WO2017050262A1

WO2017050262A1 - Phenanthroindolizidine alkaloid quaternary ammonium salt derivatives, and preparation thereof and application thereof in resistance to plant viruses

Info

Publication number: WO2017050262A1
Application number: PCT/CN2016/099788
Authority: WO
Inventors: 汪清民; 韩贵芳; 王兹稳; 刘玉秀
Original assignee: 南开大学
Priority date: 2015-09-25
Filing date: 2016-09-23
Publication date: 2017-03-30
Also published as: CN105130985A; CN105130985B

Abstract

The present invention relates to phenanthroindolizidine alkaloid quaternary ammonium salt derivatives, and preparation thereof and application thereof in resistance to plant viruses. The structure of the phenanthroindolizidine alkaloid quaternary ammonium salt derivatives is represented by a general formula (I). The phenanthroindolizidine alkaloid quaternary ammonium salt derivatives have good light stability, heat stability and water solubility, exhibit excellent plant virus resistance activity, and can well inhibit tobacco mosaic virus.

Description

Phenanthroquinone alkaloid quaternary ammonium salt derivative, preparation thereof and anti-plant virus application

Technical field

The invention relates to a phenanthroquinone alkaloid quaternary ammonium salt derivative, a preparation method thereof and an anti-plant virus application.

Background technique

In 1935, the first phenanthroline alkaloid, tylophorine, was isolated [Ratnagiriswaran A N, Venkatachalam K. The chemical examination of Tylophora asthmatica and isolation of the alkaloids tylophorine and tylophorinine [ J].Indian J.Med.Res., 1935, 22:433–441] has received extensive attention from chemists at home and abroad due to its unique chemical structure and remarkable biological activity. The phenanthroline alkaloids are mainly found in four families: Asclepiadaceae, Moraceae, Acanthaceae, and Lauraceae. The most important of these is the Ralcoaceae plant, in which five plants of the genus are found to contain phenanthrene and alumine alkaloids, namely: Tylophora, Cynanchum, Pergularia, Vinceto-xicum and Antitoxicum. Phenanthrene and alkaloids have been found to have a wide range of biological activities, such as anti-tumor, treatment of leukemia, antibacterial, anti-amebican activity, and thus have attracted great interest from many chemists and pharmacologists.

For the first time, the research team found that the extract of Boswellia chinensis has extremely high inhibitory activity against the highly harmful tobacco mosaic virus (TMV). Further biochemical tracking chemical separation studies showed that the main active substance of anti-TMV is phenanthrene. The ruthenium alkaloid, (R)-Antofin (1), also isolated a small amount of (R)-6-O-demethyl antofin (2), which has been reported in the literature. The activity of plant virus inhibitors is much higher. Subsequently, extensive structural modification and transformation were carried out to optimize the efficient plant virus disease control agent NK-007. Although phenanthroline alkaloids have good biological activity, they also have the disadvantages of greater central nervous system toxicity, poor water solubility, instability to light and heat, which affect their practical application.

Quaternary ammonium salts are similar in nature to inorganic salts and are readily soluble in water. Moreover, there are also quaternary ammonium salts in nature, many of which have certain biological activities. For example, choline is a component of lecithin, which is a source of variable methyl groups in the body. The reaction of synthesizing methyl group and the precursor of acetylcholine; betaine has anti-tumor, blood pressure lowering, anti-peptic ulcer and gastrointestinal dysfunction, treating liver disease; Muscarina natural alkaloid, mainly exists It has important pharmacological activities in the fungi of the genus Spirulina and the genus Coprinus; the Phyllostachys pubescens mainly exists in the plant of the genus Sinensis, which has the functions of anti-microbial, insecticidal, anti-cancer and anti-nephritis.

The quaternary ammonium salt derivatization of natural products by chemical methods has been applied to medicinal chemistry as a reasonable structural modification method, which can expand the chemical structure and biological activity diversity of natural products. The quaternary ammonium salt derivatization of phenanthroline alkaloids can increase its water solubility, and at the same time increase its molecular polarity, making it difficult to penetrate the blood-brain barrier, thereby solving the toxicity of the central nervous system. Big disadvantages. The quaternary ammonium salt also overcomes the disadvantage of hygroscopicity compared to inorganic salts. In the isolation and identification of valine, the iodomethane quaternary ammonium salt derivative was reported in the literature to identify its exact structure by degradation reaction [(a) Govindachari T R, Lakshmikantham M V, K. Nagarajan K, Pai B R. Chemical Examination of Tylophora Asthmatica-II Trtrahedron, 1958, 4, 311-324; (b) Gellert E, Govindachari T R, Lakshmikantham M V, Ragad I S, Rudzats R, Viswanath N. The Alkaloids of Tylophora crebriflora: Structure and Synthesis of Tylocrebrine , a New Phenanthroindolixidine Alkuloid. The Alkaloids of Tylophora crebriflora, 1962, 1008-1014; (c) Mulchandani N B, Venkatachalam S R. Alkaloids of Pergularia pallida. Phytochemistry, 1976, 15(10), 1561-1563. (d) Qi Hongxiang, Li Milling, Chu Xiaojun, Jiang Zhiming, Zhao Yanwei. Separation of alkaloids from Baiqian roots in North China and preparation of derivatives. Journal of Shandong Medical University, 1995, 33(2), 158-162.] The effect on the activity of the 10-position N substituent of phenanthroline alkaloid has never been studied, and the method of derivatization of 10-position N has also been reported.

Summary of the invention

It is an object of the present invention to provide phenanthroquinone alkaloid quaternary ammonium salt derivatives, processes for their preparation and their use in the control of plant viruses. The phenanthroline alkaloid quaternary ammonium salt derivative of the present invention exhibits excellent anti-plant virus activity.

The phenanthroquinone alkaloid quaternary ammonium salt derivative of the present invention has a structure represented by the following formula (I):

In the above formula:

R represents one to four hydroxyl groups, one to four 1-10 carbon alkoxy groups, one to two OCH ₂ O, one to two OCH ₂ CH ₂ O;

R ¹ represents a 2-10 carbon hydrocarbon group, a 1-10 carboxyallyl group, a 1-10 carbynyl propyl group, a cyanomethyl group, a 1-10 alkyl alkoxycarbonyl group, a 1-10 alkylcarbonyl group, and a methyl group, respectively. a -10 carbon aromatic ring carbonyl methyl group, a 1-10 carbon alkyl aminocarbonyl methyl group, a 1-10 carbon aromatic ring benzyl group, a 1-10 carbon nitrogen-containing heterocyclic benzyl group, a 1-10 carbon oxyheterocyclic benzyl group, 1-10 carbon sulfur-containing heterocyclic benzyl.

X ^- represents a halogen anion, a 1-10 carbon alkylsulfonate anion, a 1-10 carbon arylsulfonate anion, a carbonate anion, a phosphate anion, and the like, respectively.

All stereoisomers at positions 13a and 10 are included in the above formula.

The invention also provides a preparation method of a phenanthroquinone alkaloid quaternary ammonium salt derivative, which comprises the process shown by the following formula:

R ¹ and X ^- are as described above.

Preferably,

The above method may specifically include: reacting different phenanthroline acridine alkaloids with R ¹ X in a solvent such as chloroform or DMF, and then separating to obtain a quaternary ammonium salt product of a single configuration.

Preferably, the method specifically comprises: dissolving R-wartarenic or S-valine (for example, 590 mg, 1.5 mmol) in CHCl ₃ or DMF, and then adding bromide R ¹ X (for example, selected from 3-propenyl bromide, 3-bromopropyne, 1-bromo-2-butyne, bromoacetonitrile, bromoacetamide, 2-bromo-N-methylacetamide, 2-bromo-N,N-dimethyl Acetamide, benzyl bromide, p-trifluoromethylbenzyl bromide, p-trifluoromethylbenzyl bromide, 2-bromoacetophenone (for example, 3 mmol), the reaction is heated to reflux for 24-48 h, and the reaction is desolvated under reduced pressure to obtain The crude product was then pressure column chromatography (eluent, for example, _{_{CH 2 Cl 2: MeOH = 20}} : 1) to give the desired product isolated.

