CN115246835A - Hydrazone structure-containing Aldisin derivative and preparation and application thereof - Google Patents
Hydrazone structure-containing Aldisin derivative and preparation and application thereof Download PDFInfo
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Abstract
The invention relates to an Aldisin derivative containing a hydrazone structure, a preparation method thereof and application of the derivative in the aspects of preventing and treating plant viruses, sterilizing and killing insects, wherein the meanings of all groups in a general formula are shown in an instruction book. The hydrazone structure-containing Aldisin derivative has excellent plant virus resisting activity, and also has broad-spectrum bactericidal activity and insecticidal activity.
Description
Technical Field
The invention relates to an Aldisin derivative containing a hydrazone structure, a preparation method thereof and application of the derivative in the aspects of plant virus prevention and control, insect killing and sterilization, and belongs to the technical field of agricultural protection.
Background
In 1985, the Schmitz subject group at the university of Oklahoma was first isolated from the Gekko sponge Hymeniacidon aldis de laubenfelsThe alkaloid Aldisin with a pyrrololactam structure (j. Nat. Prod.1985, 48, 47-53). In 2004, the Tepe subject group derived the structure of the alkaloid Hymenialdisine with an Aldisin structure, and studied the biological activity of the derivative, and the research result shows that the IC of the Hymenialdisine for inhibiting the effects of interleukin-2 and tumor necrosis factor-alpha 50 Values were 2.4 μ M and 1.4 μ M (j.med.chem.2004, 11, 247-259.) respectively. In the same year, the Tepe topic group has further acted Hymenialdisine on six different kinases including CK1 δ (h), CK2 (h), MEK1 (h), PKC α (h), PKCbII (h), chk1 and Chk2, and the results of biological tests show that: hymenialrine has good inhibitory activity on MEK1 (h), and IC thereof 50 Values were 6nM (bioorg.med.chem.lett.2004, 14, 4319-4321.). Up to now, no method for synthesizing hydrazone-structure-containing Aldisin derivatives I-1 to I-37 and the application of the derivatives I-1 to I-37 in the aspects of preventing and treating plant viruses, killing insects and sterilizing exist.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides an Aldisin derivative containing a hydrazone structure, a preparation method thereof and application of the derivative in the aspects of plant virus prevention and control, insect killing and sterilization. The Aldisin derivative has good plant virus prevention and control, insecticidal activity and broad-spectrum bactericidal activity.
The hydrazone structure-containing Aldisin derivative is a compound with a structure shown in the following general formula I:
wherein R represents hydrogen, substituted or unsubstituted benzyl; the substituent of the substituted benzyl is independently selected from one or more of hydroxyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, dioxymethylene and dioxyethylene;
R 1 、R 2 each represents hydrogen or R 1 、R 2 Are combined into
R 3 ；
R 3 Represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted quinolyl group, a substituted or unsubstituted indolyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted thienyl group; the substituent of the substituted phenyl, the substituted quinolyl, the substituted indolyl, the substituted pyridyl and the substituted thienyl is independently selected from one or more of halogen, C1-C6 alkyl, C1-C6 alkoxy and phenoxy.
The invention discloses a preparation method of an Aldisin derivative containing a hydrazone structure, which comprises the following steps: taking Aldisin as a raw material and ethanol as a solvent, and carrying out condensation reaction with hydrazine hydrate under the condition of heating reflux to obtain the hydrazone-containing derivative.
The preparation method of the hydrazone structure-containing Aldisin derivative comprises the following steps: taking Aldisin as a raw material and ethanol as a solvent, and carrying out condensation reaction with hydrazine hydrate under the condition of heating reflux to obtain a hydrazone-containing derivative; ethanol is used as a solvent, and the ethanol and aromatic aldehyde are subjected to addition elimination reaction at room temperature to obtain the hydrazone with the diimine structure.
