CN108285424B - Gossypol Schiff base derivative, preparation and application thereof in resisting plant tobacco mosaic virus - Google Patents

Gossypol Schiff base derivative, preparation and application thereof in resisting plant tobacco mosaic virus Download PDF

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CN108285424B
CN108285424B CN201710017079.2A CN201710017079A CN108285424B CN 108285424 B CN108285424 B CN 108285424B CN 201710017079 A CN201710017079 A CN 201710017079A CN 108285424 B CN108285424 B CN 108285424B
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gossypol
compound
nmr
dmso
schiff base
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汪清民
张斌
刘玉秀
王兹稳
宋红健
李永强
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Nankai University
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Abstract

The invention relates to a compound shown in a general formula, a preparation method thereof and application thereof in pesticides, and provides a novel structure for resisting tobacco mosaic virus, which has the characteristics of being beneficial to industrialization, simple in synthesis and the like. Racemic gossypol D-amino acid Schiff base and levo-or dextro-gossypol Schiff baseThe derivatives have very good activity (protection, treatment, inactivation) against tobacco mosaic virus. (wherein R has the meaning as defined in the specification)
Figure DSA0000138957980000011

Description

Gossypol Schiff base derivative, preparation and application thereof in resisting plant tobacco mosaic virus
Technical Field
The invention relates to a gossypol Schiff base derivative, a preparation method thereof and application thereof in resisting plant tobacco mosaic virus.
Background
Chirality is a basic characteristic of a life process, and macromolecules such as nucleic acid, protein, polysaccharide and the like which are important bases of life activities have chirality; when a chiral drug enters a living organism, its two enantiomers will often exhibit different biological activities. Previously, due to lack of understanding, people have had a tragic training. For example, the medicine developed by German pharmaceutical company in the fifties of the last century is a medicine for treating early discomfort of pregnant women, namely the reaction stoppage, and has good efficacy, but the infants born by the pregnant women who take the reaction stoppage are quickly found to be mostly in limb disability. Later, one of the configurations of the discontinuance of the reaction was found to have teratogenic effects, while the other configuration had no teratogenic effects. After the enantiomer of the chiral drug enters a chiral environment in an organism, the pharmacodynamics, the pharmacokinetics and the toxicology of the enantiomer have the enantioselective effect, so that the research on the enantiomer of the chiral drug has profound significance for the clinical reasonable use of the chiral drug and the development and development of new drugs with single isomers.
In the field of pesticides, about 25% of the commercial pesticides used in the world today contain chiral centers (Pesticide Science, 1996, 46, 3-9; Dong Huifen. [ Master research academic thesis ]. Zhejiang university.2013). In China, this ratio is estimated to exceed 40% due to the large use of pesticides with chiral structures such as pyrethroids, organophosphorus, etc. (Chirality, 2009, 21, 421-. Chiral pesticides were studied as single compounds before the 90's of the 20 th century. Numerous studies have now shown that the biological activity of chiral pesticides displays a marked stereospecificity and that the active substance is often present in one or several isomers. Meanwhile, since macromolecules such as saccharides and proteins involved in metabolism have high stereospecificity, the utilization rate, metabolism and the like of chiral compounds are greatly different after entering organisms (Toxicological Sciences, 2009, 110, 4-30).
The pesticide is an important pillar of national agriculture and national economy, and the pesticide chemical industry of China continuously develops novel compounds with various biological activities, aiming at developing novel pesticides with high utilization rate, high selectivity and high activity. Since the new century, the country pays more and more attention to environmental protection, and advocates green chemistry and green pesticides, which brings a problem to pesticide chemists. Research and development of chiral pesticides is a new path for green pesticide development (zhongsan. [ doctor research institute paper ]. zhejiang university.2009), because each enantiomer has similar characteristics of melting point, boiling point and solubility, but has different effects on biological behavior (liu yi. [ master research institute paper ]. hunan agriculture university.2011). The stereoselectivity of a single chiral pesticide is mainly reflected in the activity of the target organism and the adverse effect on the non-target organism. Meanwhile, the use of single enantiomer pesticide will reduce the residual concentration of pesticide in the environment, change the residual composition of isomers, etc., and further reduce the stress on the environment (ecological environment, 2008, 17, 1268-.
Gossypol (gossypol) is a secondary metabolite unique to cotton plants, has a certain inhibitory activity against many cotton pests, and is one of the cotton's own antibiotics (Liu, j.; Benedict, c.r.; Stipanovic, r.d. and Bell, a.a.plant physiol.1999, 121, 1017-. It also has a wide range of biological activities (Wang, x.; Howell, c.p.; Chen, f.; Yin, j.and Jiang, y.food nutri. res.2009, 58, 215-.
Two naphthalene rings are encircled due to the existence of hydroxyl at 1, 1 'position and methyl at 3, 3' position in gossypol structureC2-C2The rotation of the' is hindered, which results in the production of a pair of atropisomers from gossypol.
