CN109422742B - 9-substituted tylophorine derivative, preparation thereof and application thereof in activity of resisting tobacco mosaic virus - Google Patents
9-substituted tylophorine derivative, preparation thereof and application thereof in activity of resisting tobacco mosaic virus Download PDFInfo
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Abstract
The invention relates to 9-substituted tylophorine derivatives, preparation thereof and application thereof in plant virus resistance, wherein R in the general formula is defined in the specification. The invention provides a novel structure for resisting tobacco mosaic virus, which is characterized by being beneficial to industrialization, simple synthesis and the like. The 9-substituted tylophorine derivatives show excellent anti-plant virus activity and can well inhibit Tobacco Mosaic Virus (TMV).
Description
Technical Field
The invention relates to 9-substituted tylophorine derivatives, a preparation method thereof and application thereof in resisting plant tobacco mosaic virus.
Background
In 1935, the first phenanthroindolizidine alkaloid, tylophorine (tylophorine), was isolated and identified (Indian j.med.res., 1935, 22, 433-441), which has received wide attention from chemists at home and abroad due to its unique chemical structure and significant biological activity. The subject group discovers for the first time that the alkaloid has very good inhibitory activity on Tobacco Mosaic Virus (TMV) with great harm, and based on the very good inhibitory activity, wide structural modification and transformation are carried out, and the efficient plant virus disease control medicament NK-007 is optimized. Although the phenanthroindolizidine alkaloid has very good biological activity, the defects of high toxicity, poor water solubility and instability to light and heat of the central nervous system exist, and the practical application of the phenanthroindolizidine alkaloid is influenced. Therefore, the method has important significance for further structural derivation of the alkaloid.
CN101348483 discloses the preparation of phenanthroindolizidine alkaloid derivatives. CN103626763A discloses preparation of phenanthroindolizidine alkaloid derivatives and application of phenanthroindolizidine alkaloid derivatives in resisting plant virus activity. CN103509012A discloses preparation of phenanthroindolizidine alkaloid C14 aminated derivative and application of phenanthroindolizidine alkaloid in resisting plant virus activity. CN105130985A discloses phenanthroindolizidine alkaloid quaternary ammonium salt derivatives, and preparation and anti-plant virus application thereof. However, the influence of the substituent at the 9-position of the phenanthroindolizidine alkaloid on the biological activity of the phenanthroindolizidine alkaloid has not been reported in documents. The 9-position of the phenanthroindolizidine alkaloid has special properties, and the C-H bond is relatively active, so that the introduction of a substituent group at the 9-position of the phenanthroindolizidine alkaloid can have a relatively large influence on the biological activity of the phenanthroindolizidine alkaloid.
Disclosure of Invention
The invention relates to a 9-substituted tylophorine derivative shown in a general formula I, a preparation method thereof and application thereof in resisting tobacco mosaic virus.
In the general formula I, R represents an aliphatic group: various alkanes, alkenes, dienes, alkynes, aromatic groups: benzene, biphenyl, fused aromatic rings, aromatic heterocycles, various electron donating and electron withdrawing aromatic rings, carboxyl groups, ester groups, cyano groups, and the like.
The invention preferably selects the tylophorine derivative (I) substituted at the 9-position in the following chemical structural formula.
The 9-substituted tylophorine derivative (I) can be prepared by the following method:
the 9-substituted tylophorine derivative compounds 1-9 shown in the general formula I can be prepared by a first method: intermediate 1 is amidated to give intermediate 2, which is then reacted with sodium borohydride via a Bischler-Napieralski reaction to give compounds 1-9.