The preparation method of the Aldisin derivative containing the hydrazone structure comprises the following steps: taking Aldisin and benzyl bromide as reactants, sodium carbonate as alkali, acetonitrile as a solvent, and heating under reflux to obtain a compound A; taking the compound A as a raw material and ethanol as a solvent, and carrying out condensation reaction with hydrazine hydrate under the condition of heating reflux to obtain the hydrazone derivative protected on pyrrole nitrogen.
The preparation method of the Aldisin derivative containing the hydrazone structure comprises the following steps: taking hydrazone derivatives protected on pyrrole nitrogen as raw materials, taking ethanol as a solvent, and carrying out addition elimination reaction with aromatic aldehyde at room temperature to obtain hydrazone with a diimine structure of the hydrazone derivatives protected on the pyrrole nitrogen.
The hydrazone structure-containing Aldisin derivative of the general formula shows good tobacco mosaic virus resistance activity.
The hydrazone-structure-containing Aldisin derivative of the general formula has the activity of killing armyworms, cotton bollworms, corn borers, diamondback moths and mosquito larvae.
The hydrazone structure-containing Aldisin derivatives of the general formula show bactericidal activity against the following 14 pathogenic bacteria: cucumber wilt, peanut brown spot, apple ring rot, wheat sharp spot, corn small spot, watermelon anthrax, rice bakanae, tomato early blight, wheat gibberella, rice blast, phytophthora capsici, rape sclerotium, cucumber gray mold and rice sharp rot.
The invention provides an Aldisin derivative containing a hydrazone structure, which is a compound shown as a general formula I:
wherein R represents hydrogen, substituted or unsubstituted benzyl; the substituent of the substituted benzyl is independently selected from one or more of hydroxyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, dioxymethylene and dioxyethylene;
R 1 、R 2 each represents hydrogen or R 1 、R 2 Are combined into
R 3 ；
R 3 Represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted quinolyl group, a substituted or unsubstituted indolyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted thienyl group; the substituent of the substituted phenyl, the substituted quinolyl, the substituted indolyl, the substituted pyridyl and the substituted thienyl is independently selected from one or more of halogen, C1-C6 alkyl, C1-C6 alkoxy and phenoxy.
In the present invention, specific examples of the alkyl group of C1 to C6 may be, for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.
The C1-C6 hydrocarbon group may be selected from the specific examples of the alkyl group described above and may satisfy the respective limitations.
The C1-C6 alkoxy group may be an alkoxy group formed by the above-mentioned specific examples of the alkyl group satisfying the definition of 1 to 6 carbon atoms.
Preferably, R represents hydrogen, substituted or unsubstituted benzyl; the substituents of the substituted benzyl groups are each independently selected from one or more of hydroxyl, F, cl, br, I, cyano, nitro, trifluoromethyl, trifluoromethoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy;
R 1 、R 2 each represents hydrogen or R 1 、R 2 Are combined into
R 3 ；
R 3 Represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted quinolyl group, a substituted or unsubstituted indolyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted thienyl group; said substitutionThe substituents of phenyl, substituted quinolyl, substituted indolyl, substituted pyridyl and substituted thienyl are each independently selected from one or more of F, cl, br, I, cyano, nitro, trifluoromethyl, trifluoromethoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy and phenoxy.
In a preferred embodiment of the present invention, the compound represented by the general formula I is one selected from the group consisting of compounds represented by the following formulae:
the invention provides a preparation method of an Aldisin derivative containing a hydrazone structure, which comprises the following steps: taking Aldisin as a raw material and ethanol as a solvent, and carrying out condensation reaction with hydrazine hydrate under the condition of heating reflux to obtain the hydrazone-containing derivative.
The invention provides a preparation method of an Aldisin derivative containing a hydrazone structure, which comprises the following steps: taking Aldisin as a raw material, taking ethanol as a solvent, carrying out condensation reaction with hydrazine hydrate under the condition of heating reflux to obtain a hydrazone-containing derivative, taking ethanol as a solvent, and carrying out addition elimination reaction with aromatic aldehyde under the condition of room temperature to obtain hydrazone with a diimine structure.