Figure DEST_PATH_GSB0000162778460000021
Structural formula of optically pure gossypol
In sea island cotton, common (-) -gossypol [ (-) -gossypol)]Predominantly, while in upland cotton, (+) -gossypol [ (+) -gossypol)]The content is higher; in the tropical poplar leaf of hibiscus, optically pure (+) -gossypol exists, but the optically pure (-) -gossypol is not directly separated from the plant so far. Generally optically pure (-) -gossypol is obtained by the resolution of racemic gossypol, such as the reaction of racemic gossypol with (+) -phenylalanine methyl ester to form diastereomers of the schiff base, followed by separation by column chromatography and subsequent hydrolysis to yield optically pure gossypol (Matlin, s.a.; Belenguer, a.; Tyson, r.g. and brooks, a.n.1987, 10, 86-91), respectively. Jiang reported a series of Schiff base derivatives of chiral gossypol, tested anticancer activities of the derivatives on three cells of human cervical cancer (HeLa), glioblastoma (U87) and gastric cancer (M85), and found that partial (-) -gossypol derivatives show better anticancer activities on three cancer cells than the parent compound and Cisplatin (Cisplatin). (Zhang, L.; Jiang, H.X.; Cao, X.X.; Zhao, H.Y.; Wang, F.; Cui, Y.X.and Jiang, B.Eur.J.Med.chem.2009, 44, 3961-. Yang et al synthesized a series of amino acid and amino acid ester gossypol derivatives in 2012, and tested them against HIV-1 and H5N1Viral activity (Yang, J.; Zhang, F.; Li, J.R.; Chen, G.; Wu, S.W.; Ouyang, W.J.; Pan, W.; Yu, R.; Yang, J.X.and Tien, P.Bioorg.Med.Chem.Lett.2012, 22, 1415-. The test results show that gossypol has anti-HIV-1 activity, but the inhibition is not strong, and (+) -gossypol has little activity. The research on the anti-HIV-1 activity of the (-) -gossypol amino acid derivative discovers that the fatty (-) -gossypol amino acid derivative has better activity and lower toxicity. The analysis of the action mechanism of alanine-derived (-) -gossypol suggests that gossypol and its derivatives may beRather than acting on reverse transcriptase to inhibit HIV-1 replication, (-) -gossypol binds to the hydrophobic pocket of gp41, blocking gp 41-mediated fusion of HIV to CD4 cells, thereby inhibiting HIV virus entry into the cell (An, t.; Ouyang, w.j.; Pan, w.; Guo, d.y.; Li, j.r.; Li, l.l.; Chen, g.and Yang, j.antipir.res.2012, 94, 276-287). Literature reports that gossypol is not only against HIV-1, H5N1 has activity [ (a) Yang, j.; chen, g.; li, l.l.; pan, w.; zhang, f.; yang, j.; wu, s.and Tien, p.bioorg.med.chem.lett.2013, 23, 2619-; (b) yang, j.; zhang, f.; li, j.r.; chen, g.; wu, s.w.; ouyang, w.j.; pan, w.; yu, r.; yang, j.x.and Tien, p.bioorg.med.chem.lett.2012, 22, 1415-; (c) field wave; wu-uncl Wen; yang Jian. Gossypol amino acid derivatives for blocking human immunodeficiency virus invasion, and its preparation method and application are provided. CN101844994A, 2010.]Also for HSV-2[ (a) Wichmann, K; vaheri, a; luukkainen, T.am.J.Obstet.Gynecol.1982, 142, 593-594; (b) radloff, r.j.; deck, l.m.; royer, R.E.and Vander Jagt, D.L.Pharmacol.Res.Commun.1986, 18, 1063-]And influenza viruses (Vichkanova, S.A.; Oifa, A.I.and Goryunova, L.V.Antibiotiki 1970, 15, 1071-1073) and the like, but are inactive against non-enveloped viruses such as polio and the like. Thus, it has been asserted that gossypol has no effect on non-enveloped viruses. However, in recent years, Wuyunfeng is the first report in Chinese invention patent (Wuyunfeng. polyhydroxy dinaphthaldehyde fatty acid preparation and preparation method CN 1489904, 2004-04-21) that gossypol fatty acid preparation has activity against tobacco mosaic disease, the most significant effect is obtained when the ratio of gossypol and fatty acid is 2: 3, and tobacco mosaic virus is a typical non-enveloped virus. This has stimulated our interest in studying the antiviral activity of gossypol compounds, and subsequently, our (wang mingmen group) study found that racemic gossypol aromatic and aliphatic amine schiff bases also have very high anti-TMV activity [ (a) Li, l.; li, z.and Wang, q.m.j.agric.food chem., 2014, 62, 11080-; li, Z.; wang, k.l.; liu, Y.X.and Wang, Q.M.Bioorg.Med.chem., 2016, 24, 474-483 (c) Wang Qingmin, Li Ling, Liuyuxiu, Li Nengqiang, Li Shang, WangAnd (5) turning on. Aromatic amine Schiff base derivatives of gossypol, and their preparation method and application in resisting plant virus are provided. CN 104910041A, 2015.(d) Wang Qingmin, Li Ling, Liuyuxiu, Wangzzhen and Li Neng Qiang. Gossypol derivatives and their preparation, application in pesticide and anticancer activity. CN105884634A, 2016]However, no report has been made on the anti-TMV activity of optically pure gossypol derivatives or after the introduction of chiral substituents into racemic gossypol.
Disclosure of Invention
The invention relates to synthesis of a gossypol Schiff base derivative (general formula I) and application of the gossypol Schiff base derivative in resisting tobacco mosaic virus.