The invention is described in general formula IThe 9-substituted tylophorine derivative compound 10 can be prepared by the method II: compound 4 undergoes S under alkaline conditionsN2 to obtain a compound 10 which is obtained by reaction,
the 9-substituted tylophorine derivative compound 11 and the compound 12 shown in the general formula I can be prepared by a third method: the intermediate 1 is subjected to Pictet-Spengler reaction to obtain a compound 11 and a compound 12,
the 9-substituted tylophorine derivative compound 13 shown in the general formula I can be prepared by a fourth method: compound 12 by LiAlH4The reduction reaction is carried out to obtain a compound 13,
the 9-substituted tylophorine derivative compound 14 shown in the general formula I can be prepared by a fifth method: the intermediate 1 is subjected to microwave-assisted formylation reaction to obtain an intermediate 3, then subjected to Bischler-Napieralski reaction to obtain an intermediate 4, and finally subjected to nucleophilic addition reaction on the intermediate 4 by using TMSCN to obtain a compound 14,
the compound of the general formula I has excellent plant virus resistance activity, the TMV resistance activity of part of the compound is superior to that of commercial varieties of ribavirin, and the compound can effectively prevent and treat virus diseases of plants such as tobacco, rice, hot pepper, tomato, sweet potato, melon, corn and the like, and is particularly suitable for preventing and treating tobacco mosaic virus diseases.
The compound can be used as an anti-tobacco mosaic virus preparation directly, can be added with a carrier for use, and can also be used as an anti-tobacco mosaic virus agent and other anti-tobacco mosaic virus preparations, such as Benzothiadiazole (BTH), Tiadinil (TDL), 4-methyl-1, 2, 3-thiadiazole-5-formic acid (TDLA), D or L-beta-aminosuccinic acid, ribavirin, ningnanmycin, bitriazole compounds XY-13 and XY-30, and virus A, salicylic acid, amino oligosaccharide and polyoligosaccharide to form an interaction composition for use. These compositions exhibit enhanced or additive effects.
Detailed Description
EXAMPLE 19 Synthesis of Methyltylophorine (Compound 1) (method one)
A 100mL reaction flask was charged with 10.76 g (1.99mmol) of the intermediate, 30mL of anhydrous dichloromethane, 0.3g (3.82mmol) of acetyl chloride, 0.4g (3.95mmol) of triethylamine, and 0.05g (0.41mmol) of 4- (N, N-dimethylamino) pyridine, and the mixture was stirred at room temperature for 6 hours, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to column chromatography under normal pressure (dichloromethane: methanol ═ 40: 1 elution) to obtain 0.42g of a white solid, which was: 49 percent; adding 20.1 g (0.24mmol) of the obtained intermediate into a 100mL reaction bottle, then adding 30mL of anhydrous toluene, adding 1mL (10.92mmol) of phosphorus oxychloride under stirring at room temperature, heating and refluxing for reaction for 1h, removing the solvent by rotary evaporation, adding 30mL of anhydrous methanol, adding 0.1g (2.64mmol) of sodium borohydride under ice-water bath, stirring for 1h at room temperature, precipitating a large amount of white solid, and performing suction filtration to obtain 0.25g of white solid with the yield of 86%;1H NMR(400MHz，CDCl3)δ7.81(s，1H)，7.80(s，1H)，7.32(s，1H)，7.31(s，1H)，4.27-4.19(m，1H)，4.11(s，6H)，4.05(s，3H)，4.05(s，3H)，3.70-3.62(m，1H)，3.26(d，J＝14.8Hz，1H)，2.92(dd，J＝14.8，10.8Hz，1H)，2.65-2.55(m，1H)，2.48(dd，J＝17.2，8.8Hz，1H)，2.20-2.11(m，1H)，2.11-2.01(m，1H)，2.00-1.87(m，1H)，1.85-1.74(m，1H)，1.59(d，J＝6.0Hz，3H)；13C NMR(100MHz，CDCl3)δ148.9，148.7，148.1，147.9，132.0，127.4，126.0，124.2，124.2，123.4，105.6，104.2，103.6，103.3，59.00，58.98，56.11，56.05，55.92，53.7，34.4，30.9，23.3，21.8；HRMS(ESI)calcd for C25H30NO4 +(M+H)+408.2169，found 408.2178.