For other phenanthroline alkaloid quaternary ammonium salt derivatives, the preparation can be carried out by referring to the above method.

The present invention is preferably a phenanthroquinone alkaloid quaternary ammonium salt derivative (I) having the following chemical structural formula:

The compound of the formula (I) of the present invention has excellent anti-plant virus activity and can well inhibit tobacco mosaic virus, capsivirus, rice virus, tomato virus, sweet potato virus, potato virus and melon virus, and corn dwarf leaf. Viruses, etc., can effectively control viral diseases of tobacco, pepper, rice, tomato, melon, food, vegetables, beans and other crops, especially suitable for controlling tobacco mosaic disease. The phenanthroline alkaloid quaternized product of the formula (I) exhibits high activity against ex vivo anti-TMV, and also exhibits good activity against tobacco mosaic virus (TMV), part of The anti-tobacco mosaic virus activity of the quaternary ammonium salt product is significantly better than that of the commercial variety ribavirin, especially the compounds IS-1a, IS-1b, IR-1a, IR-1b, IR-2a, IS-7b, IS. Anti-tobacco mosaic virus activity of -8a, IS-8b, IR-8a, IS-10a, IS-10b, IS-11a, IS-11b, IS-12 at a concentration of 500 μg/mL and the commercial variety Ningnanmycin The activity was comparable at a concentration of 500 μg/mL; the compounds IS-1b, IS-10a, and IS-10b were significantly more active against tobacco mosaic virus at a concentration of 500 μg/mL than the parental ketone, even higher than the highly efficient plant virus. Disease control agent NK-007; wherein the optimal compound I-S-1b has an activity against tobacco mosaic virus at a concentration of 100 μg/mL comparable to that of a commercial variety ribavirin at a concentration of 500 μg/mL. To the best of our knowledge, this is also the first report that phenanthrene and azepine alkaloid quaternary ammonium salt derivatives have anti-plant virus activity.

The present invention also provides an anti-plant virus agent comprising the above phenanthroquinone alkaloid quaternary ammonium salt derivative. Wherein, the compound of the formula (I) of the present invention can be used as a plant virus inhibitor as it is, or it can be used together with an agriculturally acceptable carrier, and can also be combined with other anti-plant virus agents such as benzothiadiazole (BTH) and thiophene. Ampicillin (TDL), 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (TDLA), DL-β-aminobutyric acid (BABA), ribavirin, nymidine, phenanthrene An antibiotic composition of oxacillin alkaloids antoine, bistriazoles XY-13 and XY-30, virus A, salicylic acid, polyhydroxy bis naphthaldehyde, and amino oligosaccharides, these compositions Some performance synergies, and some performance add up.

Other features and advantages of the invention will be described in detail in the detailed description which follows.

detailed description

Specific embodiments of the present invention will be described in detail below. It is to be understood that the specific embodiments described herein are merely illustrative and not restrictive.

The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to include values that are close to the ranges or values. For numerical ranges, the endpoint values of the various ranges, the endpoint values of the various ranges and the individual point values, and the individual point values can be combined with one another to yield one or more new ranges of values. The scope should be considered as specifically disclosed herein.

In the present invention, R represents one to four hydroxyl groups, and the phenanthrene ring in which R is present may be bonded to 1-4 R groups, and the R group is a hydroxyl group; other similar expressions may be similarly understood.

In the present invention, R represents one to two OCH ₂ O, and 1-2 pairs of sites on the phenanthrene ring where R is located are bonded to each other via -OCH ₂ O-bridge; R represents one to two OCH ₂ CH ₂ O can also be similarly understood.

Example 1: Synthesis of Quaternary Ammonium Saltation Products of Phenanthroquinone Alkaloids

R-Waltokinine or S-Waltoline (590 mg, 1.5 mmol) was dissolved in CHCl ₃ and then added with methyl iodide or bromide (3-propenyl bromide, 3-bromopropyne, 1-bromo-) 2-butyne, bromoacetonitrile, bromoacetamide, 2-bromo-N-methylacetamide, 2-bromo-N,N-dimethylacetamide, benzyl bromide, p-trifluoromethylbenzyl bromide, Trifluoromethylbenzyl bromide or 2-bromoacetophenone) (3 mmol). The reaction is heated to reflux for 24 to 48 h, and the reaction is evaporated to dryness to give a crude product, which is then purified by column chromatography (CH ₂ Cl ₂ : MeOH = 20:1).

among them:

Compound IS-1a: light yellow solid, Mp: 216-217 ° C. Yield: 20%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.12 (s, 1H), 8.10 (s, 1H), 7.47 (s, 1H), 7.39 (s, 1H), 5.20 (d, J = 16.0 Hz, 1H), 4.97 (d, J = 16.0 Hz, 1H), 4.52 - 4.39 (m, 2H), 4.30 (br, 1H), 4.07(s,6H), 4.00(s,3H),3.99(s,3H),3.88–3.86(m,2H), 3.70–3.55(m,2H),3.12–3.11(m,1H) , 2.44–2.42 (m, 1H), 2.29–2.19 (m, 2H), 1.94–1.78 (m, 1H); ¹³ C (100 MHz, DMSO-d ₆ ) δ 149.5, 149.1, 149.0, 149.0, 124.2, 123.7, 123.5, 123.3, 122.6, 118.1, 104.5, 104.3, 103.6, 82.5, 72.8, 67.5, 63.1, 56.0, 55.8, 55.6, 50.5, 45.6, 28.4, 25.2, 19.7; HRMS (ESI) calcd for C ₂₇ H ₃₀ NO ₄ ⁺ [M-Br ^- ]432.2169, found 432.2178.

Compound IR-1a: pale yellow solid, Mp 212-214 ℃ ^{Yield:.. 22% 1 H NMR} , 13 C NMR, and HRMS (ESI) IS-1a with the same compound.

Compound IS-1b: pale yellow solid. Mp: 237-239 ° C. Yield: 43%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.12 (s, 1H), 8.10 (s, 1H), 7.39 (s, 1H), 7.30 (s, 1H), 5.51 (d, J = 16.0 Hz, 1H), 4.97 (d, J = 16.0 Hz, 1H), 4.34 - 4.32 (m, 3H), 4.19 (br, 1H), 4.06 (s, 6H), 3.98 (s, 6H), 3.88 - 3.64 (m, 2H), 3.35 - 3.26 (m, 2H), 2.50 (br, 1H), 2.35 - 2.24 (m, 2H) , 2.20–2.10 (m, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 149.4, 149.2, 149.1, 148.9, 123.9, 123.9, 123.8, 123.6, 122.5, 118.4, 104.5, 104.5, 104.1, 103.2, 83.1 , 72.3, 68.9, 61.8, 58.7, 56.0, 55.6, 41.7, 26.2, 25.3, 18.6; HRMS (ESI) calcd for C ₂₈ H ₃₂ NO ₄ ⁺ [M-Br ^- ] 446.2326, found 446.2333.

Compound IR-1b: pale yellow solid, Mp: 235-238 ° C. Yield: 40%. ¹ H NMR, ¹³ C NMR, and HRMS (ESI) identical to compound IS-1b.