The invention provides a preparation method of an Aldisin derivative containing a hydrazone structure, which comprises the following steps: taking Aldisin and benzyl bromide as reactants, sodium carbonate as alkali, acetonitrile as solvent, and heating under reflux to obtain a compound A; taking the compound A as a raw material and ethanol as a solvent, and carrying out condensation reaction with hydrazine hydrate under the condition of heating reflux to obtain the hydrazone derivative protected on pyrrole nitrogen.
The invention provides a preparation method of an Aldisin derivative containing a hydrazone structure, which comprises the following steps: taking the hydrazone derivative protected on the pyrrole nitrogen as a raw material, taking ethanol as a solvent, and carrying out an addition elimination reaction with aromatic aldehyde at room temperature to obtain the hydrazone with the diimine structure of the hydrazone derivative protected on the pyrrole nitrogen.
Wherein R, R 3 As described above, the present invention is not described in detail herein.
The invention provides application of the hydrazone structure-containing Aldisin derivative in the aspect of plant virus activity resistance.
The hydrazone structure-containing Aldisin derivative provided by the invention has excellent anti-plant virus activity, and the hydrazone structure-containing Aldisin derivative shown in the general formula shows good anti-tobacco mosaic virus activity.
The hydrazone structure-containing Aldisin derivative provided by the invention has high insecticidal activity, and particularly has higher killing activity on one or more of armyworms, cotton bollworms, corn borers, diamond back moths and mosquito larvae.
The invention provides application of the hydrazone structure-containing Aldisin derivative in sterilization.
The hydrazone structure-containing Aldisin derivative provided by the invention has higher bactericidal activity, and especially aims at one or more of pathogenic bacteria causing cucumber wilt, peanut brown spots, apple ring rot, wheat sharp rot, corn speckles, watermelon anthracnose, rice bakanae disease, tomato early blight, wheat scab, rice blast, phytophthora capsici, rape sclerotium, cucumber gray mold and rice sharp rot.
The invention also provides a method for killing insects by using the hydrazone structure-containing Aldisin derivative as an anti-plant virus agent.
The invention also provides a method for killing insects by using the hydrazone structure-containing Aldisin derivative as an insecticide.
The invention also provides a method for sterilizing by using the hydrazone structure-containing Aldisin derivative as a bactericide.
The following examples and biological test results are provided to further illustrate the invention and are not meant to limit the invention.
Detailed Description
The following examples and biological test results are presented to further illustrate the invention and are not meant to limit the invention.
Example 1: synthesis of Aldisin derivative I-1.
I-1 Synthesis: aldisin (164mg, 1.00mmol) is weighed into a 50mL round-bottom flask, 10mL of absolute ethyl alcohol is added, then hydrazine hydrate is added, the reaction is heated and refluxed for 4h, and the reaction is detected to be complete by TLC. Pressurizing and desolventizing, then adding ethanol again, and repeatedly pressurizing and desolventizing to obtain 178mg of white solid, wherein the yield is quantitative, and the melting point is: 258 to 260 ℃. 1 H NMR(400MHz，DMSO-d 6 ) δ11.30(s，1H)，7.75(t，J＝5.3Hz，1H)，6.82(t，J＝2.8Hz，1H)，6.36(t，J＝2.7Hz，1H)，6.05(s， 2H)，3.24(q，J＝5.4Hz，2H)，2.54(d，J＝5.4Hz，2H). 13 C NMR(100MHz，DMSO-d 6 )δ164.9， 143.4，126.2，122.6，122.3，106.8，38.1，30.5.HRMS(ESI)：calcd for C 8 H 11 N 4 O[M+H] + 179.0927， found 179.0923.
Example 2: and (5) synthesizing Aldisin derivatives I-2 to I-14.