example 2
The 9-substituted tylophorine derivatives (Compounds 2-9) were prepared by following the procedure of example 1
Compound 2, white solid, yield 95%; melting point: 164-165 ℃;1H NMR(400MHz，CDCl3)δ7.82(s，1H)，7.81(s，1H)，7.34(s，2H)，4.33-4.25(m，1H)，4.11(s，6H)，4.06(s，3H)，4.05(s，3H)，3.57(t，J＝7.2Hz，1H)，3.25(d，J＝14.8Hz，1H)，2.89-2.76(m，1H)，2.61-2.51(m，1H)，2.46(dd，J＝16.8，8.4Hz，1H)，2.16-1.97(m，3H)，1.97-1.82(m，2H)，1.79-1.65(m，2H)，1.49-1.35(m，1H)，1.16-0.95(m，4H)，0.71(t，J＝6.8Hz，3H)；13C NMR(100MHz，CDCl3)δ148.7，148.5，148.0，147.9，130.7，128.9，125.8，124.4，124.0，123.3，105.3，104.2，103.5，103.2，62.9，59.0，56.1，56.0，55.9，53.9，35.6，34.3，32.3，30.9，24.6，22.5，22.0，14.1；HRMS(ESI)calcd for C29H38NO4 +(M+H)+464.2795，found 464.2804.
compound 3, light yellow solid, 18% yield; melting point: 210 ℃ and 211 ℃;1H NMR(400MHz，CDCl3)δ7.81(s，1H)，7.79(s，1H)，7.53(s，1H)，7.35(s，1H)，4.44(s，1H)，4.12(s，3H)，4.11(s，3H)，4.07(s，3H)，4.06(s，3H)，3.51(t，J＝8.4Hz，1H)，3.22(d，J＝13.2Hz，1H)，2.80(dd，J＝14.8，11.1Hz，1H)，2.59(q，J＝8.4Hz，1H)，2.44-2.35(m，1H)，2.04-1.92(m，1H)，1.92-1.83(m，1H)，1.82-1.71(m，1H)，1.67-1.55(m，1H)，0.78(s，9H)；13C NMR(100MHz，CDCl3)δ148.8，148.6，148.0，147.4，132.5，130.3，126.9，125.8，123.2，123.1，106.6，104.2，103.1，103.1，66.9，61.9，56.1，56.0，55.8，55.8，41.4，33.2，29.7，28.6，22.4；HRMS(ESI)calcd for C28H36NO4 +(M+H)+450.2639，found 450.2644.
compound 4, light yellow solid, 71% yield; melting point: 183-184 ℃;1H NMR(400MHz，CDCl3)δ7.86(s，1H)，7.83(s，1H)，7.36(s，1H)，7.32(s，1H)，4.56-4.49(m，1H)，4.14(s，6H)，4.12(s，3H)，4.10-4.04(m，4H)，3.87(td，J＝8.4，2.0Hz，1H)，3.80(dd，J＝11.6，5.2Hz，1H)，3.32(d，J＝15.2Hz，1H)，2.89(dd，J＝14.8，11.2Hz，1H)，2.64(dd，J＝17.2，9.2Hz，2H)，2.18-2.03(m，2H)，2.02-1.90(m，1H)，1.82-1.68(m，1H)；13C NMR(100MHz，CDCl3)δ149.1，149.0，148.6，148.3，129.7，127.5，125.5，124.1，124.0，123.9，104.5，104.3，103.8，103.2，66.9，59.4，56.1，55.9，54.5，52.3，33.9，30.4，22.2；HRMS(ESI)calcd for C25H29ClNO4 +(M+H)+442.1780，found 442.1788.