Figure DEST_PATH_GSB0000162778460000031
General formula I
When the configuration of the gossypol Schiff base in the general formula I is levo (-) or dextro (+), R represents an aromatic group: benzene, biphenyl, fused aromatic rings, aromatic heterocycles, various electron donating and electron withdrawing aromatic rings; fatty group: various alkanes, alkenes, dienes, alkynes, alkylsulfonic acids; amino acids: various D and L configuration natural and unnatural amino acids; when the configuration of the gossypol Schiff base is racemic, R represents various natural and unnatural amino acids with D configuration and L configuration. The compounds of the present invention, including but not limited to the compounds of figures 1 and 2.
The invention also aims to provide a preparation method of the racemic gossypol amino acid compound, which is characterized by three points, the first point and simple operation. Secondly, the raw material is made of cheaper gossypol acetate rather than more expensive gossypol. And the third point is that the pure gossypol polar amino acid compound which cannot be prepared by the conventional method can be prepared.
The racemic gossypol amino acid compound shown in the general formula I can be prepared by the first method: the condensation reaction of the racemized gossypol acetate and the D or L amino acid in the methanol solution in the presence of alkali,
Figure DEST_PATH_GSB0000162778460000041
method 1
The invention also aims to provide a preparation method of the optically pure gossypol Schiff base, which is characterized by simple operation, mild reaction conditions and easy purification.
The chiral gossypol Schiff base compound shown in the general formula I can be prepared by a second method: the condensation reaction of levo-or dextro-gossypol and primary amine,
Figure DEST_PATH_GSB0000162778460000042
method two
The chiral gossypol Schiff base compound shown in the general formula I can be prepared by a third method: the condensation reaction of levo-or dextro-gossypol and primary amine,
Figure DEST_PATH_GSB0000162778460000051
method III
The invention also aims to provide application of racemic gossypol D or L amino acid Schiff base and optically pure gossypol Schiff base derivatives in tobacco mosaic virus resistance. Compared with ribavirin, the compound shown in the general formula I has remarkable TMV (Tetramethylbenzidine) resisting activity, can effectively inhibit tobacco mosaic virus, can effectively prevent tobacco, rice, hot pepper, tomato, sweet potato, melons, corn and the like, and is particularly suitable for preventing the tobacco mosaic virus.
The compound can be used as a gossypol tobacco mosaic virus resistant preparation directly, can be added with a carrier for use, and can also be used as a tobacco mosaic virus resistant agent and other tobacco mosaic virus resistant preparations, such as diazosulfide (BTH), Tiadinil (TDL), 4-methyl-1, 2, 3-thiadiazole-5-carboxylic acid (TDLA), D or L-beta-aminosuccinic acid, ribavirin, ningnanmycin, benzindolidine alkaloid, bitriazole compounds XY-13 and XY-30, virus A, salicylic acid, amino oligosaccharide and polyoligosaccharide for forming an interaction composition. These compositions exhibit either a competing or additive effect.
The invention has the following advantages: the compound is characterized by good water solubility, thermal stability, water solubility, organic solvent solubility and biological activity, easy synthesis, good environmental compatibility and safety to non-target organisms.
Description of the drawings:
FIG. 1 Structure of gossypol amino acid compound.
FIG. 2 shows the structure of optically pure derivatives of gossypol.
Detailed Description
EXAMPLE 1 Synthesis of Gossypol D-phenylglycine Schiff base (method one)
Figure DEST_PATH_GSB0000162778460000061
Method 1
In a 100mL round-bottomed flask, 0.069g (1.73mmol) of sodium hydroxide, 0.50g (0.86mmol) of gossypol acetate and 40mL of anhydrous methanol were added, and after complete dissolution, D-phenylglycine (1.73mmol) was added, and the reaction mixture was refluxed for 5 hours. Naturally cooling to room temperature, filtering the reaction solution, spin-drying the mother solution to 1/3 of the original volume, adding dichloromethane into the mother solution to form a light yellow solid, and filtering to obtain a solid 1, a yellow solid; moisture absorption is easy, and the yield is 53%;1H NMR(400MHz，DMSO-d6)，δ13.64(s，2H)，9.67(s，2H)，8.60(s，2H)，7.35-7.22(m，12H)，4.86(s，2H)，3.66(s，2H)，1.83(s，6H)，1.42(s，12H)；13C NMR(100MHz，DMSO-d6)，δ171.8，170.4，162.3，160.5，146.6，142.0，135.5，131.3，129.2，128.8，128.6，128.4，127.4，127.3，126.5，116.9，104.3，68.7，64.4，27.0，20.9.HRMS(ESI)m/z calcd for C46H43N2O10(M-2Na+H)-783.2923，found 783.2916.
general synthetic methods: in a 100mL round-bottomed flask, 0.46g (0.86mmol) of gossypol, 0.069g (1.73mmol) of sodium hydroxide and 40mL of absolute ethanol were added after complete dissolution, and then D-phenylglycine (1.73mmol) was added, and the reaction solution was heated under reflux for 5 hours. Naturally cooling to room temperature, filtering the reaction solution, and obtaining the solid product (the gossypol amino acid derivative for blocking the invasion of the human immunodeficiency virus, the preparation method and the application). The synthesis innovation point is that pure gossypol polar amino acid Schiff base is obtained by the method of changing the solvent from ethanol to methanol and adding dichloromethane to precipitate a product, which cannot be obtained by the conventional method. For example, a compound such as gossypol serine cannot be obtained by a conventional method, and a compound with a pure nuclear magnetic spectrum cannot be obtained by the conventional method, so that the problem is solved by the conventional method. Secondly, the synthesis of the amino acid compounds of gossypol from gossypol acetate instead of the prior art which uses relatively expensive gossypol as the raw material provides a more economical method for the preparation of gossypol amino acids.