I-2 synthesis: i-1 (356mg, 2mmol) is weighed into a 100mL round-bottom flask, 40mL absolute ethanol is added, benzaldehyde (318mg, 3mmol) is added, the reaction is carried out for 4h at room temperature, and the completion of the reaction is detected by TLC. Decompression desolventizing, column chromatography separation to obtain yellow solid 490mg, yield 92%, smelting point 186-188 deg.c. 1 H NMR(400MHz，DMSO-d 6 )δ11.81(s，1H)，8.45(s，1H)，8.08(t，J＝5.1Hz，1H)，7.88-7.82(m，2H)，7.51-7.42(m，3H)，6.97(t，J＝2.8Hz， 1H)，6.71(t，J＝2.6Hz，1H)，3.32-3.26(m，2H)，3.18-3.07(m，2H). 13 C NMR(100MHz， DMSO-d 6 )δ163.0，162.9，156.8，134.5，130.7，128.8，128.0，126.2，122.9，122.2，107.7，37.6，31.6. HRMS(ESI)：calcd for[M+H] + 165.0659，found 165.0660.HRMS(ESI)：calcd for C 15 H 15 N 4 O [M+H] + 267.1240，found 267.1235.
Synthesis of I-3: the synthesis method is the same as I-2. Yellow solid, yield 89%, melting point 212-213 ℃. 1 H NMR(400 MHz，CDCl 3 )δ10.28(s，1H)，8.44(s，1H)，7.75(d，J＝8.4Hz，2H)，7.46(d，J＝8.4Hz，2H)，6.99 (dt，J＝13.3，2.8Hz，2H)，6.78(d，J＝5.4Hz，1H)，3.51(q，J＝5.0Hz，2H)，3.39-3.30(m，2H)， 1.35(s，9H). 13 C NMR(100MHz，CDCl 3 )δ165.1，162.4，157.9，154.3，132.0，128.2，125.7，125.1， 125.0，122.8，109.0，39.0，35.0，31.4，31.2.HRMS(ESI)：calcd for C 19 H 23 N 4 O[M+H] + 323.1866， found 323.1862.
I-4 Synthesis: the synthesis method is the same as I-2. Yellow solid, yield 92%, melting point 252-254 ℃. 1 H NMR(400 MHz，DMSO-d 6 )δ11.85(s，1H)，8.47(s，1H)，8.10(t，J＝5.1Hz，1H)，7.90-7.84(m，2H)，7.59- 7.52(m，2H)，6.97(t，J＝2.8Hz，1H)，6.71(t，J＝2.6Hz，1H)，3.29(q，J＝5.1Hz，2H)，3.13(d，J＝ 9.8Hz，2H). 13 C NMR(100MHz，DMSO-d 6 )δ163.8，163.5，156.2，135.7，133.9，130.1，129.4， 126.8，123.3，122.7，108.3，38.0，32.0.HRMS(ESI)：calcd for C 15 H 14 ClN 4 O[M+H] + 301.0851， found 301.0846.
Synthesis of I-5: the synthesis method is the same as I-2. Yellow solid, yield 93%, melting point 226-228 ℃. 1 H NMR(400 MHz，DMSO-d 6 )δ11.87(s，1H)，8.63(d，J＝7.6Hz，1H)，8.15-8.02(m，2H)，7.83-7.71(m，1H)， 7.54(t，J＝7.8Hz，1H)，6.98(dd，J＝6.8，3.9Hz，1H)，6.77-6.66(m，1H)，3.28(s，2H)，3.12(s， 2H). 13 C NMR(100MHz，DMSO-d 6 )δ164.3，162.9，151.7，135.9，134.7，130.6，129.5，129.2， 127.9，126.6，122.5，122.3，108.0，37.5，31.8.HRMS(ESI)：calcd for C 15 H 13 Cl 2 N 4 O[M+H] + 335.0461，found 335.0461.