compound 5, white solid, yield 76%; melting point: 275 ℃ to 276 ℃;1H NMR(400MHz，CDCl3)δ7.80(s，1H)，7.72(s，1H)，7.42(s，1H)，7.23-7.10(m，5H)，7.00(s，1H)，4.93(s，1H)，4.11(s，3H)，4.09(s，3H)，4.02(s，3H)，3.58(s，3H)，3.45-3.35(m，1H)，3.20-3.12(m，1H)，3.12-3.02(m，1H)，2.77-2.66(m，1H)，2.49(dd，J＝16.8，8.4Hz，1H)，2.24-2.12(m，1H)，1.93-1.74(m，3H)；13C NMR(100MHz，CDCl3)δ148.8，147.7，147.5，145.3，129.6，129.1，128.8，128.4，126.8，125.7，124.3，124.0，107.2，104.4，103.2，102.9，70.2，59.5，56.1，56.0，55.9，55.6，53.6，34.6，31.0，21.3；HRMS(ESI)calcd for C30H32NO4 +(M+H)+470.2326，found 470.2333.
compound 6, a light yellow solid, 69% yield. Melting point: 253 and 254 ℃;1H NMR(400MHz，CDCl3)δ7.81(s，1H)，7.74(s，1H)，7.42(s，1H)，7.16(d，J＝7.6Hz，2H)，7.10(d，J＝7.6Hz，2H)，6.93(s，1H)，4.95(s，1H)，4.13(s，3H)，4.10(s，3H)，4.04(s，3H)，3.63(s，3H)，3.41(d，J＝15.2Hz，1H)，3.19-2.96(m，2H)，2.81-2.67(m，1H)，2.49(dd，J＝16.4，7.6Hz，1H)，2.27-2.11(m，1H)，1.95-1.72(m，2H)，1.71-1.55(m，1H)；13C NMR(100MHz，CDCl3)δ149.0，148.9，147.8，147.6，143.9，132.4，130.1，129.3，129.0，128.5，125.6，124.14，124.08，123.99，106.8，104.4，103.2，103.1，69.3，59.3，56.1，56.0，55.9，55.6，53.5，34.5，31.0，21.45；HRMS(ESI)calcd for C30H31ClNO4 +(M+H)+504.1936，found 504.1947.
compound 7, white solid, yield 93%; melting point: 258 ℃ and 259 ℃;1H NMR(400MHz，CDCl3)δ8.11(s，1H)，8.01(d，J＝7.6Hz，1H)，7.80(s，1H)，7.74(s，1H)，7.51-7.40(m，2H)，7.32(t，J＝7.6Hz，1H)，6.90(s，1H)，5.08(s，1H)，4.12(s，3H)，4.10(s，3H)，4.02(s，3H)，3.63(s，3H)，3.43(d，J＝15.6Hz，1H)，3.13-2.99(m，2H)，2.81-2.71(m，1H)，2.58-2.47(m，1H)，2.25-2.13(m，1H)，1.94-1.66(m，3H)；13C NMR(100MHz，CDCl3)δ149.1，149.0，148.1，147.9，147.8，135.0，129.5，129.3，128.1，125.5，124.3，124.2，123.7，123.6，122.1，106.2，104.4，103.3，103.2，69.3，59.2，56.1，56.0，55.9，55.6，53.2，34.4，31.0，21.4；HRMS(ESI)calcd for C30H31N2O6 +(M+H)+515.2177，found 515.2183.
compound 8, white solid, 92% yield; melting point: 137-138 ℃;1H NMR(400MHz，CDCl3)δ8.73(dd，J＝4.4，1.2Hz，2H)，8.28(s，1H)，7.84(s，1H)，7.80(s，1H)，7.47-7.39(m，3H)，7.19(s，1H)，4.77-4.68(m，1H)，4.24(s，3H)，4.18(dd，J＝13.2，2.8Hz，1H)，4.14(s，3H)，4.13(s，3H)，4.04(s，3H)，3.56-3.46(m，1H)，3.43-3.34(m，1H)，2.73(dd，J＝12.8，11.2Hz，1H)，2.09-2.01(m，1H)，1.99-1.91(m，1H)，1.87-1.76(m，3H)；13C NMR(100MHz，CDCl3)δ167.8，150.3，149.2，149.1，149.0，148.8，144.9，130.7，126.1，125.9，125.5，124.8，124.1，121.2，107.9，106.2，103.1，102.9，57.7，56.8，56.2，56.1，55.9，50.0，37.9，29.5，24.5；HRMS(ESI)calcd for C29H31N2O4 +(M+H)+471.2278，found 471.2283.