Compound IS-2 ^a : White solid. Mp: 220-224 ° C. Yield: 24%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.16 (s, 1H), 8.14 (s, 1H), 7.51 ( s,1H), 7.45(s,1H), 5.26(d,J=16.0Hz,1H),5.03(d,J=16.0Hz,1H), 4.53–4.29(m,3H),4.11(s,6H ), 4.05 (s, 3H), 4.03 (s, 3H), 3.96 - 3.78 (m, 2H), 3.65 (br, 2H), 2.50 - 2.40 (m, 1H), 2.31 - 2.22 (m, 2H), 2.00 (s, 3H), 1.94 - 1.80 (m, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 149.9, 149.5, 149.5, 149.4, 124.6, 124.1, 124.0, 123.7, 123.1, 118.8, 105.0, 104.7 , 104.1, 88.6, 68.7, 67.3, 63.2, 56.5, 56.5, 56.4, 56.1, 55.4, 53.6, 51.6, 28.9, 25.7, 20.1, 3.9; HRMS (ESI) calcd for C ₂₈ H ₃₂ NO ₄ ⁺ [M-Br ^- ] 446.2326, found 446.2331.

Compound IR-2a: white solid, Mp: 222-223 ° C. Yield: 22%. ¹ H NMR, ¹³ C NMR, and HRMS (ESI) identical to compound IS-2a.

Compound IS-2b: White solid. Mp: 240-242 ° C. Yield: 24%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.16 (s, 1H), 8.14 (s, 1H), 7.43 (s) , 1H), 7.34 (s, 1H), 5.57 (d, J = 16.0 Hz, 1H), 4.99 (d, J = 16.0 Hz, 1H), 4.38 - 4.35 (m, 4H), 4.12 (s, 6H) , 4.04 (s, 3H), 4.03 (s, 3H), 3.88 - 3.60 (m, 2H), 3.40 - 3.26 (m, 1H), 2.50 (br, 1H), 2.34 - 2.24 (m, 2H), 2.20 –2.10(m,1H), 1.98(s,3H); ¹³ C NMR (100MHz, DMSO-d ₆ ) δ 149.4, 149.1, 149.0, 148.8, 123.8, 123.8, 123.7, 123.6, 122.5, 118.5, 104.5, 104.0, 103.3, 88.7, 68.6, 67.5, 61.4, 58.5, 56.0, 56.0, 55.6, 55.0, 42.2, 26.2, 25.3, 18.6, 3.4; HRMS (ESI) calcd for C ₂₇ H ₃₀ NO ₄ ⁺ [M-Br ^- ] 432.2169 , found 432.2177.

Compound IR-2b: white solid, Mp: 240-243 ° C. Yield: 30%. ¹ H NMR, ¹³ C NMR, and HRMS (ESI) identical to compound IS-2b.

Compound IS-3a: pale yellow solid. Mp: 212-215 ° C. Yield: 45%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.11 (s, 1H), 8.10 (s, 1H), 7.49 ( s, 1H), 7.44 (s, 1H), 5.32 (d, J = 16.0 Hz, 1H), 5.15 (d, J = 16.0 Hz, 1H), 5.07 (s, 2H), 4.40 - 4.38 (m, 1H) ), 4.07 (s, 6H), 4.02 (s, 3H), 4.00 (s, 3H), 3.74 - 3.63 (m, 2H), 2.48 - 2.45 (m, 1H), 2.31 - 2.27 (m, 2H), 1.94–1.84 (m, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 149.6, 149.1, 149.0, 149.0, 124.4, 123.7, 123.5, 123.4, 122.5, 117.8, 112.5, 104.5, 104.3, 103.6, 69.7, 65.0, 56.0, 55.9, 55.6, 55.0, 48.7, 28.6, 25.3, 20.1. HRMS (ESI) calcd for C ₂₆ H ₂₉ N ₂ O ₄ ⁺ [M-Br ^- ] 433.2122, found 433.2127.

Compound IR-3a: pale yellow solid, Mp: 212-214 ° C. Yield: 44%. ¹ H NMR, ¹³ C NMR, and HRMS (ESI) identical to compound IS-3a.

Compound IS-3b: pale yellow solid, Mp: 217-219 ° C. Yield: 28%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.10 (s, 1H), 8.06 (s, 1H), 7.37 ( s, 1H), 7.31 (s, 1H), 5.54 (d, J = 16.0 Hz, 1H), 5.21 (d, J = 16.0 Hz, 1H), 4.98 (d, J = 16.8 Hz, 1H), 4.81 ( d, J = 16.8 Hz, 1H), 4.44 - 4.36 (m, 1H), 4.29 - 4.22 (m, 1H), 4.06 (s, 3H), 4.05 (s, 3H), 4.00 (s, 3H), 3.98 (s, 3H), 4.01–3.95 (m, 1H), 3.88–3.83 (m, 1H), 3.24–3.19 (m, 1H), 2.58–2.55 (m, 1H), 2.43–2.31 (m, 2H) , 2.23–2.13 (m, 1H). ¹³ C NMR (100MHz, DMSO-d ₆ ) δ 149.5, 149.2, 149.0, 148.9, 124.0, 123.9, 123.7, 123.3, 122.4, 118.1, 112.5, 104.5, 104.1, 103.4, 70.5 , 64.1, 60.8, 56.0, 55.6, 41.1, 26.2, 25.1, 18.8. HRMS (ESI) calcd for C ₂₆ H ₂₉ N ₂ O ₄ ⁺ [M-Br ^- ] 433.2122, found 433.2127.

Compound IR-3b: pale yellow solid Mp: 216-220 ° C. Yield: 30%. ¹ H NMR, ¹³ C NMR, and HRMS (ESI) identical to compound IS-3b.

Compound IS-4a: white solid, Mp: 173-175 ° C. Yield: 47%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.10 (s, 1H), 8.09 (s, 1H), 7. , 1H), 7.34 (s, 1H), 5.28 (d, J = 16.0 Hz, 1H), 5.07 (d, J = 16.0 Hz, 1H), 4.57 - 4.43 (m, 3H), 4.19 (q, J = 6.8 Hz, 2H), 4.06 (s, 3H), 4.06 (s, 3H), 3.99 (s, 3H), 3.98 (s, 3H), 3.99 - 3.98 (m, 2H), 3.74 - 3.68 (m, 1H) ), 2.43–2.38 (m, 1H), 2.27–2.14 (m, 2H), 1.80–1.68 (m, 1H), 1.19 (t, J = 6.8 Hz, 3H). ¹³ C NMR (100 MHz, DMSO-d) ₆ ) δ165.3, 149.5, 149.1, 149.0, 124.2, 123.7, 123.6, 123.5, 122.7, 118.3, 104.5, 104.2, 103.4, 69.8, 64.0, 62.0, 59.4, 56.0, 55.8, 55.6, 53.4, 28.2, 25.3, 20.0, 13.7. HRMS (ESI) calcd for C ₂₈ H ₃₄ NO ₆ ⁺ [M-Br ^- ] 480.2381, found 480.2384.

Compound IR-4a: white solid, Mp: 175-176 ° C. Yield: 42%. ¹ H NMR, ¹³ C NMR, and HRMS (ESI) identical to compound IS-4a.

Compound IS-4b: White solid. Mp: 174-177 ° C. Yield: 40%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.86 (s, 1H), 7.84 (s, 1H), 7.13 (s) , 1H), 6.95 (s, 1H), 5.52 (d, J = 17.2 Hz, 1H), 4.86 (d, J = 16.0 Hz, 1H), 4.30 - 4.27 (m, 1H), 4.05 - 3.99 (m, 2H), 3.90 (q, J = 7.2 Hz, 2H), 3.90 - 3.78 (m, 7H), 3.75 - 3.73 (m, 7H), 3.66 - 3.44 (m, 2H), 2.28 (br, 1H), 2.13 -1.91 (m, 3H), 0.86 (t, J = 7.2 Hz, 3H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 165.1, 149.4, 149.1, 148.9, 148.8, 123.9, 123.7, 123.4, 122.5, 118.6 , 104.5, 104.1, 103.1, 71.8, 62.5, 62.1, 59.4, 56.0, 55.9, 55.6, 48.9, 26.2, 24.9, 18.8, 13.6. HRMS (ESI) calcd for C ₂₈ H ₃₄ NO ₆ ⁺ [M-Br ^- ] 480.2381, found 480.2387.