Example 2
Derivatives of the Schiff base of gossypol amino acids (2-16) the procedure of example 1 was followed
Compound 2, yellow solid, is moisture-absorbing; yield, 72%;1H NMR(400MHz，DMSO-d6)，δ13.19(m，2H)，9.62(d，J＝12.3Hz，1H)，9.50(d，J＝12.3Hz，1H)，8.45(s，2H)，7.38-7.09(m，14H)，3.96(s，2H)，3.68(m，2H)，3.09-2.85(m，4H)，1.92(s，3H)，1.89(s，3H)，1.43(m，12H)；13C NMR(100MHz，DMSO-d6)，δ171.5，170.9，160.5，149.9，146.4，138.1，130.7，129.4，128.1，126.5，126.0，125.5， 120.5，116.3，116.1，103.0，65.9，36.9，26.4，20.3.HRMS(ESI)m/z calcd for C48H47N2O10(M-2Na+H)-811.3236，found 811.3222.
compound 3, yellow solid, is moisture-absorbing; yield, 43%;1H NMR(400MHz，DMSO-d6)，δ13.28-13.19(m，2H)，10.91(s，1H)，10.75(s，1H)，9.63(s，1H)，9.44(s，1H)，8.47(s，2H)，7.53-6.84(m，12H)，4.04(s，2H)，3.66(m，2H)，3.15-3.06(m，4H)，1.91(s，3H)，1.86(s，3H)，1.42(s，12H)；13C NMR(100MHz，DMSO-d6)，δ172.3，171.1，161.1，146.9，136.6，131.0，127.8，127.0，125.7，124.4，124.2，121.0，118.8，118.6，116.6，111.6，110.7，103.27，65.3，55.1，31.2，26.9，20.9.HRMS(ESI)m/z calcd for C52H49N4O10(M-2Na+H)-889.3454，found 889.3477.
compound 4, yellow solid, is moisture-absorbing; yield, 39%;1H NMR(400MHz，DMSO-d6)，δ13.16(s，2H)，9.69-9.65(m，2H)，8.51(s，2H)，7.40-7.39(m，2H)，3.89-3.88(m，2H)，3.68-3.62(m，4H)，1.92-1.90(m，6H)，1.43-1.41(m，12H)，1.05-1.02(m，6H)；13C NMR(100MHz，DMSO-d6)，δ172.0，171.3，161.7，151.8，146.7，131.2，126.8，126.2，122.7，117.1，115.9，103.9，70.1，67.7，55.5，27.0，22.7，20.9，20.2.HRMS(ESI)m/z calcd for C38H49N2O12(M-2Na+H)-719.2821，found719.2804.
compound 5, yellow solid, is moisture-absorbing; yield, 67%;1H NMR(400MHz，DMSO-d6)，δ13.25(s，2H)，9.76-9.72(m，2H)，8.52(s，2H)，7.39(d，J＝6.1Hz，2H)，3.81-3.51(m，10H)，1.92-1.90(m，6H)，1.43-1.42(m，12H)；13C NMR(100MHz，DMSO-d6)，δ170.8，169.8，161.0，149.9，146.4，130.6，126.5，125.4，120.2，116.5，116.1，103.2，66.4，63.8，60.7，26.4，20.4，20.2.HRMS(ESI)m/z calcd for C36H39N2O12(M-2Na+H)-691.2508，found 691.2479.
compound 6, yellow solid, is moisture-absorbing; yield, 86%;1H NMR(400MHz，DMSO-d6)，δ13.25(s，2H)，9.74(s，2H)，8.47(s，2H)，7.37(d，J＝12.0Hz，2H)，4.18-4.09(m，2H)，3.80-3.78(m，4H)，3.00-2.90(m，2H)，1.89-1.86(m-，6H)，1.42-1.38(m，12H)，0.83(s，2H).C36H39N2O10S2(M-2Na+H)-723.2054，found 723.1992.
compound 7, yellow solid, is moisture-absorbing; yield, 83%;1H NMR(400MHz，DMSO-d6)，δ13.20(s，2H)，9.68(d，J＝12.5Hz，2H)，8.52(s，2H)，7.39(s，2H)，3.68(m，2H)，3.51(s，2H)，2.21(m，2H)，1.94-1.91(m，6H)，1.45-1.41(m，12H)，0.88-0.84(m，12H)；13C NMR(100MHz，DMSO-d6)，δ172.4，171.4，161.3，150.7，146.9，131.1，126.9，126.1，121.3，117.0，116.6，103.5，71.2，32.1，27.0，20.9，20.1，17.7.HRMS(ESI)m/z calcd for C40H47N2O10(M-2Na+H)-715.3236，found 715.3231.
compound 8, yellow solid, is hygroscopic; yield, 82%;1H NMR(400MHz，DMSO-d6)，δ13.27(s，2H)，9.77(s，2H)，8.51(s，2H)，7.39(s，2H)，3.77(s，2H)，3.69(s，2H)，1.92(s，6H)，1.65-1.57(m，6H)，1.43(s，12H)，0.86(s，12H)；13C NMR(100MHz，DMSO-d6)，δ172.9，171.3，160.9，151.0，146.9，131.3，127.0，126.1，121.9，117.3，116.6，103.6，64.0，43.8，26.9，24.6，23.6，22.13，20.8.HRMS(ESI)m/z calcd for C42H51N2O10(M-2Na+H)-743.3549，found 743.3535.