Synthesis of I-6: the synthesis method is the same as I-2. Yellow solid, yield 95%, m.p. 272-274 ℃. 1 H NMR(400 MHz，DMSO-d 6 )δ11.91(s，1H)，8.64(s，1H)，8.13(t，J＝5.1Hz，1H)，8.07(d，J＝2.5Hz，1H)， 7.99(d，J＝2.5Hz，1H)，6.99(t，J＝2.8Hz，1H)，6.74(t，J＝2.7Hz，1H)，3.30(q，J＝5.2Hz，2H)， 3.14(t，J＝5.3Hz，2H). 13 C NMR(100MHz，DMSO-d 6 )δ164.9，162.9，151.4，134.9，133.6，132.5， 131.3，130.7，126.9，125.8，122.4，122.3，108.0，37.5，31.9.HRMS(ESI)：calcd for C 15 H 12 Cl 3 N 4 O [M+H] + 369.0071，found 369.0066.
Synthesis of I-7: the synthesis method is the same as I-2. Yellow solid, yield 88%, melting point 240-242 ℃. 1 H NMR(400 MHz，DMSO-d 6 )δ11.79(s，1H)，8.42(s，1H)，8.07(t，J＝5.0Hz，1H)，7.80(d，J＝8.8Hz，2H)， 7.04(d，J＝8.8Hz，2H)，6.96(t，J＝2.8Hz，1H)，6.70(t，J＝2.7Hz，1H)，3.82(s，3H)，3.28(q，J＝ 5.2Hz，2H)，3.15(d，J＝4.1Hz，2H). 13 C NMR(100MHz，DMSO-d 6 )δ163.1，162.5，161.3，156.8， 129.74，127.2，126.0，123.1，122.1，114.2，107.6，55.3，37.6，31.4.HRMS(ESI)：calcd for C 16 H 17 N 4 O 2 [M+H] + 297.1346，found 297.1344.
Synthesis of I-8: the synthesis method is the same as I-2. Yellow solid, yield 87%, melting point 228-230 ℃. 1 H NMR(400 MHz，DMSO-d 6 )δ11.80(s，1H)，8.45-8.39(m，1H)，8.08(d，J＝5.7Hz，1H)，7.79(t，J＝7.3Hz， 2H)，7.07-7.00(m，2H)，6.99-6.91(m，1H)，4.10(dd，J＝7.4，3.9Hz，2H)，3.29(s，2H)，1.37(t，J ＝6.5Hz，3H). 13 C NMR(100MHz，DMSO-d 6 )δ163.6，163.0，161.1，157.3，130.3，127.5，126.5， 123.6，122.6，115.1，108.1，63.8，38.1，32.0，15.0.HRMS(ESI)：calcd for C 17 H 19 N 4 O 2 [M+H] + 311.1503，found 311.1504.
Synthesis of I-9: the synthesis method is the same as I-2. Yellow solid, yield 86%, melting point 223-225 ℃. 1 H NMR(400 MHz，DMSO-d 6 )δ11.79(s，1H)，8.41(s，1H)，8.07(t，J＝5.1Hz，1H)，7.78(d，J＝8.7Hz，2H)， 7.02(d，J＝8.7Hz，2H)，6.96(t，J＝2.8Hz，1H)，6.70(t，J＝2.7Hz，1H)，3.99(t，J＝6.5Hz，2H)， 3.28(q，J＝5.1Hz，2H)，3.18-3.09(m，2H)，1.76(p，J＝7.1Hz，2H)，0.99(t，J＝7.4Hz，3H). 13 C NMR(100MHz，DMSO-d 6 )δ163.6，163.0，161.3，157.3，130.2，127.5，126.5，123.6，122.6，115.2， 108.1，69.6，38.1，32.0，22.4，10.8.HRMS(ESI)：calcd for C 18 H 21 N 4 O 2 [M+H] + 325.1659，found 325.1660.
