含偕二甲基环丙烷的1, 3, 4-噻二唑-硫脲化合物的合成、抑菌活性及3D-QSAR研究

doi:10.3969/j.issn.0253-2417.2022.05.007

摘要/Abstract

摘要：

为了探寻有效的新型抗植物病原菌活性分子, 通过多步反应设计并合成了一系列20个新型含偕二甲基环丙烷的1, 3, 4-噻二唑-硫脲化合物8a~8t, 采用FT-IR、¹H NMR、¹³C NMR、ESI-MS和元素分析等技术对所有目标化合物的结构进行了表征，并初步测定了目标化合物对8种植物病原菌的抑菌活性。研究结果表明: 在质量浓度50 mg/L下，化合物8l(R=m-BrC₆H₄)对苹果轮纹菌的抑制率为79.5%, 优于阳性对照百菌清。为了设计更有效的抗苹果轮纹菌化合物, 采用比较分子力场分析方法(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, 建立了合理有效的3D-QSAR模型(r²=0.991, q²=0.514)。

关键词: 3-蒈烯, 偕二甲基环丙烷, 1, 3, 4-噻二唑-硫脲, 抗植物病原菌活性, 3D-QSAR

Abstract:

A series of novel 1, 3, 4-thiadiazole-thiourea compounds containing gem-dimethylcyclopropane ring 8a-8t were designed and synthesized by multi-step reactions in search of novel antifungal molecules. Structures of all target compounds were characterized by FT-IR, ¹H NMR, ¹³C NMR, ESI-MS and elemental analysis. The antifungal activities of the target compounds were preliminarily evaluated. The bioassay results revealed that, at 50 mg/L, the inhibitory rate of compound 8l(R=m-BrC₆H₄) against P.piricola was 79.5%, which was better than that of the positive control chlorothalonil. In order to design more effective antifungal compounds against P.piricola, analysis of the three-dimensional quantitative structure-activity relationship(3D-QSAR) was performed using the comparative molecular field analysis(CoMFA) method. The reasonable and effective 3D-QSAR model(r²=0.991, q²=0.514) was established.

Key words: 3-carene, gem-dimethylcyclopropane ring, 1, 3, 4-thiadiazole-thiourea, antifungal activity, 3D-QSAR

中图分类号:

TQ35

邹壬萱, 段文贵, 林桂汕, 李宝谕, 崔玉成. 含偕二甲基环丙烷的1, 3, 4-噻二唑-硫脲化合物的合成、抑菌活性及3D-QSAR研究[J]. 林产化学与工业, 2022, 42(5): 45-55.

Renxuan ZOU, Wengui DUAN, Guishan LIN, Baoyu LI, Yucheng CUI. Synthesis, Antifungal Activity and 3D-QSAR Study of Novel 1, 3, 4-Thiadiazole-Thiourea Compounds Containing gem-Dimethylcyclopropane Ring[J]. Chemistry and Industry of Forest Products, 2022, 42(5): 45-55.