Compound IR-4b: white solid. Mp: 169-171 ° C. Yield: 46%. ¹ H NMR, ¹³ C NMR, and HRMS (ESI) identical to compound IS-4b.

Compound IS-5 ^a : pale yellow solid. Mp: 211-215 ° C. Yield: 40%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.11 (s, 1H), 8.10 (s, 1H), 7.83 (s, 1H), 7.71 (s, 1H), 7.46 (s, 1H), 7.31 (s, 1H), 5.38 (d, J = 16.4 Hz, 1H), 4.90 (d, J = 16.4 Hz, 1H) , 4.30 (br, 1H), 4.17 - 4.12 (m, 10H), 3.98 (s, 3H), 3.97 (s, 6H), 3.68 - 3.56 (m, 2H), 2.45 - 2.39 (m, 1H), 2.28 -2.19 (m, 2H), 1.88 - 1.78 (m, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 165.6, 149.5, 149.1, 149.0, 148.9, 124.2, 123.7, 123.53, 122.8, 122.6, 118.2, 104.5, 104.3, 103.4, 68.8, 63.6, 59.1, 56.0, 55.7, 55.6, 53.3, 27.7, 25.3, 19.7. HRMS (ESI) calcd for C ₂₆ H ₃₁ N ₂ O ₅ ⁺ [M-Br ^- ] 451.2227, found 451.2236.

Compound IR-5a: pale yellow solid, Mp: 211-213 ° C. Yield: 40%. ¹ H NMR, ¹³ C NMR, and HRMS (ESI) identical to compound IS-5a.

Compound IS-5b: pale yellow solid. Mp: 228-231 ° C. Yield: 37.5%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.10 (s, 1H), 8.08 (s, 1H), 7.87 ( s, 1H), 7.72 (s, 1H), 7.41 (s, 1H), 7.16 (s, 1H), 5.96 (d, J = 16.0 Hz, 1H), 4.96 (d, J = 16.0 Hz, 1H), 4.57(br,1H), 4.23–4.15(m,1H), 4.06(s,6H),3.98(s,3H),3.95(s,3H),3.98–3.95(m,1H),3.81–3.69 ( m,3H), 3.24–3.16 (m, 1H), 2.57–2.53 (m, 1H), 2.35–2.28 (m, 2H), 2.14–2.03 (m, 1H). ¹³ C NMR (100 MHz, DMSO-d) ₆ ) δ165.6, 149.4, 149.1, 148.9, 148.9, 123.9, 123.9, 123.8, 123.4, 122.5, 118.8, 104.5, 104.4, 104.1, 103.0, 71.1, 62.2, 59.1, 56.0, 55.8, 55.6, 48.6, 26.6, 25.3, 18.8. HRMS (ESI) calcd for C ₂₆ H ₃₁ N ₂ O ₅ ⁺ [M-Br ^- ] 451.2227, found 451.2231.

Compound IR-5b: pale yellow solid, Mp: 230-232 ° C. Yield: 39%. ¹ H NMR, ¹³ C NMR, and HRMS (ESI) identical to compound IS-5b.

Compound IS-6a: yellow solid. Mp 205-209 ° C. yield: 35%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.48 (d, J = 4.4 Hz, 1H), 8.10 (s, 1H) , 8.09 (s, 1H), 7.46 (s, 1H), 7.33 (s, 1H), 5.42 (d, J = 16.0 Hz, 1H), 4.94 (d, J = 16.0 Hz, 1H), 4.21 (br, 1H), 4.24–4.14 (m, 3H), 4.06 (s, 6H), 3.99 (s, 3H), 3.98 (s, 3H), 3.69–3.56 (m, 2H), 2.62 (d, J = 4.4 Hz) , 3H), 2.45 - 2.38 (m, 1H), 2.28 - 2.19 (m, 2H), 1.87 - 1.81 (m, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 163.8, 149.5, 149.1, 148.9, 148.9, 124.2, 123.7, 123.5, 122.7, 122.6, 118.2, 104.5, 104.3, 103.5, 68.7, 63.6, 59.5, 56.0, 55.8, 55.6, 53.5, 27.8, 25.5, 25.2, 19.6. HRMS (ESI) calcd for C ₂₇ H ₃₃ N ₂ O ₅ ⁺ [M-Br ^- ] 465.2384, found 465.2378.

Compound IR-6a: yellow solid, Mp: 217-219 ° C. Yield: 33%. ¹ H NMR, ¹³ C NMR, and HRMS (ESI) identical to compound IS-6a.

Compound IS-6b: White solid. Mp: 232-234 ° C. Yield: 35%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.50 (d, J = 4.4 Hz, 1H), 8.10 (s, 1H) ), 8.09 (s, 1H), 7.41 (s, 1H), 7.18 (s, 1H), 6.00 (d, J = 15.6 Hz, 1H), 4.95 (d, J = 15.6 Hz, 1H), 4.49 - 4.11 (m, 1H), 4.24–4.14 (m, 1H), 4.06 (s, 6H), 3.99 (s, 3H), 3.96 (s, 3H), 3.81–3.67 (m, 3H), 3.25–3.18 (m) , 1H), 2.58 (d, J = 4.4 Hz, 3H), 2.58 (m, 1H), 2.33 - 2.25 (m, 2H), 2.13 - 2.01 (m, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ163.8, 149.4, 149.1, 149.0, 148.9, 123.9, 123.9, 123.8, 123.5, 122.6, 118.8, 104.5, 104.4, 104.2, 103.0, 71.0, 62.1, 59.2, 56.0, 55.8, 55.6, 49.1, 26.5, 25.6, 25.3, 18.8. HRMS (ESI) calcd for C ₂₇ H ₃₃ N ₂ O ₅ ⁺ [M-Br ^- ] 465.2384, found 465.2388.

Compound IR-6b: white solid. Mp: 232-235 ° C. Yield: 38%. ¹ H NMR, ¹³ C NMR, and HRMS (ESI) identical to compound IS-6b.

Compound IS-7a: yellow solid. Mp: 190-194 ° C. Yield: 23.3%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.09 (s, 1H), 8.08 (s, 1H), 7. ,1H), 7.27(s,1H),5.53(d,J=16.0Hz,1H),5.02(d,J=16.0Hz,1H),4.62–4.57(m,2H),4.53(br,1H) , 4.05 (s, 6H), 3.98 (s, 3H), 3.97 (s, 3H), 4.00 - 3.97 (m, 1H), 3.89 - 3.65 (m, 3H), 2.87 (s, 3H), 2.86 (s , 3H), 2.37 - 2.35 (m, 1H), 2.20 - 2.16 (m, 2H), 1.78 - 1.70 (m, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 164.1, 149.4, 149.0, 148.9, 124.1, 123.7, 123.6, 123.4, 122.7, 118.5, 104.5, 104.2, 103.2, 70.1, 63.8, 59.2, 56.0, 55.7, 55.6, 52.6, 36.1, 35.2, 27.8, 25.3, 19.8. HRMS (ESI) calcd for C ₂₈ H ₃₅ N ₂ O ₅ ⁺ [M-Br ^- ] 479.2540, found 479.2541.

Compound IR-7a: yellow solid. Mp: 191-193 ° C. Yield: 25%. ¹ H NMR, ¹³ C NMR, and HRMS (ESI) identical to compound IS-7a.