Synthesis of I-10: the synthesis method is the same as I-2. Yellow solid, yield 89%, melting point 206-208 ℃. 1 H NMR(400 MHz，DMSO-d 6 )δ11.79(s，1H)，8.41(s，1H)，8.07(t，J＝5.1Hz，1H)，7.78(d，J＝8.7Hz，2H)， 7.05-7.00(m，2H)，6.96(t，J＝2.8Hz，1H)，6.70(t，J＝2.7Hz，1H)，4.03(t，J＝6.5Hz，2H)，3.28 (q，J＝5.1Hz，2H)，3.14(d，J＝8.7Hz，2H)，1.77-1.67(m，2H)，1.50-1.40(m，2H)，0.94(t，J＝ 7.4Hz，3H). 13 C NMR(100MHz，DMSO-d 6 )δ163.1，162.5，160.8，156.8，129.7，127.0，126.04， 123.1，122.1，114.7，107.6，67.3，37.6，31.4，30.6，18.7，13.7.HRMS(ESI)：calcd for C 19 H 23 N 4 O 2 [M+H] + 339.1816，found 339.1819.
Synthesis of I-11: the synthesis method is the same as I-2. Yellow solid, yield 89%, melting point 116-118 ℃. 1 H NMR(400 MHz，DMSO-d 6 )δ11.80(s，1H)，8.41(s，1H)，8.08(t，J＝5.1Hz，1H)，7.77(d，J＝8.6Hz，2H)， 7.10-7.04(m，2H)，6.96(t，J＝2.8Hz，1H)，6.70(t，J＝2.7Hz，1H)，3.29(q，J＝5.2Hz，2H)，3.17 -3.07(m，2H)，1.35(s，9H). 13 C NMR(100MHz，DMSO-d 6 )δ163.1，162.6，157.6，156.5，129.1， 129.1，126.1，123.02，123.0，122.2，107.7，78.8，37.6，31.5，28.5.HRMS(ESI)：calcd for C 19 H 24 N 4 O 2 [M+H] + 339.1816，found 339.1817.
Synthesis of I-12: the synthesis method is the same as I-2. Pale yellow solid, yield 87%, melting point 182-184 ℃. 1 H NMR (400MHz，DMSO-d 6 )δ11.81(s，1H)，8.44(s，1H)，8.08(t，J＝5.2Hz，1H)，7.86(d，J＝8.7Hz， 2H)，7.48-7.41(m，2H)，7.21(t，J＝7.4Hz，1H)，7.09(t，J＝9.5Hz，4H)，6.97(t，J＝2.7Hz，1H)， 6.70(t，J＝2.7Hz，1H)，3.31-3.25(m，2H)，3.18-3.07(m，2H). 13 C NMR(100MHz，DMSO-d 6 ) δ163.0，162.8，159.0，156.2，155.7，130.2，123.0，129.6，126.2，124.1，122.9，122.2，119.3，118.2， 107.7，37.6，31.5.HRMS(ESI)：calcd for C 21 H 19 N 4 O 2 [M+H] + 359.1503，found 359.1502.
Synthesis of I-13: the synthesis method is the same as I-2. Yellow solid, yield 87%, melting point 194-196 ℃. 1 H NMR(400 MHz，DMSO-d 6 )δ11.84(s，1H)，8.37(s，1H)，8.10(t，J＝5.1Hz，1H)，7.03(d，J＝2.3Hz，2H)， 6.98(t，J＝2.7Hz，1H)，6.71(s，1H)，6.62(d，J＝2.3Hz，1H)，3.81(s，6H)，3.29(t，J＝5.2Hz，2H)， 3.18-3.09(m，2H). 13 C NMR(100MHz，DMSO-d 6 )δ163.0，162.9，160.6，156.6，136.5，126.3， 122.8，122.2，107.7，105.8，102.7，55.3，37.6，31.5.HRMS(ESI)：calcd for C 17 H 19 N 4 O 3 [M+H] + 327.1452，found 327.1451.
