amino-1,2,4-triazole-thioether derivatives containing natural pinene structure were designed and synthesized in search of novel natural product-based bioactive molecules. Their structures were characterized by IR, ¹H NMR, ¹³C NMR, ESI-MS, and elemental analysis. The in vitro antifungal activity test of the target compounds showed that, at the concentration of 50 µg/mL, the target compounds displayed certain antifungal activity against the eight tested plant pathogens, in which 4 compounds exhibited good to excellent antifungal activity against Physalospora piricola, much better than that of the positive control chlorothalonil. Also, 2 compounds exhibited good inhibitory activity against Cercospora arachidicola, much better than that of the positive control chlorothalonil. The preliminary analysis of three-dimensional quantitative structure-activity relationship (3D-QSAR) was carried out using the molecular field analysis (CoMFA) method for the inhibitory activity of the target compounds against P. piricola, and a reasonable 3D-QSAR model (r²=0.961, q²=0.613) has been established. Furthermore, the molecular docking results showed that the binding mode of the target compound nopol-derived 4-(4'-fluorobenzoyl)-3-amino-1,2,4-triazole-thioether (5k) in the active cavity of succinate dehydrogenase (SDH) was similar to that of the commercial fungicide carboxin.

Key words: β-pinene, nopol, 1,2,4-triazole-thioether, 3D-QSAR, molecular docking, antifungal activity

引用此文

王秀, 段文贵, 林桂汕, 李宝谕, 张文静, 雷福厚. 含天然蒎烯结构的4-酰基-3-氨基-1,2,4-三唑-硫醚衍生物的合成、抑菌活性、三维定量构效关系及分子对接研究[J]. 有机化学, 2022, 42(3): 871-883.

Xiu Wang, Wengui Duan, Guishan Lin, Baoyu Li, Wenjing Zhang, Fuhou Lei. Synthesis, Antifungal Activity, Three-Dimensional Quantitative Structure-Activity Relationship and Molecular Docking Study of 4-Acyl-3-amino-1,2,4-triazole-thioether Derivatives Containing Natural Pinene Structure[J]. Chinese Journal of Organic Chemistry, 2022, 42(3): 871-883.

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Compd.	Inhibition rate/%
Compd.	F. oxysporum f. sp. Cucumerinum	C. arachidicola	P. piricola	A. solani	G. zeae	R. solani	B. myadis	C. orbicalare
5a	24.5	48.6	45.0	41.4	58.7	63.5	43.8	40.0
5b	42.2	82.9	83.0	66.2	66.6	21.2	49.8	39.6
5c	29.1	34.3	45.0	48.6	52.3	57.0	34.3	35.0
5d	33.6	27.1	38.8	34.3	29.7	30.9	34.3	30.0
5e	66.3	74.3	85.2	84.1	73.4	90.5	77.4	72.9
5f	24.5	27.1	38.8	41.4	26.5	41.7	24.8	30.0
5g	33.6	41.4	54.4	41.4	42.6	35.2	34.3	35.0
5h	24.5	41.4	51.3	34.3	45.8	59.1	43.8	35.0
5i	24.5	24.3	28.8	27.1	61.9	30.9	29.5	30.0
5j	24.5	48.6	41.9	34.3	39.4	59.1	43.8	40.0
5k	51.5	80.0	93.9	79.0	47.6	24.9	34.9	33.7
5l	29.1	41.4	41.9	41.4	36.1	30.9	29.5	30.0
5m	38.2	41.4	70.0	41.4	71.6	57.0	34.3	40.0
5n	24.5	34.3	38.8	41.4	36.1	41.7	34.3	30.0
5o	24.5	41.4	54.4	48.6	58.7	50.4	43.8	35.0
5p	88.2	77.1	70.0	77.1	84.5	89.6	67.6	80.0
5q	33.6	41.4	51.3	48.6	55.5	57.0	39.0	30.0
5r	24.5	41.4	45.0	41.4	45.8	70.0	29.5	40.0
5s	38.2	34.3	32.5	41.4	52.3	46.1	43.8	30.0
5t	45.9	68.6	61.3	61.0	37.2	27.3	41.3	39.6
5u	42.2	74.3	93.5	71.3	66.6	26.1	34.9	39.6
5u	33.6	34.3	35.6	41.4	26.5	28.7	39.0	30.0
5w	16.2	30.4	47.6	40.0	34.0	12.3	18.9	33.3
5x	24.5	27.1	38.8	41.4	52.3	37.4	24.8	30.0
Chlorothalonil	100	73.3	75.0	73.9	73.1	96.1	90.4	91.3