图/表 8

Fig.1

Fig.2

Fig.3

Table 1

Table 2

Fig.4

Fig.5

Fig.6

参考文献 34

1	BASHOLLI-SALIHU M , SCHUSTER R , HAJDARI A , et al. Phytochemical composition, anti-inflammatory activity and cytotoxic effects of essential oils from three Pinus spp[J]. Pharmaceutical Biology, 2017, 55 (1): 1553- 1560. doi: 10.1080/13880209.2017.1309555
2	GARCIA G, TISSANDIE L, FILIPPI J J, et al. New pinane derivatives found in essential oils of Calocedrus decurrens[J/OL]. Molecules, 2017, 22(6): 1-12[2021-10-15]. https://doi.org/10.3390/molecules22060921.
3	KARAPANDZOVA M , STEFKOV G , KARANFILOVA I C , et al. Chemical characterization and antioxidant activity of mountain pine(Pinus mugo Turra, Pinaceae) from Republic of Macedonia[J]. Records of Natural Products, 2018, 13 (1): 50- 63. doi: 10.25135/rnp.73.18.02.233
4	虞友培, 段文贵, 林桂汕, 等. 新型含偕二甲基环丙烷的4-甲基-1, 2, 4-三唑硫醚化合物的合成、生物活性及三维定量构效关系(3D-QSAR)研究[J]. 有机化学, 2020, 40 (6): 1647- 1657.
	YU Y P , DUAN W G , LIN G S , et al. Synthesis, biological activity and three-dimensional quantitative structure-activity relationship(3D-QSAR) study of novel 4-methyl-1, 2, 4-triazole-thioethers containing gem-dimethylcyclopropane ring[J]. Chinese Journal of Organic Chemistry, 2020, 40 (6): 1647- 1657.
5	何丽芝, 王婧, 赵振东, 等. 3-蒈烯资源及其生物活性应用研究进展[J]. 林产化学与工业, 2011, 31 (3): 122- 126.
	HE L Z , WANG J , ZHAO Z D , et al. Research progress on resources and bioactivity applications of 3-carene[J]. Chemistry and Industry of Forest Products, 2011, 31 (3): 122- 126.
6	SILVA B G D , FILETI A M F , FOGLIO M A , et al. Supercritical carbon dioxide extraction of compounds from Schinus terebinthifolius Raddi fruits: Effects of operating conditions on global yield, volatile compounds, and antiproliferative activity against human tumor cell lines[J]. The Journal of Supercritical Fluids, 2017, 130, 10- 16. doi: 10.1016/j.supflu.2017.07.006
7	SHU H Z, ZHANG W M, YUN Y H, et al. Metabolomics study on revealing the inhibition and metabolic dysregulation in Pseudomonas fluorescens induced by 3-carene[J/OL]. Food Chemistry, 2020, 329: 127220[2021-10-15]. https://doi.org/10.1016/j.foodchem.2020.127220.
8	SMERIGLIO A , DENARO M , BARRECA D , et al. In vitro evaluation of the antioxidant, cytoprotective, and antimicrobial properties of essential oil from Pistacia vera L.Variety Bronte hull[J]. International Journal of Molecular Sciences, 2017, 18 (6): 1212- 1224.
9	HU W , ZHANG N , CHEN H L , et al. Fumigant activity of sweet orange essential oil fractions against red imported fire ants(Hymenoptera: formicidae)[J]. Journal of Economic Entomology, 2017, 110 (4): 1556- 1562.
10	ULIANA M P , FRONZA M , DA SILVA A G , et al. Composition and biological activity of Brazilian rose pepper(Schinus terebinthifolius Raddi) leaves[J]. Industrial Crops and Products, 2016, 83, 235- 240.
11	KOHOUDE M J , GBAGUIDI F , AGBANI P , et al. Chemical composition and biological activities of extracts and essential oil of Boswellia dalzielii leaves[J]. Pharmaceutical Biology, 2017, 55 (1): 33- 42. doi: 10.1080/13880209.2016.1226356
12	KELSEY R G , WESTLIND D J . Attraction of red turpentine beetle and other Scolytinae to ethanol, 3-carene or ethanol + 3-carene in an Oregon pine forest[J]. Agricultural and Forest Entomology, 2018, 20 (2): 272- 278.
13	NAIR L G , SAKSENA A , LOVEY R , et al. A facile and efficient synthesis of 3, 3-dimethyl isopropylidene proline from(+)-3-carene[J]. Journal of Organic Chemistry, 2010, 75 (4): 1285- 1288. doi: 10.1021/jo9022759
14	BURMUDZIJA A Z, MUSKINJA J M, KOSANIC M M, et al. Cytotoxic and antimicrobial activity of dehydrozingerone based cyclopropyl derivatives[J/OL]. Chemistry & Biodiversity, 2017, 14(8): e1700077[2021-10-15]. https://doi.org/10.1002/cbdv.201700077.
15	GHOSH A K , REDDY G C , KOVELA S , et al. Enantioselective synthesis of a cyclopropane derivative of spliceostatin A and evaluation of bioactivity[J]. Organic Letters, 2018, 20 (22): 7293- 7297. doi: 10.1021/acs.orglett.8b03228
16	CHANG F , DUTTA S , BECNEL J J , et al. Synthesis of the insecticide prothrin and its analogues from biomass-derived 5-(chloromethyl)furfural[J]. Journal of Agricultural and Food Chemistry, 2014, 62 (2): 476- 480. doi: 10.1021/jf4045843
17	MOUSSA B A , EL-ZAHER A A , EL-ASHREY M K , et al. Synthesis and molecular docking of new roflumilast analogues as preferential-selective potent PDE-4B inhibitors with improved pharmacokinetic profile[J]. European Journal of Medicinal Chemistry, 2018, 148, 477- 486.
18	ZHU Y Q , ZHANG J , YUAN Y W , et al. Synthesis and herbicidal activities of novel 3-(α-hydroxymethylene) pyrrolidine-2, 4-dione derivatives containing a cyclopropane moiety[J]. Journal of Heterocyclic Chemistry, 2013, 50 (2): 202- 205.
19	ISMAIL M F , MADKOUR H M F , SALEM M S , et al. Design, synthesis and insecticidal activity of new 1, 3, 4-thiadiazole and 1, 3, 4-thiadiazolo[3, 2-a] pyrimidine derivatives under solvent-free conditions[J]. Synthetic Communications, 2021, 51 (17): 2644- 2660.
20	BRAI A , RONZINI S , RIVA V , et al. Synthesis and antiviral activity of novel 1, 3, 4-thiadiazole inhibitors of DDX3X[J]. Molecules, 2019, 24 (21): 3988- 4005.
21	CHEN M , DUAN W G , LIN G S , et al. Synthesis, antifungal activity, and 3D-QSAR study of novel nopol-derived 1, 3, 4-thiadiazole-thiourea compounds[J]. Molecules, 2021, 26 (6): 1708- 1723.
22	FEI B L , TU S , WEI Z , et al. Optically pure chiral copper(Ⅱ) complexes of rosin derivative as attractive anticancer agents with potential anti-metastatic and anti-angiogenic activities[J]. European Journal of Medicinal Chemistry, 2019, 176, 175- 186.
23	XU X Y , QIAN X H , LI Z , et al. Synthesis and insecticidal activity of new substituted N-aryl-N'-benzoylthiourea compounds[J]. Journal of Fluorine Chemistry, 2003, 121 (1): 51- 54.
24	MA S J , WU L L , LIU M , et al. Asymmetric aza-Michael additions of 4-nitrophthalimide to nitroalkenes and preliminary study of the products for herbicidal activities[J]. Tetrahedron, 2013, 69 (12): 2613- 2618.
25	何云, 段文贵, 林桂汕, 等. 柠檬醛基缩氨基硫脲化合物的合成及除草活性[J]. 林产化学与工业, 2020, 40 (3): 76- 84.
	HE Y , DUAN W G , LIN G S , et al. Synthesis and herbicidal activity of citral-based thiosemicarbazone compounds[J]. Chemistry and Industry of Forest Products, 2020, 40 (3): 76- 84.
26	KECHE A P , HATNAPURE G D , TALE R H , et al. A novel pyrimidine derivatives with aryl urea, thiourea and sulfonamide moieties: Synthesis, anti-inflammatory and antimicrobial evaluation[J]. Bioorganic & Medicinal Chemistry Letters, 2012, 22 (10): 3445- 3448.
27	RAJESH S M , KUMAR R S , LIBERTSEN L A , et al. A green expedient synthesis of pyridopyrimidine-2-thiones and their antitubercular activity[J]. Bioorganic & Medicinal Chemistry Letters, 2011, 21 (10): 3012- 3016.
28	SUHAS R , CHANDRASHEKAR S , GOWDA D C . Synthesis of uriedo and thiouriedo derivatives of peptide conjugated heterocycles: A new class of promising antimicrobials[J]. European Journal of Medicinal Chemistry, 2012, 48, 179- 191.
29	HUANG M , DUAN W G , LIN G S , et al. Synthesis and antifungal activity of novel 3-caren-5-one oxime esters[J]. Molecules, 2017, 22 (9): 1538- 1552.
30	KANG G Q , DUAN W G , LIN G S , et al. Synthesis of bioactive compounds from 3-carene(Ⅱ): Synthesis, antifungal activity and 3D-QSAR study of (Z)-and(E)-3-caren-5-one oxime sulfonates[J]. Molecules, 2019, 24 (3): 477- 490.
31	HUANG M , HUANG M , WANG X , et al. Synthesis, antifungal activity and 3D-QSAR study of novel acyl thiourea compounds containing gem-dimethylcyclopropane ring[J]. Molecular Diversity, 2021, 26, 125- 136.
32	SLYVKA Y I . Structural features of CuCl and Cu₂SiF₆ π-complexes with 2-allylamino-5-phenyl-1, 3, 4-thiadiazole of the composition[CuCl(C₁₁H₁₁N₃S)] and[Cu(C₁₁H₁₁N₃S)(H₂O)(CH₃CN)]₂SiF₆·2CH₃CN[J]. Journal of Structural Chemistry, 2016, 56 (6): 1118- 1123.
33	SU N N , LI Y , YU S J , et al. Microwave-assisted synthesis of some novel 1, 2, 3-triazoles by click chemistry, and their biological activity[J]. Research on Chemical Intermediates, 2013, 39 (2): 759- 766.
34	王晓宇, 段文贵, 林桂汕, 等. (Z)-/(E)-马鞭草烯酮肟醚的合成及抑菌活性[J]. 林产化学与工业, 2019, 39 (4): 27- 34.
	WANG X Y , DUAN W G , LIN G S , et al. Synthesis and antifungal activity of(Z)-/(E)-verbenone oxime ether compounds[J]. Chemistry and Industry of Forest Products, 2019, 39 (4): 27- 34.