Compound IS-7b: pale yellow solid. Mp: 195-197 ° C. Yield: 40%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.07 (s, 1H), 8.03 (s, 1H), 7.36 ( s, 1H), 7.09 (s, 1H), 6.09 (d, J = 16.0 Hz, 1H), 5.00 (d, J = 16.0 Hz, 1H), 4.66 (br, 1H), 4.16 - 4.12 (m, 3H) ), 4.05 (s, 6H), 4.02 (s, 6H), 3.98 (s, 3H), 3.95 (s, 3H), 3.69 - 3.51 (m, 2H), 3.51 - 3.49 (m, 1H), 2.78 ( s, 6H), 2.51 (br, 1H), 2.27 (br, 3H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 163.4, 149.3, 149.1, 148.9, 148.8, 123.9, 123.8, 123.6, 122.5, 118.7, 104.5, 104.0, 102.8, 72.0, 62.7, 59.4, 56.0, 55.8, 55.5, 47.2, 36.4, 35.4, 26.1, 24.9, 18.7. HRMS (ESI) calcd for C ₂₈ H ₃₅ N ₂ O ₅ ⁺ [M-Br ^- ]479.2540, found479.2540.

Compound IR-7b: pale yellow solid. Mp: 197-199 ° C. Yield: 40%. ¹ H NMR, ¹³ C NMR, and HRMS (ESI) identical to compound IS-7b.

Compound IS-8a: light yellow solid. Mp: 175-178 ° C. Yield: 35.6%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.14 (s, 1H), 8.13 (s, 1H), 7.85 ( d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.45 (s, 1H), 7.17 (s, 1H), 4.87 (d, J = 17.2 Hz, 1H), 4.71 ( s, 2H), 4.60 (d, J = 17.2 Hz, 1H), 4.36 - 4.30 (m, 1H), 4.08 (s, 6H), 4.06 - 3.97 (m, 4H), 4.89 (s, 3H), 3.82 -3.67 (m, 3H), 2.51 - 2.50 (m, 1H), 2.20 (br, 2H), 2.02 - 1.97 (m, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 149.5, 149.1, 149.0, 148.9, 133.5, 133.0, 130.5 (q, J = 31.8 Hz), 125.8, 125.8, 124.1, 123.9 (q, J = 271.0 Hz), 123.9, 123.8, 122.2, 121.2, 117.0, 104.6, 104.3, 103.4, 66.6, 61.5, 60.8, 56.1, 56.1, 55.7, 55.6, 50.2, 27.2, 24.3, 18.1. HRMS (ESI) calcd for C ₃₂ H ₃₃ F ₃ NO ₄ ⁺ [M-Br ^- ] 552.2356, found 552.2363.

Compound IR-8a: pale yellow solid. Mp: 174-176 ° C. Yield: 35.6%. ¹ H NMR, ¹³ C NMR, and HRMS (ESI) identical to compound IS-8a.

Compound IS-8b: white solid. Mp: 181-183 ° C. Yield: 53.3%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.13 (s, 1H), 8.11 (s, 1H), 7.79 (d) , J=8.0Hz, 2H), 7.44(s,1H), 7.32(d, J=8.0Hz, 2H), 7.10(s,1H), 5.13(d,J=16.4Hz,1H), 4.60(d , J = 16.4 Hz, 1H), 4.49 (d, J = 13.2 Hz, 1H), 4.36 (d, J = 13.2 Hz, 1H), 4.32 - 4.31 (m, 1H), 4.09 (s, 3H), 4.09 (s, 3H), 4.00 (s, 3H), 3.94 - 3.89 (m, 1H), 3.84 - 3.82 (m, 4H), 3.55 - 3.46 (m, 2H), 2.70 - 2.53 (m, 2H), 2.40 -2.25 (m, 2H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 149.5, 149.2, 149.2, 148.9, 133.8, 132.3, 130.4 (q, J = 31.8 Hz), 125.8, 125.7, 124.1, 124.1, 124.0 , 123.9, 123.8 (q, J = 270.7 Hz), 122.2, 118.5, 104.6, 104.5, 104.2, 103.0, 70.4, 59.6, 57.2, 56.1, 56.0, 55.9, 55.6, 50.9, 26.5, 25.4, 18.6. HRMS (ESI) Calcd for C ₃₂ H ₃₃ F ₃ NO ₄ ⁺ [M-Br ^- ] 552.2356, found 552.2367.

Compound IR-8b: white solid. Mp: 183-184 ° C. Yield: 53.3%. ¹ H NMR, ¹³ C NMR, and HRMS (ESI) identical to compound IS-8b.

Compound IS-9a: white solid. Mp: 179-180 ° C. Yield: 33%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.08 (s, 2H), 8.02 (d, J = 7.6 Hz, 2H ), 7.70 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.50 (s, 1H), 7.27 (s, 1H), 5.42 (s, 2H), 5.34 (d) , J = 16.0 Hz, 1H), 5.13 (d, J = 16.0 Hz, 1H), 4.56 - 4.48 (m, 1H), 4.19 - 4.13 (m, 1H), 4.06 (s, 3H), 4.03 (s, 3H), 4.00 (s, 3H), 3.97 (s, 3H), 3.95 - 3.86 (m, 2H), 3.69 (d, J = 16.8 Hz, 1H), 2.43 - 2.36 (m, 1H), 2.25 - 2.20 (m, 2H), 1.80 - 1.70 (m, 1H). ¹³ C NMR (100MHz, DMSO-d ₆ ) δ 191.8, 149.4, 149.0, 148.9, 148.9, 134.5, 134.3, 128.7, 128.2, 124.1, 123.8, 123.6, 123.2, 122.8, 118.6, 104.5, 104.3, 103.4, 70.4, 64.5, 63.9, 56.0, 55.7, 55.6, 53.0, 27.7, 25.0, 20.0. HRMS (ESI) calcd for C ₃₂ H ₃₄ NO ₅ ⁺ [M-Br ^- ] 512.2431, found 512.2435.

Compound IR-9a: white solid. Mp: 175-178 ° C. Yield: 33%. ¹ H NMR, ¹³ C NMR, and HRMS (ESI) identical to compound IS-9a.

Compound IS-9b: white solid. Mp: 182-183 ° C. Yield: 42%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.04 - 8.01 (m, 4H), 7.63 (t, J = 7.2 Hz , 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.39 (s, 1H), 7.12 (s, 1H), 5.89 (d, J = 16.0 Hz, 1H), 5.16 (d, J = 16.0 Hz) , 1H), 5.05 (d, J = 18.0 Hz, 1H), 4.82 (d, J = 18.0 Hz, 1H), 4.68 - 4.64 (m, 1H), 4.20 - 4.16 (m, 1H), 4.03 (s, 3H), 4.02 (s, 3H), 4.01 (s, 3H), 3.97 (s, 3H), 3.92 - 3.89 (m, 1H), 3.77 - 3.64 (m, 2H), 2.42 - 2.27 (m, 4H) ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 191.5, 149.3, 149.0, 148.8, 148.7, 134.5, 134.4, 128.5, 128.4, 123.9, 123.8, 123.5, 122.6, 118.9, 104.6, 104.5, 104.0, 103.0, 72.6, 62.8, 59.7, 56.0, 55.8, 55.5, 52.5, 26.0, 24.8, 18.9. HRMS (ESI) calcd for C ₃₂ H ₃₄ NO ₅ ⁺ [M-Br ^- ] 512.2431, found 512.2435.

Compound IR-9b: white solid. Mp: 180-181 ° C. Yield: 40%. ¹ H NMR, ¹³ C NMR, and HRMS (ESI) identical to compound IS-9b.

Compound IS-10a: White solid. Mp: 185-188 ° C. Yield: 35%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (s, 2H), 7.36 (br, 4H), 7.28 (s, 1H) ), 7.22 (s, 1H), 5.22–5.15 (m, 2H), 5.04–5.00 (m, 1H), 4.71–4.64 (m, 2H), 4.61–4.53 (m, 1H), 4.16 (s, 3H) ), 4.15 (s, 3H), 4.09 (s, 3H), 4.08 (s, 3H), 3.86 - 3.68 (m, 2H), 3.54 (d, J = 18 Hz, 1H), 2.57 - 2.50 (m, 1H) ), 2.36–2.26 (m, 1H), 2.22–2.11 (m, 1H), 1.96–1.85 (m, 1H), 1.28 (s, 9H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.2, 149.9, 149.8 , 149.6, 149.5, 132.5, 126.2, 124.7, 124.3, 123.9, 122.7, 121.1, 117.1, 103.6, 103.6, 103.5, 103.0, 65.8, 62.2, 61.7, 56.9, 56.2, 56.2, 56.1, 51.1, 34.8, 31.1, 28.2 , 25.4, 18.8. HRMS (ESI) calcd for C ₃₅ H ₄₂ NO4 ⁺ [M-Br ^- ] 540.3108, found 540.3108.