compound 9, a yellow solid, is moisture-absorbing; yield, 43%;1H NMR(400MHz，DMSO-d6)，δ13.22(s，2H)，9.71(s，2H)，8.47(s，2H)，7.56(s，2H)，7.37(s，2H)，6.86(d，J＝32.5Hz，2H)，4.05(m，2H)，3.69-3.66(m，2H)，2.75-2.71(m，2H)，2.44-2.38(m，2H)，1.94-1.90(m，6H)，1.45-1.41(m，12H).13C NMR(100MHz，DMSO-d6)，δ172.0，171.8，170.7，161.1，151.2，146.5，130.6，126.4，125.5，120.7，116.4，115.8，103.0，61.354.8，26.4，21.8，20.3，20.2.HRMS(ESI)m/z calcd for C38H43N4O12(M-2Na+3H)+747.2877，found 747.2871.
compound 10, yellow solid, is moisture-absorbing; yield, 42%;1H NMR(400MHz，DMSO-d6)，δ13.22(s，2H)，9.74(s，2H)，8.48(s，2H)，7.38(d，J＝10.4Hz，4H)，6.89(s，2H)，3.78-3.68(m，4H)，2.09-1.92(m，14H)，1.45-1.42(m，6H)；13C NMR(100MHz，DMSO-d6)，δ174.3，172.3，171.4，160.5，151.0，146.9，131.2，127.0，126.1，121.0116.9，109.9，103.6，64.5，64.3，56.49，31.8，30.8，27.0，20.9，20.7.HRMS(ESI)m/z calcd for C40H45N4O12(M-2Na+3H)+775.3190，found 775.3192.
compound 11, yellow solid, is hygroscopic; yield, 70%;1H NMR(400MHz，DMSO-d6)，δ13.16(m，2H)，9.62(d，J＝12.3Hz，1H)，9.58(d，J＝12.3Hz，1H)，8.46(s，2H)，7.38-7.09(m，14H)，3.96(s，2H)，3.68(m，2H)，3.09-2.85(m，4H)，1.90-1.87(d，J＝13.6H，6H)，1.42(t，J＝5.6Hz，12H).
compound 12, a yellow solid, is moisture-absorbing; yield, 41%;1H NMR(400MHz，DMSO-d6)，δ13.12(s，2H)，9.73-9.66(m，2H)，8.51(s，2H)，7.40-7.38(m，2H)，3.89-3.88(m，2H)，3.68-3.62(m，4H)，1.92(s，6H)，1.43-1.41(m，12H)，1.04-1.00(m，6H).
compound 13, yellow solid, is hygroscopic; yield, 71%;1H NMR(400MHz，DMSO-d6)，δ13.25(s，2H)，9.70(m，2H)，8.50(s，2H)，7.39(d，J＝6.1Hz，2H)，3.76-3.50(m，10H)，1.94-1.89(m，J＝10.8Hz，6H)，1.45-1.42(m，12H).
compound 14, a yellow solid, is hygroscopic; yield, 46%;1H NMR(400MHz，DMSO-d6)，δ13.22(s，2H)，9.71(s，2H)，8.48(s，2H)，7.56(s，2H)，7.37(s，2H)，6.86(d，J＝32.5Hz，2H)，4.05(m，2H)，3.71-3.64(m，2H)，2.74-2.71(m，2H)，2.44-2.38(m，2H)，1.92-1.90(m，6H)，1.43(m，12H).
compound 15, yellow solid, is moisture-absorbing; yield, 47%;1H NMR(400MHz，DMSO-d6)，δ13.28-13.19(m，2H)，10.91(s，1H)，10.75(s，1H)，9.63(s，1H)，9.42(s，1H)，8.47(s，2H)，7.53-6.82(m，12H)，4.04(s，2H)，3.69-3.63(m，2H)，3.39(m，2H)，3.16-3.06(m，4H)，1.89-1.85(m，6H)，1.42(s，12H).
compound 16, a yellow solid, is hygroscopic; yield, 88%;1H NMR(400MHz，DMSO-d6)，δ13.25-13.18(s，2H)，9.75(t，J＝12.8Hz，2H)，8.50(s，2H)，7.39(s，2H)，3.88-3.79(m，2H)，3.72-3.65(m，2H)，2.08-1.81(m，20H)，1.45-1.38(m，12H).
example 3 Synthesis of L-gossypol and D-gossypol o-trifluoroaniline Schiff base (method two)
Figure DEST_PATH_GSB0000162778460000091
Method two
In a 100mL round-bottomed flask, 0.46g (0.86mmol) of L-or D-gossypol was added to 40mL of anhydrous ethanol, after complete dissolution, o-trifluoroaniline (1.73mmol) was added, and the reaction solution was heated under reflux for 5 hours. Naturally cooling to room temperature, filtering the reaction solution, and recrystallizing the solid with pyridine to obtain the target compound. Compound 21, yellow solid; yield, 67%;1H NMR(400MHz，DMSO-d6)δ15.38(d，J＝8.4Hz，2H)，10.38(d，J＝8.4Hz，2H)，8.79(s，2H)，8.35(s，2H)，7.81(d，J＝7.6Hz，2H)，7.75(t，J＝7.2Hz，2H)，7.57(J＝8.4Hz，2H)，7.42(t，J＝7.6Hz，2H)，3.81-3.74(m，2H)，2.01(s，6H)，1.43(m，12H).13C NMR(100MHz，DMSO-d6)δ171.4，157.2，151.0，147.8，146.2，140.4，134.9，133.6，131.0，128.8，127.3，126.1，125.7，123.0，121.7，119.7，117.6，115.8，108.1，27.1，20.6.HRMS(ESI)m/z calcd for C44H37F6N2O6(M-H)-803.2561，found803.2541.
