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

doi:10.6023/cjoc202108031

Abstract

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

Cite this article

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

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