Compound IS-10b: White solid. Mp: 193-197 ° C. Yield: 45% ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (s, 1H), 7.86 (s, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.09 (s, 1H), 6.98 (s, 1H), 6.82 (d, J = 8.4 Hz, 2H), 5.35 (d, J = 15.2 Hz, 1H), 4.94 (d, J = 15.2 Hz, 1H), 4.43 (br, 1H), 4.35 - 4.25 (m, 1H), 4.20 (s, 3H), 4.19 (s, 3H), 4.09 - 4.05 (m, 4H), 4.01 - 3.97 (m , 4H), 3.94–3.87 (m, 1H), 3.52–3.44 (m, 1H), 3.33–3.21 (m, 1H), 2.70 (br, 1H), 2.56 (br, 1H), 2.45–2.22 (m) , 2H), 1.77(s, 9H). ¹³ C NMR (100MHz, CDCl ₃ ) δ 154.5, 149.9, 149.6, 149.5, 149.4, 132.2, 126.4, 124.4, 124.3, 123.9, 123.3, 123.2, 122.4, 118.3, 103.7, 103.3, 102.7, 70.1, 59.0, 57.5, 56.7, 56.4, 56.2, 52.0, 34.8, 31.0, 27.5, 26.3, 19.1. HRMS (ESI) calcd for C ₃₅ H ₄₂ NO4 ⁺ [M-Br ^- ] 540.3108, found 540.3110 .

Compound IS-11a: White solid. Mp: 178-181 ° C. Yield: 30%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (s, 2H), 7.49 (d, J = 7.2 Hz, 2H), 7.45 (t, J = 7.2 Hz, 1H), 7.37 (t, J = 7.2 Hz, 2H), 7.28 (s, 1H), 7.22 (s, 1H), 5.30 (d, J = 12.8 Hz, 1H), 5.15 (d, J = 16.0 Hz, 1H), 5.07 - 4.96 (m, 1H), 4.77 - 4.67 (m, 2H), 4.61 (dd, J = 19.6, 9.6 Hz, 1H), 4.16 (s, 3H) , 4.14 (s, 3H), 4.09 (s, 3H), 4.07 (s, 3H), 3.75 (dd, J = 18.0, 6.8 Hz, 2H), 3.55 (d, J = 18.0 Hz, 1H), 2.62 - 2.43 (m, 1H), 2.32 - 2.24 (m, 1H), 2.19 - 2.15 (m, 1H), 1.93 - 1.83 (m, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 149.9, 149.7, 149.5, 149.5 , 132.8, 130.7, 129.3, 127.9, 124.7, 124.2, 123.8, 122.7, 121.3, 117.1, 103.6, 103.5, 103.4, 103.0, 66.2, 62.3, 61.7, 57.0, 56.2, 56.2, 56.1, 51.3, 28.2, 25.5, 18.9 .HRMS (ESI) calcd for C ₃₁ H ₃₄ NO ₄ ⁺ [M-Br ^- ] 484.2482, found 484.2480.

Compound IS-11b: White solid. Mp: 192-194 ° C. Yield: 58%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.88 (s, 1H), 7.86 (s, 1H), 7.42 (t, J) = 7.4 Hz, 1H), 7.30 (t, J = 7.7 Hz, 2H), 7.11 (s, 1H), 6.96 (s, 1H), 6.92 (d, J = 7.3 Hz, 2H), 5.38 (d, J) =16.0 Hz, 1H), 4.96 (d, J = 16.0 Hz, 1H), 4.65 - 4.52 (m, 1H), 4.36 (dd, J = 20.4, 10.0 Hz, 1H), 4.19 (s, 3H), 4.19 (s, 3H), 4.14–4.03 (m, 5H), 3.98 (s, 3H), 3.94–3.86 (m, 1H), 3.53 (dd, J=17.5, 4.8 Hz, 1H), 3.29 (dd, J = 17.4, 12.1 Hz, 1H), 2.78 - 2.68 (m, 1H), 2.64 - 2.53 (m, 1H), 2.43 - 2.26 (m, 2H). HRMS (ESI) calcd for C ₃₁ H ₃₄ NO ₄ ⁺ [ M-Br ^- ] 484.2482, found 484.2486.

Compound IS-12: pale yellow solid. Mp: 200-204 ° C. Yield: 60%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.10 (s, 1H), 8.09 (s, 1H), 7.40 ( d, J = 8.0 Hz, 2H), 7.25 (s, 1H), 6.23 - 6.13 (m, 1H), 5.53 (d, J = 11.2 Hz, 1H), 5.41 - 5.36 (m, 1H), 4.79 (d , J = 16.0 Hz, 1H), 4.26 - 4.14 (m, 1H), 4.12 - 4.08 (m, 1H), 4.06 (m, 1H), 4.06 (s, 3H), 3.98 (s, 3H), 3.97 ( s, 3H), 3.87–3.79 (m, 2H), 3.76–3.68 (m, 2H), 3.58–3.50 (m, 1H), 2.53–2.50 (m, 1H), 2.29–2.14 (m, 3H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 149.4, 149.1, 149.0, 148.9, 127.0, 125.9, 123.9, 123.8, 123.8, 122.5, 118.8, 104.5, 104.2, 103.4, 69.4, 60.2, 57.7, 56.0, 56.0, 55.9 , 55.6, 51.6, 26.2, 25.2, 18.5. HRMS (ESI) calcd for C ₂₇ H ₃₂ NO ₄ ⁺ [M-Br ^- ] 434.2326, found 434.2328.

Example 2: Physicochemical properties of phenanthroline alkaloid quaternary ammonium salt derivatives

The above preferred phenanthroquinone alkaloid quaternary ammonium salt derivatives IS-1a, IS-1b, IR-1a, IR-1b, IR-2a, IS-7b, IS-8a, IS-8b, IR- 8a, IS-10a, IS-10b, IS-11a, IS-11b, IS-12 compared to the respective control sample (R) / (S) - valine, these preferred compounds are compared to known compounds It has outstanding advantages, which are manifested in: (1) chemical stability is obviously enhanced. Under the same conditions, room temperature or sunlight irradiation is equivalent, the metamorphic speed is obviously slower than them; (2) water solubility is obviously enhanced, (R)/(S) - Wakagic acid is insoluble in water, and the water solubility of the above quaternary ammonium salt derivatives is more than 5 mg/mL; the above two points have a crucial effect on the application of the compound to pesticides.

Example 3: Determination of anti-tobacco mosaic virus activity, the assay procedure is as follows:

1. Virus purification and concentration determination:

Viral purification and concentration determination were carried out in accordance with the SOP specification for the preparation of tobacco mosaic virus in the laboratory of the elemental laboratory of Nankai University. After the crude virus extract was centrifuged twice with polyethylene glycol, the concentration was measured and stored at 4 ° C for use.

2. Compound solution preparation:

After weighing, the original drug was dissolved in DMF to prepare 1×10 ⁵ μg/mL mother liquor, and then diluted to the desired concentration with a solution containing 1 Torr Tween 80; the Ningnanmycin preparation was directly diluted with water.

3, in vitro role:

The leaves of the appropriate age of Sanxi smoke were rubbed and washed with running water at a virus concentration of 10 μg/mL. Cut it out and cut it along the midrib of the leaf. The left and right half leaves are immersed in 1 ‰ Tween water and the drug. After 30 minutes, they are taken out and moisturized at a suitable light temperature. Each 3 leaves is repeated once, repeating 3 times. . After 3 days, the number of lesions was recorded and the control effect was calculated.