Figure DEST_PATH_GSB0000162778460000092
(c 0.105，CH3OH).
compound 22, yellow solid;yield, 85%;1H NMR(400MHz，DMSO-d6)δ15.38(d，J＝8.4Hz，2H)，10.38(d，J＝8.4Hz，2H)，8.78(s，2H)，8.35(s，2H)，7.82(d，J＝7.6Hz，2H)，7.74(t，J＝7.2Hz，2H)，7.57(s，2H)，7.42(t，J＝7.6Hz，2H)，3.81-3.74(m，2H)，2.01(s，6H)，1.45(d，4H).13C NMR(101 MHz，DMSO-d6)δ171.4，157.2，150.9，146.2，140.4，134.8，133.5，130.9，128.8，127.4，126.1，123.0，121.7，119.7，119.3，117.6，115.8，108.0，27.1，20.6.HRMS(ESI)m/z calcd for C44H37F6N2O6(M-H)-803.2561，found 803.2537.
Figure DEST_PATH_GSB0000162778460000101
(c 0.105，CH3OH).
example 4
The steps of the process of example 3 are followed to obtain 17-20, 23-24, 29-30 derivatives of gossypol Schiff base
Compound 17, yellow solid, yield, 84%;1H NMR(300MHz，DMSO-d6)，δ13.48(dd，J＝4.8，12.5Hz，2H)，10.92(s，2H)，9.64(d，J＝12.6Hz，2H)，8.44(s，2H)，7.61(s，2H)，7.48-6.89(m，12H)，4.82-4.76(m，2H)，3.67(s，8H)，3.43-3.35(m，4H)，1.92(s，6H)，1.42(d，J＝6.4Hz，12H)；13C NMR(100MHz，DMSO-d6)，δ238.3，173.1，171.4，170.3，169.0，161.8，150.2，146.7，136.6，132.0，127.6，127.4，124.7，121.5，121.0，119.0，118.5，117.1，116.2，111.0，108.2，104.4，62.5，53.0，29.4，27.0，20.8，20.7.
compound 18, yellow solid, yield, 75%;1H NMR(300MHz，DMSO-d6)，δ13.47(dd，J＝4.8，12.5Hz，2H)，10.92(s，2H)，9.76(d，J＝12.6Hz，2H)，8.44(s，2H)，7.81(s，2H)，7.48-6.91(m，12H)，4.82-4.76(m，2H)，3.66(s，8H)，3.46-3.35(m，4H)，1.93(s，6H)，1.43(d，J＝6.4Hz，12H).13C NMR(100MHz，DMSO-d6)，δ238.34，173.12，171.35，170.3，161.8，150.2，146.7，136.6，132.0，127.6，127.4，124.7，121.5，121.0，119.0，118.5，117.1，116.2，112.0，108.2，104.4，62.5，53.0，29.4，27.0，20.8，20.7.
compound 19, yellow solid, yield, 84%;1H NMR(300MHz，DMSO-d6)，δ13.51-13.45(m，2H)，10.92(s，2H)，9.77(d，J＝12.6Hz，2H)，8.44(s，2H)，7.81(s，2H)，7.48-6.93(m，12H)，4.82-4.76(m，2H)，3.66(s，8H)，3.46-3.35(m，4H)，1.93(s，6H)，1.43(d，J＝6.4Hz，12H).
compound 20, yellow solid, yield, 84%;1H NMR(400MHz，DMSO-d6)，δ13.48-13.43(m，2H)，10.92(s，2H)，9.64(d，J＝12.6Hz，2H)，8.43(s，2H)，7.61(s，2H)，7.48-6.89(m，12H)，4.82-4.76(m，2H)，3.67(s，8H)，3.43-3.35(m，4H)，1.92(s，6H)，1.42(d，J＝6.4Hz，12H).
compound 23, yellow solid; yield, 88%;1H NMR(400MHz，DMSO-d6)δ13.29(d，J＝12Hz，2H)，9.76(d，J＝12Hz，2H)，8.41(s，2H)，7.84(s，2H)，7.44(s，2H)，3.72-3.68(m，2H)，3.52-3.45(m，4H)，1.93(s，6H)，1.66-1.63(m，4H)，1.45-1.42(m，12H)，0.96-0.92(m，6H).13C NMR(100MHz，DMSO-d6)δ171.6，162.5，149.6，146.2，131.1，126.8，126.3，120.1，116.5，115.9，103.0，51.5，26.5，23.2，20.3，20.3，20.2，10.9.HRMS(ESI)m/z calcd for C36H43N2O6(M-H)-599.3127，found599.3117.