compounds¹⁾	inhibition rate against the tested fungi/%
compounds¹⁾	F. oxysporum f. sp. cucumerinum	C. arachidicola	P. piricola	A. solani	G. zeae	R. solani	B. myadis	C. orbicalare
8a	43.5	27.6	71.8	40.6	11.1	6.0	5.0	10.9
8b	12.5	30.8	15.4	21.4	19.4	26.8	14.3	13.6
8c	37.0	20.7	71.8	31.3	38.9	8.4	2.5	10.9
8d	41.3	10.3	5.1	21.9	33.3	10.8	5.0	8.7
8e	39.1	24.1	12.8	37.5	27.8	14.5	0	10.9
8f	47.8	10.3	20.5	21.9	38.9	2.4	7.5	8.7
8g	54.3	31.0	59.0	34.4	22.2	8.4	0	6.5
8h	26.1	41.4	10.3	43.8	0	8.4	20.0	19.6
8i	8.3	7.7	7.7	21.4	6.5	26.8	9.5	2.3
8j	12.5	30.8	15.4	21.4	6.5	35.7	9.5	4.5
8k	20.8	38.5	11.5	21.4	29.0	26.8	14.3	13.6
8l	43.5	6.9	79.5	25.0	38.9	4.8	5.0	6.5
8m	12.5	53.8	34.6	28.6	32.3	30.4	19.0	22.7
8n	43.5	27.6	51.3	34.4	33.3	2.4	12.5	8.7
8o	8.3	23.1	26.9	21.4	9.7	30.4	19.0	13.6
8p	20.8	23.1	26.9	14.3	16.1	17.9	9.5	4.5
8q	52.2	3.4	30.8	25.0	33.3	6.0	2.5	10.9
8r	12.5	53.8	19.2	35.7	19.4	58.9	14.3	13.6
8s	8.3	7.7	15.4	21.4	9.7	26.8	9.5	2.3
8t	22.5	48.5	40.8	31.4	16.5	27.9	24.3	23.6
chlorothalonil^*	100	73.3	75.0	73.9	73.1	96.1	90.4	91.3