4, the role of living protection:

The 3-5 leaf stage Shanxi smoke with uniform growth was selected, and the whole plant was sprayed, and each treatment was repeated 3 times, and 1 ‰Tween 80 aqueous solution was set. After 24 hours, the leaf surface was sprinkled with emery (500 mesh), and the virus solution was extracted with a brush. The whole leaf surface was gently rubbed twice along the direction of the branch vein, and the leaf was supported by the palm of the hand. The virus concentration was 10 μg/mL, and it was washed with running water after inoculation. After 3 days, the number of lesions was recorded and the control effect was calculated.

5, the role of living body treatment:

Select the 3-5 leaf stage Shanxi smoke with uniform growth, and inoculate the virus with the whole leaf of the brush, the virus concentration is 10μg/mL. Rinse with running water after inoculation. After the leaves were dried, the whole plant was sprayed, and each treatment was repeated 3 times, and 1 ‰Tween 80 aqueous solution was set. After 3 days, the number of lesions was recorded and the control effect was calculated.

6, living body passivation:

Select a uniform 3-5 leaf stage Shanxi smoke, mix the agent with an equal volume of virus juice for 30 minutes, rub the inoculation, the virus concentration is 20μg/mL, rinse with running water after inoculation, repeat 3 times, set 1 ‰Tween 80 aqueous solution control. After 3 days, the number of lesions was counted and the results were calculated.

Inhibition rate (%) = [(control number of spots - number of treated spots) / number of control spots] × 100%

Table 1 Test results of anti-TMV activity of quaternary ammonium salt of phenanthroline and alkaloids:

As can be seen from Table 1, the phenanthroline quaternary ammonium salt derivative exhibits high activity against tobacco mosaic virus (TMV), and most of the compounds exhibit excellent resistance to tobacco mosaic virus (TMV). ) In vivo activity, most of the phenanthroquinone quaternary ammonium salt derivatives are significantly more active against tobacco mosaic virus than the commercial varieties ribavirin, especially the compounds IS-1a, IS-1b, IR-1a, IR. -1b, IR-2a, IS-7b, IS-8a, IS-8b, IR-8a, IS-10a, IS-10b, IS-11a, IS-11b, IS-12 resistant to tobacco at a concentration of 100 μg/mL The activity of mosaic virus was similar to that of the commercial variety Ningnanmycin at 100μg/mL. The anti-tobacco mosaic virus activity of compounds IS-1b, IS-10a and IS-10b was significantly higher than that of the parent at 500μg/mL. Was vines, even higher than efficient plants The virus disease control agent NK-007; wherein the optimal compound I-S-1b has an activity against tobacco mosaic virus at a concentration of 100 μg/mL and the activity of the commercially available variety ribavirin at a concentration of 500 μg/mL, and has great development value.

Example 4: Field efficacy test of NK117 (I-S-1b) against tobacco virus disease

1 Selection of test subjects, crops and varieties

Test subject: Tobacco virus disease

Test crop: Tobacco (variety name: Yunyan 85)

2 environmental conditions

The test site is located in Xikanghe Village, Jietou Town, Tengchong County, Yunnan Province. The test site is a sloping land. The former is used as rapeseed. About 1,500 plants per acre are cultivated. The cultivation and management conditions are good, and tobacco virus disease has occurred, which is suitable for the experiment.

3 agents and control agents

The test agent NK117 (I-S-1b) was supplied by the Institute of Elemental Organic Chemistry of Nankai University.

Control agent: 20% virus A wettable powder, amino oligosaccharide 5% AS.

4 pharmacodynamic calculation method

Disease index%=[Σ(number of diseases at each level×relative level)/(total number of surveys×4)]×100

5 experimental results

Compound IS-1b (NK-117) also has good anti-TMV activity in field plot experiments, preventing 100% at 100g/ha, 90.17% at 50g/ha, and control at 10g/ha. The % amino oligosaccharide aqueous solution 100 g/ha and 20% WP morpholinium hydrochloride copper acetate 600 g/ha have the same control effect.

Example 5: Acute toxicity study of NK117 (I-S-1b) in rats

1: test sample

2: experimental animals

basic situation

3: Experimental method

(1) Test process

First, the experimental animals were randomly divided into groups. The animals were fasted one day before the administration, and the drugs were used now and administered orally according to the body weight. The response of the rats to the pesticides after administration was observed and recorded. The drug configuration is in accordance with the requirements of the Test Method.

(2) Observation indicators

a poisoning symptoms: comprehensive observation of the occurrence, development process and regularity of poisoning and the characteristics of poisoning and target organs of poison (see Table 4)

b Body weight: Weighed once before administration and at the time of death, and weighed every 3 days during the observation period.

c Pathological tissue: Generally, pathological histological examination and biochemical index examination are not performed, but gross pathological observation should be made on the dead animals. For surviving animals above 24h, pathological histology should be performed when visually examining the lesion.

(3) Method of animal sacrifice

After anesthesia, put it into a carbon dioxide box and suffocate it. The corpse treatment was recorded in the Recorded Animal Carcass, Tissue Disposal and Storage Record Form (BG-040-V00).

(4) Result determination

a result of poisoning symptoms (see Tables 4 and 6 for results):

1) Central nervous system and neuromuscular system: abnormal position, abnormal sound, restlessness, sluggishness, paralysis, convulsions, movement disorders, allergic or retarded external reactions;

2) autonomic nervous system: enlargement or contraction of the pupil, runny or tearing;

3) Respiratory system: nostril fluid, nasal snoring, slow breathing, rapid breathing, bee waist;

4) genitourinary system: perineal contamination, secretions, vaginal or breast swelling;

5) skin and hair: skin congestion, purpura, fluffy hair, filth;

6) Eyes: prominent eyeballs, conjunctival hyperemia, corneal opacity;

7) Digestive system: diarrhea, anorexia.

b Body weight: Statistical analysis was performed for differences between groups. The results are shown in Tables 2, 3 and 5.

c toxicity grading standards:

1) highly toxic: LD ₅₀ <5mg/kg

2) High toxicity: LD ₅₀ 5-50mg/kg

3) Poisoning: LD ₅₀ 50-500mg/kg

4) Low toxicity: LD ₅₀ >500mg/kg

(5) Animal carcass treatment

The animal carcass has been temporarily stored in the freezer in the 19F animal carcass processing room of the platform. When the freezer reaches 4/5 full, the animal management team informs Tianjin Hejia Weiliya Company to carry out harmless treatment, and the corpse treatment special order Submitted to the Animal Management Group for preservation.

(6) Statistical analysis method

SPSS, EXCEL for statistics

4 The experimental results are shown in the following table:

Table 2 Rat body weight statistics table (x ± s, n = 4 units: g)

Table 3 Rat body weight statistics table (x ± s, n = 4 units: g) continued

Table 4 Animal clinical symptoms observed individual data

Table 5 Rat body weight change rate

Table 6 Animal clinical symptoms observation statistics

(1) Symptoms of poisoning: NK117 (I-S-1b) compound has no obvious symptoms of poisoning at high dose of 500mg/kg. NK118 (parent S-valine) mice were all poisoned and died after 2 days at a low dose of 50 mg/kg.

(2) Body weight: There was no significant difference in body weight between any two groups of animals.

(3) Pathological observation: All animals were not abnormal under visual observation after dissection.

(4) Toxicity classification: NK-117 compounds belong to low toxicity standards.

Therefore, under the experimental conditions, it is preliminarily judged that the toxicity of NK-117 at different doses in rats is low toxicity, and it can be concluded that the toxicity of ketone is significantly reduced after the formation of quaternary ammonium salt.