Synthesis of I-14: the synthesis method is the same as I-2. Yellow solid, yield 80%, melting point 215-217 ℃. 1 H NMR(400 MHz，DMSO-d 6 )δ11.86(s，1H)，9.63(s，1H)，9.02(dd，J＝4.2，1.8Hz，1H)，8.49(ddd，J＝15.2， 7.9，1.7Hz，2H)，8.16(dd，J＝8.2，1.5Hz，1H)，8.12(t，J＝5.0Hz，1H)，7.75(t，J＝7.7Hz，1H)， 7.65(dd，J＝8.3，4.1Hz，1H)，7.01(t，J＝2.8Hz，1H)，6.80(t，J＝2.6Hz，1H)，3.33(q，J＝5.2Hz， 2H)，3.23(d，J＝7.4Hz，2H). 13 C NMR(100MHz，DMSO-d 6 )δ163.2，163.0，153.8，150.6，145.7， 136.6，131.1，130.8，128.0，126.8，126.4，126.3，123.0，122.2，121.9，107.9，37.6，31.6.HRMS(ESI)： calcd for C 18 H 16 N 5 O[M+H] + 318.1349，found 318.1349.
Example 3: synthesis of Aldisin derivative I-15.
Synthesis of I-15: compound a was first synthesized according to literature reported methods (bioorg.med.chem.lett.2011, 21, 4306-4309.); then, weigh A (1.27g, 5.00mmol) in 100mL round bottom flask, add 45mL absolute ethanol, then add hydrazine hydrate (981. Mu.L, 20.00 mmol), heat reflux reaction for 6h, TLC detect reaction complete. Pressurizing to desolventize, then adding ethanol again, and repeatedly pressurizing to desolventize to obtain 1.34g of yellow solid, wherein the yield is quantitative and the melting point is 178-179 ℃. 1 H NMR (400MHz，MeOD-d 4 )δ7.30-7.19(m，3H)，7.11-7.05(m，2H)，7.00(d，J＝2.7Hz，1H)，6.43(d， J＝2.8Hz，1H)，5.50(s，2H)，3.38-3.32(m，2H)，2.70-2.62(m，2H). 13 C NMR(100MHz， MeOD-d 4 )δ147.2，138.8，128.2，128.2，128.0，127.7，127.0，126.5，121.7，106.4，51.3，37.6，31.9. HRMS(ESI)：calcd for C 15 H 17 N 4 O[M+H] + 269.1397，found 269.1396.
Example 4: and (5) synthesizing Aldisin derivatives I-16 to I-37.
Synthesis of I-16: i-15 (268mg, 1.00mmol) was weighed into a 50mL round-bottomed flask, 25mL of anhydrous ethanol was added, followed by benzaldehyde (159mg, 1.5mmol), reaction was carried out at room temperature for 4h, and completion of the reaction was checked by TLC. Vacuum desolventizing, column chromatography separation (V) Petroleum ether ∶V Acetic acid ethyl ester = 2: 1) to obtain 292mg of light yellow solid, the yield is 81%, and the melting point is 180-181 ℃. 1 H NMR (400MHz，CDCl 3 -d)δ7.80(dd，J＝6.5，3.0Hz，2H)，7.45-7.38(m，3H)，7.29(t，J＝7.2Hz，2H)， 7.13(d，J＝7.1Hz，2H)，6.92(t，J＝6.0Hz，1H)，6.86(d，J＝2.8Hz，1H)，5.60(s，2H)，3.37(q，J＝ 5.9Hz，2H)，3.21-3.13(m，2H). 13 C NMR(100MHz，CDCl 3 -d)δ164.7，163.3，157.3，138.3， 134.7，130.8，128.7，128.6，128.3，128.0，127.5，127.1，126.4，124.3，107.9，52.4，38.5，34.1.HRMS (ESI)：calcd for C 22 H 21 N 4 O[M+H] + 357.1710，found 357.1707.