Compd.	Inhibition rate/%
Compd.	F. oxysporum f. sp. Cucumerinum	C. arachidicola	P. piricola	A. solani	G. zeae	R. solani	B. myadis	C. orbicalare
5a	24.5	48.6	45.0	41.4	58.7	63.5	43.8	40.0
5b	42.2	82.9	83.0	66.2	66.6	21.2	49.8	39.6
5c	29.1	34.3	45.0	48.6	52.3	57.0	34.3	35.0
5d	33.6	27.1	38.8	34.3	29.7	30.9	34.3	30.0
5e	66.3	74.3	85.2	84.1	73.4	90.5	77.4	72.9
5f	24.5	27.1	38.8	41.4	26.5	41.7	24.8	30.0
5g	33.6	41.4	54.4	41.4	42.6	35.2	34.3	35.0
5h	24.5	41.4	51.3	34.3	45.8	59.1	43.8	35.0
5i	24.5	24.3	28.8	27.1	61.9	30.9	29.5	30.0
5j	24.5	48.6	41.9	34.3	39.4	59.1	43.8	40.0
5k	51.5	80.0	93.9	79.0	47.6	24.9	34.9	33.7
5l	29.1	41.4	41.9	41.4	36.1	30.9	29.5	30.0
5m	38.2	41.4	70.0	41.4	71.6	57.0	34.3	40.0
5n	24.5	34.3	38.8	41.4	36.1	41.7	34.3	30.0
5o	24.5	41.4	54.4	48.6	58.7	50.4	43.8	35.0
5p	88.2	77.1	70.0	77.1	84.5	89.6	67.6	80.0
5q	33.6	41.4	51.3	48.6	55.5	57.0	39.0	30.0
5r	24.5	41.4	45.0	41.4	45.8	70.0	29.5	40.0
5s	38.2	34.3	32.5	41.4	52.3	46.1	43.8	30.0
5t	45.9	68.6	61.3	61.0	37.2	27.3	41.3	39.6
5u	42.2	74.3	93.5	71.3	66.6	26.1	34.9	39.6
5u	33.6	34.3	35.6	41.4	26.5	28.7	39.0	30.0
5w	16.2	30.4	47.6	40.0	34.0	12.3	18.9	33.3
5x	24.5	27.1	38.8	41.4	52.3	37.4	24.8	30.0
Chlorothalonil	100	73.3	75.0	73.9	73.1	96.1	90.4	91.3

Compd.	R	MW	AF	AF"	Residue
5a	C₆H₅	368.17	–2.65	–2.68	0.03
5b	o-CH₃C₆H₄	382.18	–1.89	–1.94	0.05
5c	m-CH₃C₆H₄	382.18	–2.67	–2.79	0.12
5d	p-CH₃C₆H₄	382.18	–2.78	–2.66	–0.12
5e	o-CH₃OC₆H₄	398.18	–1.84	–1.84	0.00
5f	m-CH₃OC₆H₄	398.18	–2.8	–2.82	0.02
5g	p-CH₃CH₂OC₆H₄	412.19	–2.54	–2.63	0.09
5h	p-CH₃CH₂C₆H₄	396.20	–2.58	–2.63	0.05
5i	o-FC₆H₄	386.16	–2.98	–3.14	0.16
5j	m-FC₆H₄	386.16	–2.73	–2.71	–0.02
5k	p-FC₆H₄	386.16	–1.40	–1.44	0.04
5m	m-ClC₆H₄	402.13	–2.24	–2.40	0.16
5o	m-BrC₆H₄	446.08	–2.57	–2.45	–0.12
5p	p-BrC₆H₄	446.08	–2.28	–2.14	–0.14
5q	p-NCC₆H₄	393.16	–2.57	–2.61	0.04
5r	o-O₂NC₆H₄	413.15	–2.70	–2.75	0.05
5t	p-CF₃C₆H₄	436.15	–2.44	–2.45	0.01
5l*	o-ClC₆H₄	402.13	–2.75	–2.49	–0.26
5n*	o-BrC₆H₄	446.08	–2.85	–2.51	–0.34
5s*	p-O₂NC₆H₄	413.15	–2.93	–2.68	–0.25
5u*	o,m-Cl₂C₆H₃	436.09	–1.48	–1.73	0.25
5v*	o,o,p-(CH₃)₃C₆H₂	410.21	–2.87	–3.08	0.21

Compd.	R	MW	AF	AF"	Residue
5a	C₆H₅	368.17	–2.65	–2.68	0.03
5b	o-CH₃C₆H₄	382.18	–1.89	–1.94	0.05
5c	m-CH₃C₆H₄	382.18	–2.67	–2.79	0.12
5d	p-CH₃C₆H₄	382.18	–2.78	–2.66	–0.12
5e	o-CH₃OC₆H₄	398.18	–1.84	–1.84	0.00
5f	m-CH₃OC₆H₄	398.18	–2.8	–2.82	0.02
5g	p-CH₃CH₂OC₆H₄	412.19	–2.54	–2.63	0.09
5h	p-CH₃CH₂C₆H₄	396.20	–2.58	–2.63	0.05
5i	o-FC₆H₄	386.16	–2.98	–3.14	0.16
5j	m-FC₆H₄	386.16	–2.73	–2.71	–0.02
5k	p-FC₆H₄	386.16	–1.40	–1.44	0.04
5m	m-ClC₆H₄	402.13	–2.24	–2.40	0.16
5o	m-BrC₆H₄	446.08	–2.57	–2.45	–0.12
5p	p-BrC₆H₄	446.08	–2.28	–2.14	–0.14
5q	p-NCC₆H₄	393.16	–2.57	–2.61	0.04
5r	o-O₂NC₆H₄	413.15	–2.70	–2.75	0.05
5t	p-CF₃C₆H₄	436.15	–2.44	–2.45	0.01
5l*	o-ClC₆H₄	402.13	–2.75	–2.49	–0.26
5n*	o-BrC₆H₄	446.08	–2.85	–2.51	–0.34
5s*	p-O₂NC₆H₄	413.15	–2.93	–2.68	–0.25
5u*	o,m-Cl₂C₆H₃	436.09	–1.48	–1.73	0.25
5v*	o,o,p-(CH₃)₃C₆H₂	410.21	–2.87	–3.08	0.21

Statistical parameters	CoMFA
r²^a	0.961
q²^b	0.613
S ^c	0.016
F-value^d	124.113
ONC^e	5
Field contribution/%	CoMFA
Steric	78.2
Electrostatic	21.8