compound 9, white solid, yield 85%; melting point: 232-233 ℃;1H NMR(400MHz，CDCl3)δ7.81(s，1H)，7.74(s，1H)，7.41(s，1H)，7.21(s，1H)，7.08(d，J＝4.0Hz，1H)，7.00-6.94(m，1H)，6.88-6.81(m，1H)，5.29(s，1H)，4.12(s，3H)，4.08(s，3H)，4.05(s，3H)，3.69(s，3H)，3.43-3.33(m，2H)，3.11-3.01(m，1H)，2.77-2.67(m，1H)，2.54(dd，J＝17.2，8.4Hz，1H)，2.25-2.14(m，1H)，1.99-1.74(m，3H)；13C NMR(100MHz，CDCl3)δ149.8，149.0，148.8，147.8，129.2，128.9，125.9，125.7，125.6，124.61，124.56，124.2，124.0，106.3，104.5，103.2，103.0，64.4，59.3，56.1，56.0，55.9，55.7，54.0，34.4，31.2，21.3；HRMS(ESI)calcd for C28H30NO4S+(M+H)+476.1890，found 476.1898.
EXAMPLE 39 Synthesis of Ethoxymethyl tylophorine (Compound 10) (method two)
Adding 40.2 g (0.45mmol) of the compound, 20mL of absolute ethyl alcohol and 0.05g (0.89mmol) of potassium hydroxide into a 50mL reaction bottle, heating and refluxing for 8h, spin-drying, adding a proper amount of dichloromethane and water for dissolving, separating, washing an organic phase with water, washing with saturated salt water, drying with anhydrous sodium sulfate, and performing decompression and desolventizing to obtain 0.12g of a white solid, wherein the yield is 61 percent, and the melting point is 155 ℃ plus 156 ℃;1H NMR(400MHz，CDCl3)δ7.81(s，1H)，7.80(s，1H)，7.50(s，1H)，7.32(s，1H)，4.35-4.29(m，1H)，4.11(s，6H)，4.05(s，6H)，3.97(d，J＝9.6Hz，1H)，3.76(t，J＝8.4Hz，1H)，3.60-3.47(m，3H)，3.26(d，J＝15.2Hz，1H)，2.94-2.84(m，1H)，2.61-2.50(m，2H)，2.16-1.98(m，2H)，1.97-1.83(m，1H)，1.81-1.67(m，1H)，1.24(t，J＝6.8Hz，4H)；13C NMR(100MHz，CDCl3)δ148.82，148.77，148.23，148.18，129.0，128.1，125.8，124.4，124.0，123.7，105.1，104.2，103.4，103.2，79.3，66.3，64.9，59.4，56.1，56.0，55.9，55.8，54.6，34.1，30.3，21.9，15.4；HRMS(ESI)calcd for C27H34NO5 +(M+H)+452.2431，found 452.2441.