Figure DEST_PATH_GSB0000162778460000102
(c 0.105，CH3OH).
compound 24, yellow solid; yield, 77%;1H NMR(400MHz，DMSO-d6)13.29(d，J＝12.8Hz，2H)，9.77(d，J＝12.8Hz，2H)，8.41(s，2H)，7.84(s，2H)，7.44(s，2H)，3.721(m，2H)，3.47(m，4H)，1.93(s，6H)，1.66(m，4H)，1.44(m，12H)，0.93(m，6H).13C NMR(100MHz，DMSO-d6)δ171.5，162.4，149.5，146.2，131.1，126.7，125.3，120.1，116.4，115.8，103.5，51.4，26.4，23.2，20.8，20.8，20.7.HRMS(ESI)m/z calcd for C36H43N2O6(M-H)-599.3127，found 599.3103.
Figure DEST_PATH_GSB0000162778460000111
(c 0.105，CH3OH).
compound 29, yellow solid; yield, 94%;1H NMR(400MHz，CDCl3)δ14.84(d，J＝12Hz，2H)，10.13(d，J＝12Hz，2H)，8.62(s，2H)，8.25-8.23(m，4H)，7.69(s，2H)，7.38-7.35(m，4H)，5.84(s，2H)，3.73-3.70(m，2H)，2.17(s，6H)，1.55-1.51(m，12H).13C NMR(101MHz，DMSO-d6)δ155.7，152.8，147.2，139.7，138.6，136.0，126.3，125.9，124.2，121.3，117.0，115.0，113.6，113.2，108.9，90.1，26.6，21.4，21.3.HRMS(ESI)m/z calcd for C42H37N4O10(M-H)-757.2515，found 757.2486.
Figure DEST_PATH_GSB0000162778460000112
(c 0.109，DMF).
compound 30, yellow solid; yield, 83%;1H NMR(400MHz，CDCl3)δ14.84(d，J＝12Hz，2H)，10.12(d，J＝12Hz，2H)，8.62(s，2H)，8.25-8.23(m，4H)，7.69(s，2H)，7.38-7.35(m，4H)，5.81(s，2H)，3.73-3.70(m，2H)，2.17(s，6H)，1.55-1.51(m，12H).13C NMR(101MHz，DMSO-d6).δ155.3，152.3，146.7，139.1，138.1，138.0，135.7，125.8，125.6，123.7，120.9，114.6，113.2，112.7，108.4，89.7，26.1，20.8，20.7.HRMS(ESI)m/z calcd for C42H37N4O10(M-H)-757.2515，found 757.2426.
Figure DEST_PATH_GSB0000162778460000113
(c 0.109，DMF).
example 5 Synthesis of Hiff base Levogossypol and D-gossypol aminomethanesulfonic acid (method three)
Figure DEST_PATH_GSB0000162778460000114
Figure DEST_PATH_GSB0000162778460000121
Method III
In a 100mL round-bottomed flask, 0.069g (1.73mmol) of sodium hydroxide, 0.46g (0.86mmol) of L-or D-gossypol and 40mL of absolute ethanol were added, and after complete dissolution, aminomethanesulfonic acid (1.73mmol) was added, and the reaction solution was heated under reflux for 5 hours. Naturally cooling to room temperature, filtering the reaction solution, and recrystallizing the solid with a proper pyridine solvent to obtain the target compound. Compound 25, yellow solid; deliquescence, yield, 81%;1H NMR(400MHz，DMSO-d6)δ13.37(s，2H)，9.68(d，J＝8Hz)，8.42(s，2H)，7.43(s，2H)，4.22(s，4H)，3.71-3.64(m，2H)，1.93(s，6H)，1.44(s，12H)13C NMR(100MHz，DMSO-d6)δ172.3，162.8，149.8，146.3，131.3，127.0，126.7，120.2，116.5，115.8，103.7，65.5，26.5，20.3.HRMS(ESI)m/z calcd for C32H35N2O12S2(M-2Na+H)-703.1637，found703.1607.
Figure DEST_PATH_GSB0000162778460000124
(c 0.112，CH3OH) compound 26, yellow solid; deliquescence, yield, 79%;1H NMR(400MHz，DMSO-d6)δ13.38(d，J＝12Hz，2H)，9.69(d，J＝12Hz，2H)，8.44(s，2H)，7.43(s，2H)，4.20(s，4H)，3.73-3.68(m，2H)，1.92(s，6H)，1.43(s，12H).13C NMR(101MHz，DMSO-d6)δ172.3，162.8，149.9，146.2，131.3，126.9，126.7，120.2，116.4，115.8，103.7，65.6，26.5，20.2.HRMS(ESI)m/z calcd for C32H35N2O12S2(M-2Na+H)-703.1637，found 703.1620.
Figure DEST_PATH_GSB0000162778460000122
(c 0.112，CH3OH).
example 6
The gossypol Schiff base derivatives 27-28 were prepared according to the procedure of example 5
Compound 27, yellow solid; deliquescence, yield, 87%;1H NMR(400MHz，DMSO-d6)1H NMR(400MHz，DMSO-d6)δ13.03(d，J＝9.6Hz，2H)，9.76(d，J＝9.6Hz，2H)，8.54(s，2H)，7.42(s，2H)，3.78-3.77(m，4H)，3.71-3.69(m，2H)，2.80-2.84(m，4H)，1.93(s，6H)，1.44(s，12H).13C NMR(101MHz，DMSO-d6)δ171.6，168.9，149.8，146.5，131.0，126.8，126.4，120.4，116.1，103.2，9.6，50.9，47.7，26.2，20.2，19.7.HRMS(ESI)m/z calcd for C34H39N2O12S2(M-2Na+H)-731.1950，found731.1915.