Claims

A phenanthroquinone alkaloid quaternary ammonium salt derivative characterized in that the structure of the phenanthroquinone alkaloid quaternary ammonium salt derivative is represented by the following formula (I):

among them,

R represents one to four hydroxyl groups, one to four 1-10 carbon alkoxy groups, one to two OCH 2 O, one to two OCH 2 CH 2 O;

R 1 represents a 2-10 carbon hydrocarbon group, a 1-10 carboxyallyl group, a 1-10 carbynyl propyl group, a cyanomethyl group, a 1-10 alkyl alkoxycarbonyl group, a 1-10 alkylcarbonyl group, and a methyl group, respectively. a -10 carbon aromatic ring carbonyl methyl group, a 1-10 carbon alkyl aminocarbonyl methyl group, a 1-10 carbon aromatic ring benzyl group, a 1-10 carbon nitrogen-containing heterocyclic benzyl group, a 1-10 carbon oxyheterocyclic benzyl group, 1-10 carbon sulfur-containing heterocyclic benzyl;

X - represents a halogen anion, a 1-10 alkyl sulfonate anion, a 1-10 carbon aryl sulfonate anion, a carbonate anion, a phosphate anion, respectively;

All stereoisomers at positions 13a and 10 are included in the above formula.
The phenanthroquinone alkaloid quaternary ammonium salt derivative according to claim 1, wherein the phenanthrenequinone alkaloid quaternary ammonium salt derivative is selected from the group consisting of the following compounds:

(10S,13aS)-N-propargyl valine oxychloride (I-S-1a);

(10R,13aS)-N-propargyl keto-alkine bromide (I-S-1b);

(10R,13aR)-N-propargyl valine base bromide (I-R-1a);

(10S,13aR)-N-propargyl valine oxychloride bromide (I-R-1b);

(10S,13aS)-N-(2-Alkynyl)-wasaltolide bromide (I-S-2a);

(10R,13aS)-N-(2-Alkynyl)-wasaltolide bromide (I-S-2b);

(10R,13aR)-N-(2-Alkynyl)-wasaltolide bromide (I-R-2a);

(10S,13aR)-N-(2-Alkynyl)-wasaltolide bromide (I-R-2b);

(10R,13aS)-N-cyanomethyl ketokin bromide (I-S-3a);

(10S,13aS)-N-Cyanomethylwasic acid bromide (I-S-3b);

(10S,13aR)-N-cyanomethyl ketokin bromide (I-R-3a);

(10R,13aR)-N-cyanomethyl ketokin bromide (I-R-3b);

(10R,13aS)-N-(ethoxyformylmethyl)-wasaltolide bromide (I-S-4a);

(10S,13aS)-N-(ethoxyformylmethyl)-wasaltolide bromide (I-S-4b);

(10S,13aR)-N-(ethoxyformylmethyl)-wasinoline bromide (I-R-4a);

(10R,13aR)-N-(ethoxyformylmethyl)-wasinoline bromide (I-R-4b);

(10R,13aS)-N-(carbamoylmethyl)-wasinoline bromide (I-S-5a);

(10S,13aS)-N-(carbamoylmethyl)-wasinoline bromide (I-S-5b);

(10S,13aR)-N-(carbamoylmethyl)-wasinoline bromide (I-R-5a);

(10R,13aR)-N-(carbamoylmethyl)-wasinoline bromide (I-R-5b);

(10R,13aS)-N-(methylcarbamoylmethyl)-wasinoline bromide (I-S-6a);

(10S,13aS)-N-(methylcarbamoylmethyl)-wasinoline bromide (I-S-6b);

(10S,13aR)-N-(methylcarbamoylmethyl)-wasinoline bromide (I-R-6a);

(10R,13aR)-N-(methylcarbamoylmethyl)-wasinoline bromide (I-R-6b);

(10R,13aS)-N-(dimethylcarbamoylmethyl)-wasinoline bromide (I-S-7a);

(10S,13aS)-N-(dimethylcarbamoylmethyl)-carbinoline bromide (I-S-7b);

(10S,13aR)-N-(dimethylcarbamoylmethyl)-carbamicin bromide (I-R-7a);

(10R,13aR)-N-(dimethylcarbamoylmethyl)-wasinoline bromide (I-R-7b);

(10S,13aS)-N-(4-trifluoromethylbenzyl)-wasinoline bromide (I-S-8a);

(10R,13aS)-N-(4-trifluoromethylbenzyl)-wasinoline bromide (I-S-8b);

(10R,13aR)-N-(4-trifluoromethylbenzyl)-wasinoline bromide (I-R-8a);

(10S,13aR)-N-(4-trifluoromethylbenzyl)-wasinoline bromide (I-R-8b);

(10R,13aS)-N-(2-oxo-2-phenylethyl)-wasaltolide bromide (I-S-9a);

(10S,13aS)-N-(2-oxo-2-phenylethyl)-wasinoline bromide (I-S-9b);

(10S,13aR)-N-(2-oxo-2-phenylethyl)-wasaltolide bromide (I-R-9a);

(10R,13aR)-N-(2-oxo-2-phenylethyl)-wasaltolide bromide (I-R-9a);

(10S,13aS)-N-(4-tert-butylbenzyl)-wasinoline bromide (I-S-10a);

(10R,13aS)-N-(4-tert-butylbenzyl)-wasinoline bromide (I-S-10b);

(10S,13aS)-N-benzyl ketokin bromide (I-S-11a);

(10R,13aS)-N-benzylwascartosine bromide (I-S-11b);

(10R, 13aS)-N-allyl wagenine bromide (I-S-12).
A method for preparing a phenanthroquinone alkaloid quaternary ammonium salt derivative, the method comprising the process of the following formula:

R 1 represents a 2-10 carbon hydrocarbon group, a 1-10 carboxyallyl group, a 1-10 carbynyl propyl group, a cyanomethyl group, a 1-10 alkyl alkoxycarbonyl group, a 1-10 alkylcarbonyl group, and a methyl group, respectively. a -10 carbon aromatic ring carbonyl methyl group, a 1-10 carbon alkyl aminocarbonyl methyl group, a 1-10 carbon aromatic ring benzyl group, a 1-10 carbon nitrogen-containing heterocyclic benzyl group, a 1-10 carbon oxyheterocyclic benzyl group, 1-10 carbon sulfur-containing heterocyclic benzyl;

X - represent a halogen anion, sulfonic acid anion 1-10 carbon alkyl, 1-10 carbon aryl sulfonic acid anion, carbonate anion, phosphate anion.
The method of claim 3 wherein R 1 X is:
The method according to claim 3 or 4, wherein the method comprises: dissolving R-Wascarda or S-Wascarinine in CHCl 3 or DMF, then adding bromide R 1 X, and heating and refluxing 24 After -48h, the reaction was desolvated under reduced pressure to give a crude product which was then purified by column chromatography to give the desired product.
Use of the phenanthroquinone alkaloid quaternary ammonium salt derivative according to claim 1 or 2 for the treatment of a plant virus.
The use according to claim 6, wherein the plant viral disease comprises tobacco mosaic virus disease, capsicum virus disease, tomato virus disease, sweet potato virus disease, potato virus disease, and corn dwarf mosaic virus disease.
Anti-plant containing the phenanthroquinone alkaloid quaternary ammonium salt derivative according to claim 1 or 2 Viral agent.
The anti-plant virus agent according to claim 8, wherein the anti-plant virus agent, the phenanthroquinone alkaloid quaternary ammonium salt derivative and benzothiadiazole, thiazide, 4-methyl-1,2,3-thiadiazol-5-carboxylic acid, DL-β-aminobutyric acid, ribavirin, nymidine, phenanthroline alkaloids antoine, lignin The azole compound XY-13, the bitriazole compound XY-30, the virus A, the salicylic acid, the polyhydroxy bis naphthaldehyde, and the amino oligosaccharide form an interaction composition.
Use of the phenanthroquinone alkaloid quaternary ammonium salt derivative according to claim 1 or 2 as an anti-plant virus agent.