example 4 Synthesis of tylophorine-9-carboxylic acid (Compound 11) (method III)
A100 mL reaction flask was charged with 10.5 g (1.31mmol) of intermediate, 30mL of acetonitrile, and 1.0g (13.51mmol) of glyoxylic acid, and the reaction was stirred at room temperature for 24 hours. Desolventizing under reduced pressure and recrystallizing with methanol. Obtaining 0.32g of off-white solid, the yield is 56 percent, and the melting point is 225-226 ℃;1H NMR(400MHz，DMSO-d6)δ8.03(s，2H)，7.51(s，1H)，7.40(s，1H)，5.29(s，1H)，4.04(s，3H)，4.03(s，3H)，3.95(s，3H)，3.89(s，3H)，3.71-3.61(m，1H)，3.07-2.83(m，3H)，2.26-2.09(m，1H)，1.92-1.69(m，2H)，1.59-1.39(m，1H)；13C NMR(100MHz，DMSO-d6)δ171.2，149.3，149.1，149.0，148.8，125.2，124.9，124.6，124.2，123.7，104.8，104.7，104.6，62.5，56.4，56.4，55.9，55.8，54.2，51.2，31.3，31.0，22.0.HRMS(ESI)calcd for C25H28NO6 +(M+H)+438.1911，found 438.1913.
example 5 tylophorine-9-carboxylic acid ethyl ester (Compound 12) the procedure of example 4 was followed to complete
Compound 12, 2.0g of a yellow solid, 82% yield, mp 227-;1H NMR(400MHz，CDCl3)δ7.81(s，2H)，7.40(s，1H)，7.36(s，1H)，5.33(s，1H)，4.18(dd，J＝14.0，7.2Hz，2H)，4.11(s，3H)，4.10(s，3H)，4.06(s，3H)，4.03(s，3H)，3.55-3.45(m，2H)，3.31(td，J＝8.4，2.8Hz，1H)，2.85(dd，J＝16.8，10.8Hz，1H)，2.68(q，J＝8.4Hz，1H)，2.31-2.20(m，1H)，2.05-1.95(m，1H)，1.95-1.84(m，2H)，1.75-1.65(m，1H)，1.24(t，J＝7.2Hz，3H)；13C NMR(100MHz，CDCl3)δ171.5，148.91，148.86，148.7，148.3，127.6，125.7，124.4，124.3，124.0，123.7，104.2，103.6，103.5，103.2，62.2，60.6，56.0，56.0，55.9，55.8，52.5，50.0，33.0，31.5，21.6，14.6；HRMS(ESI)calcd for C27H32NO6 +(M+H)+466.2224，found 466.2230.
EXAMPLE 69 Synthesis of Hydroxymethyl tylophorine (Compound 13) (method four)
A100 mL reaction flask was charged with 120.5 g (1.07mmol) of the compound and 50mL of tetrahydrofuran, and then 1.5g (39.5mmol) of lithium aluminum hydride was added to the flask in an ice-water bath, followed by stirring and reacting for 1.5 hours. Adding water to terminate the reaction, slowly adding a small amount of 3mol/L dilute hydrochloric acid to acidify to be clear, adding dichloromethane to extract, washing an organic phase once by using saturated saline solution, adding anhydrous sodium sulfate to dry, filtering to remove solvent, washing by using petroleum ether and then drying to obtain 0.34g of yellow solid, wherein the yield is 77%, and the melting point is 231-;1H NMR(400MHz，CDCl3)δ7.85(s，2H)，7.32(s，1H)，7.25(s，1H)，5.36(d，J＝6.8Hz，1H)，4.75(s，1H)，4.27-4.19(m，1H)，4.14(s，6H)，4.12(s，3H)，4.08(s，3H)，4.05-3.99(m，2H)，3.55(dd，J＝17.2，6.3Hz，1H)，3.20(dd，J＝16.8，4.8Hz，1H)，2.98(dd，J＝18.0，8.8Hz，1H)，2.78-2.65(m，1H)，2.41-2.27(m，1H)，2.14-2.01(m，2H)，2.00-1.88(m，1H)；13C NMR(100MHz，CDCl3)δ149.9，149.6，149.4，125.0，124.4，123.8，123.0，122.8，118.6，103.6，103.4，102.8，63.5，62.8，56.5，56.14，56.09，55.6，53.7，31.1，26.3，21.4，20.6；HRMS(ESI)calcd for C25H30NO5(M+H)+424.2118，found 424.2124.