compounds¹⁾	experimental value	predictive value	residue
8a	-2.151	-2.228	0.077
8b	-3.528	-3.504	-0.024
8c	-2.167	-2.093	-0.074
8d	-3.843	-3.744	-0.099
8e	-3.425	-3.416	-0.008
8f	-3.18	-3.203	0.023
8g	-2.42	-2.33	-0.090
8j	-3.336	-3.353	0.018
8k	-3.528	-3.560	0.033
8l	-2.053	-2.096	0.043
8m	-2.884	-2.877	-0.007
8n	-2.585	-2.603	0.018
8o	-3.042	-3.046	0.004
8q	-2.941	-2.941	0.000
8r	-3.256	-3.264	0.008
8s	-3.371	-3.449	0.078
8h^*	-3.518	-3.541	0.023
8i^*	-3.674	-3.730	0.056

[1]	王晓宇,段文贵,林桂汕,康国强,商明昊,雷福厚. (Z)-/(E)-马鞭草烯酮肟醚的合成及抑菌活性[J]. 林产化学与工业, 2019, 39(4): 27-34.
[2]	王婧, 杨学兵, 赵振东, 徐士超, 古研, 卢言菊. 3-蒈烯催化转化反应及应用研究[J]. 林产化学与工业, 2017, 37(1): 36-42.
[3]	王婧;赵振东;毕良武;李冬梅;. 松节油中主要单萜烯的异构方法综述[J]. 林产化学与工业, 2013, 33(2): 144-150.
[4]	何丽芝;赵振东;王婧;李冬梅;陈玉湘;毕良武;. 催化氢化3-蒈烯合成蒈烷反应的研究[J]. 林产化学与工业, 2012, 32(2): 107-109.
[5]	何丽芝;王婧;赵振东;陈玉湘;古研;. 3-蒈烯资源及其生物活性应用研究进展[J]. 林产化学与工业, 2011, 31(3): 122-126.
[6]	耿树香;尹晓兵;郑畹;武力. 云南3-蒈烯资源的调查研究[J]. 林产化学与工业, 2006, 26(04): 57-60.