Figure DEST_PATH_GSB0000162778460000123
(c 0.111，CH3OH).
compound 28, yellow solid; deliquescence, yield, 89%;1H NMR(400MHz，DMSO-d6)δ13.03(d，J＝9.6Hz，2H)，9.76(d，J＝9.6Hz，2H)，8.50(s，2H)，7.41(s，2H)，3.77-3.76(m，4H)，3.71-3.67(m，2H)，2.80-2.84(m，4H)，1.93(s，6H)，1.44(s，12H).13C NMR(101MHz，DMSO-d6)δ172.1，162.2，150.0，147.1，131.5，127.4，126.9，120.7，116.9，116.6，103.7，51.3，48.1，27.0，20.8.HRMS(ESI)m/z calcd for C34H39N2O12S2(M-2Na+H)-731.1950，found 731.1929.
Figure DEST_PATH_GSB0000162778460000131
(c 0.111，CH3OH).
example 7: method for measuring activity of resisting tobacco mosaic virus by conventional in vivo bioassay method
1. 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 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 leaf surfaces are supported by palms, the virus concentration is 10 mu g/mL, and the inoculated leaf surfaces are washed by running water. And recording the number of the disease spots after 3d, and calculating the prevention effect.
2. 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.
3. 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. And counting the number of the scabs 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%
Table 1 shows the results of the activity test of some compounds against tobacco mosaic virus.
Figure DEST_PATH_GSB0000162778460000132
Figure DEST_PATH_GSB0000162778460000141
Figure DEST_PATH_GSB0000162778460000151
Figure DEST_PATH_GSB0000162778460000161
As can be seen from Table 1, the activity (inactivation, induction and protection) of the racemic gossypol Schiff base compound obtained by introducing chiral L-or D-amino acid into racemic gossypol is obviously higher than that of racemic gossypol bulk and ribavirin. In particular, the Schiff base of racemic gossypol aspartic acid (compounds 9 and 14) has activity approaching that of gossypol bulk at 500. mu.g/mL even at 100. mu.g/mL. Meanwhile, the activity of the Schiff base of the gossypol D-amino acid is generally higher than that of the Schiff base of the gossypol L-amino acid, such as a compound 2 is more than a compound 11, a compound 4 is more than a compound 12, a compound 5 is more than a compound 13 and the like, so that the compound introducing the D-amino acid into the gossypol has more important effect on improving the activity of the gossypol. It can also be seen from the data in the table that the three anti-tobamoviral activities (inactivation, induction, protection) of levo-gossypol schiff base are generally higher than those of dextro-gossypol schiff base, such as compound 23 > compound 24, compound 25 > compound 26 (except for inactivating activity), compound 27 > compound 28, compound 29 > compound 30, while the activities of both schiff bases are higher than those of gossypol bulk or ribavirin. Further comparison of the products of the reaction of L-and D-gossypol with D-tryptophan methyl ester and L-tryptophan methyl ester (compounds 17, 18, 19 and 20) shows that the Schiff base compound 21 of L-gossypol D-tryptophan methyl ester has the best activity.
However, because the toxicity and activity of dextro-gossypol is much less than that of levo-gossypol, dextro-gossypol is often regarded as a useless and harmless configuration, and as can be seen from the above table, the schiff base of dextro-gossypol has good activity against tobacco mosaic virus compared with the gossypol itself, especially the compounds 26 and 28. Dextro-gossypol schiff base is also a very potent antiviral agent. From the above data, we can conclude that the introduction of chiral groups into racemic gossypol Schiff base or achiral groups into optically pure gossypol can improve the activity of gossypol against tobacco mosaic virus. The compounds in the class can be very potential anti-tobacco mosaic virus drugs.

Claims (1)

1. The application of the gossypol Schiff base derivative 25 with the structure shown in the specification in the aspect of protecting tobacco leaves at the concentration of 500 mu g/mL is characterized in that the compound 25 can protect the tobacco leaves from being invaded by tobacco mosaic virus at the concentration of 500 mu g/mL
Figure FSB0000190325920000011
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Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104910041A (en) * 2014-03-12 2015-09-16 南开大学 Aromatic amine schiff base derivative of gossypol and preparation method and plant-virus resisting application thereof

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
An expedient route for the practical preparation of optically active (-)-gossypol;Hai-Xia Jiang等;《Tetrahedron: Asymmetry》;20071231;第18卷;第2437–2441页 *
Antiviral mechanism study of gossypol and its Schiff base derivatives based on reactive oxygen species (ROS);Bin Zhang等;《RSC Adv.》;20160819;第87637-87648页 *
Synthesis and antiviral, insecticidal, and fungicidal activities of gossypol derivatives containing alkylimine, oxime or hydrazine moiety;Ling Li等;《Bioorganic & Medicinal Chemistry》;20150820;第24卷;第474-483页 *
ynthesis and antiviral activities of novel gossypol derivatives;Jian Yang等;《Bioorganic & Medicinal Chemistry Letters》;20111221;第22卷;第1415–1420页 *
无;无;《STN REGISTRY》;20120307 *

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