example 7: synthesis of 9-cyano tylophorine (Compound 14) (method five)
A 35mL microwave reactor was charged with 10.2 g (0.52mmol) of the intermediate and 20mL of ethyl formate, and T was set at 100 ℃, P was set at 100W, and P was set atmaxReaction for 1h at 250 psi. Decompression desolventizing, dichloromethane diluting, 3mol/L hydrochloric acid washing, water washing, saturated salt water washing, anhydrous sodium sulfate drying, normal pressure column chromatography (dichloromethane: methanol is 40: 1), desolventizing to obtain white solid intermediate 30.2 g, yield 95%.
30.2 g (0.49mmol) of the intermediate and 20mL of anhydrous toluene are added into a 50mL reaction bottle, 0.75g (4.89mmol) of phosphorus oxychloride is added under stirring at room temperature, heating reflux reaction is carried out for 1h, suction filtration is carried out, and a filter cake is washed by a small amount of methanol to obtain 40.2 g of yellow solid intermediate with the yield of 95%.
A100 mL reaction flask was charged with 40.1 g (0.26mmol) of the intermediate, 30mL of anhydrous dichloromethane, 0.025g (0.25mmol) of trimethylsilyl cyanide and 0.04g (0.33mmol) of DMAP, and the reaction was stirred at room temperature for 10 hours until the yellow color in the reaction mixture was substantially removed. Removing solvent under reduced pressure to obtain light yellow solid, washing with methanol to obtain white solid 0.07g, yield 83%;1H NMR(400MHz，CDCl3)δ7.79(s，1H)，7.77(s，1H)，7.26(s，1H)，7.17(s，1H)，5.48(s，1H)，4.12(s，3H)，4.11(s，3H)，4.08(s，3H)，4.05(s，3H)，3.41(dd，J＝15.6，3.6Hz，1H)，3.35(td，J＝8.4，3.6Hz，1H)，3.04-2.92(m，2H)，2.86(dd，J＝15.6，10.8Hz，1H)，2.40-2.30(m，1H)，2.12-1.98(m，2H)，1.86-1.73(m，1H)；13C NMR(100MHz，CDCl3)δ148.2，148.1，147.8，147.7，126.8，124.0，123.6，122.8，121.8，119.9，115.3，102.9，102.5，102.0，101.5，55.00，54.96，54.9，54.7，51.7，50.1，32.4，30.4，20.7.HRMS(ESI)calcd for C24H26NO4(M-CN)+392.1856，found 392.1861.
example 8: method for measuring activity of resisting tobacco mosaic virus by conventional in vivo bioassay method
1. Virus purification and concentration determination:
virus purification and concentration determinations were performed with reference to the SOP specifications for tobacco mosaic virus compiled by the institute of life and testing laboratory at the university of south china. Centrifuging the virus crude extract with polyethylene glycol for 2 times, measuring concentration, and refrigerating at 4 deg.C for use.
2. Compound solution preparation:
weighing, adding DMF to dissolve to obtain 1 × 10 solution5Mu g/mL of the mother liquor is diluted to the required concentration by using an aqueous solution containing 1 per mill of Tween 80.
3. The protection effect of the living body is as follows:
selecting 3-5 leaf-period Saxisi tobacco with uniform growth, spraying the whole plant, repeating for 3 times, and setting 1 ‰ Tween 80 aqueous solution as control. After 24h, the leaf surfaces are scattered with carborundum (500 meshes), the virus liquid (the virus concentration is 10 mu g/mL) is dipped by a writing brush, the whole leaf surfaces are lightly wiped for 2 times along the branch vein direction, the lower parts of the leaves are supported by palms, and the leaves are washed by running water after inoculation. And recording the number of the disease spots after 3d, and calculating the prevention effect.
4. Therapeutic action in vivo:
selecting 3-5 leaf-stage Saxismoke with uniform growth vigor, inoculating virus with whole leaf of writing brush at a virus concentration of 10 μ g/mL, and washing with running water after inoculation. After the leaves are harvested, the whole plant is sprayed with the pesticide, the treatment is repeated for 3 times, and a 1 per mill tween 80 aqueous solution is set for comparison. And recording the number of the disease spots after 3d, and calculating the prevention effect.
5. The living body passivation effect is as follows:
selecting 3-5 leaf-period Saxismoke with uniform growth, mixing the preparation with virus juice of the same volume, inactivating for 30min, performing friction inoculation with virus concentration of 20 μ g/mL, washing with running water after inoculation, repeating for 3 times, and setting Tween 80 water solution of 1 ‰ as reference. The number of lesions after 3d was counted and the result was calculated.
6. In vitro effect:
the Shanxi tobacco leaves with the proper age are inoculated by rubbing, the virus concentration is 10 mug/mL, and the leaves are washed by running water after inoculation. Cutting off after drying, cutting along the vein of the leaf, soaking the left and right half leaves in 1 ‰ of expectorant water and medicinal preparation respectively, taking out after 30min, performing moisture-keeping culture at suitable illumination temperature, repeating for 1 time and 3 times for each 3 leaves. And recording the number of the disease spots after 3d, and calculating the prevention effect.
Inhibition (%) < percent [ (control number of scorched spots-number of treated scorched spots)/control number of scorched spots ]. times.100%
anti-TMV activity of tylophorine derivatives substituted at position 19 of table
As can be seen from table 1, the 9-substituted tylophorine derivatives showed excellent anti-TMV activity. Particularly, the anti-TMV activity of 9-methyl tylophorine (compound 1), 9-n-amyl tylophorine (compound 2), 9-ethoxymethyl tylophorine (compound 10) and 9-hydroxymethyl tylophorine (compound 13) is superior to that of commercial varieties of ribavirin, wherein the activity of the compound 2 and the compound 13 is equivalent to that of tylophorine, while the activity of the compound 10 is the best and is slightly superior to that of a high-activity variety NK-007 created by a subject group, and the tylophorine has great development value.
Claims (6)
1. A tylophorine derivative with 9-substituted position of the structure shown in the general formula I,
characterized in that the compound represented by the general formula is a compound represented by the following structure:
2. the method for preparing the compounds 1-9 in the 9-substituted tylophorine derivative of claim 1: the intermediate 1 is amidated to obtain an intermediate 2, then the intermediate is subjected to Bischler-Napieralski reaction and sodium borohydride reduction reaction to obtain a compound 1-9,
method 1
3. A process for the preparation of compound 10 of claim 1: the compound 4 is subjected to SN2 reaction under alkaline conditions to obtain a compound 10,
method two
4. A process for the preparation of compound 11 according to claim 1: intermediate 1 was subjected to Pictet-Spengler reaction to give compound 11,
method III
5. A process for the preparation of compound 13 according to claim 1: compound 12 by LiAlH4The reduction reaction is carried out to obtain a compound 13,
method IV
6. The use of the 9-substituted tylophorine derivative of claim 1 for preventing and treating tobacco mosaic virus diseases.
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| EP1604990A1 (en) * | 2004-06-11 | 2005-12-14 | National Health Research Institutes | Phenanthroindolizidine alkaloids |
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| CN101189968A (en) * | 2006-11-23 | 2008-06-04 | 南开大学 | Phenanthroindolizidine and phenanthroquinolizidine derivatives and applications of salts in pesticides |
| CN102150670A (en) * | 2006-11-23 | 2011-08-17 | 南开大学 | Application of phenanthroindolizidine and phenanthroquinolizidine derivatives and salts thereof in pesticides |
| WO2011049704A1 (en) * | 2009-10-22 | 2011-04-28 | The University Of North Carolina At Chapel Hill | Antofine and cryptopleurine derivatives as anticancer agents |
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