Synthesis of I-17: the synthesis method is the same as I-16. Pale yellow solid, yield 51%, melting point 131-133 ℃. 1 H NMR (400MHz，CDCl 3 -d)δ7.56(s，1H)，7.28(dd，J＝14.3，7.0Hz，4H)，7.16-7.11(m，2H)，6.85(d，J ＝2.9Hz，1H)，6.75(d，J＝2.9Hz，1H)，5.60(s，2H)，3.34(q，J＝5.8Hz，2H)，3.04-2.94(m，2H)， 1.18(s，9H). 13 C NMR(100MHz，CDCl 3 -d)δ167.0，165.0，161.3，138.4，128.6，127.9，127.5， 127.1，126.4，124.0，107.7，52.2，38.4，35.2，33.9，27.4.HRMS(ESI)：calcd for C 20 H 25 N 4 O[M+H] + 337.2023，found 337.2017.
Synthesis of I-18: the synthesis method is the same as I-16. Pale yellow solid, yield 82%, melting point 189-190 ℃. 1 H NMR (400MHz，CDCl 3 -d)δ8.40(s，1H)，7.73(d，J＝7.8Hz，2H)，7.34(t，J＝7.3Hz，2H)，7.26(d，J＝7.7Hz，3H)，7.17(d，J＝7.4Hz，2H)，6.91(d，J＝2.8Hz，1H)，6.86(d，J＝2.8Hz，1H)，6.32(s， 1H)，5.63(s，2H)，3.44(q，J＝5.8Hz，2H)，3.29-3.21(m，2H)，2.43(s，3H). 13 C NMR(100MHz， CDCl 3 -d)δ164.6，163.0，157.5，141.2，138.3，132.0，129.5，128.6，128.3，128.0，127.5，127.1，126.5， 124.2，107.9，52.3，38.5，34.1，21.6.HRMS(ESI)：calcd for C 23 H 23 N 4 O[M+H] + 371.1866，found 371.1867.
Synthesis of I-19: the synthesis method is the same as I-16. Pale yellow solid, yield 83%, m.p. 162-163 ℃. 1 H NMR (400MHz，CDCl 3 -d)δ8.39(s，1H)，7.67(s，1H)，7.62(d，J＝7.6Hz，1H)，7.39-7.32(m，3H)， 7.27(d，J＝3.7Hz，2H)，7.18(d，J＝7.4Hz，2H)，6.91(d，J＝2.7Hz，1H)，6.87(d，J＝2.8Hz，1H)， 6.69(dd，J＝15.5，7.1Hz，1H)，5.64(s，2H)，3.43(q，J＝5.7Hz，2H)，3.28-3.19(m，2H)，2.44(s， 3H). 13 C NMR(100MHz，CDCl 3 -d)δ164.8，163.2，157.5，138.4，138.4，134.7，131.6，128.8，128.6， 128.0，127.5，127.2，127.1，126.4，125.7，124.3，107.9，52.4，38.5，34.1，21.4.HRMS(ESI)：calcd for C 23 H 23 N 4 O[M+H] + 371.1866，found 371.1868.
Synthesis of I-20: the synthesis method is the same as I-16. Pale yellow solid, yield 82%, m.p. 174-175 ℃. 1 H NMR (400MHz，CDCl 3 -d)δ8.68(s，1H)，7.95(dd，J＝7.7，1.5Hz，1H)，7.33-7.29(m，1H)，7.29-7.24 (m，3H)，7.21(dd，J＝10.3，5.5Hz，2H)，7.13(d，J＝6.9Hz，2H)，7.08(d，J＝6.2Hz，1H)，6.86(d， J＝2.8Hz，1H)，6.83(d，J＝2.8Hz，1H)，5.59(s，2H)，3.37(q，J＝5.9Hz，2H)，3.21-3.12(m，2H)， 2.52(s，3H). 13 C NMR(100MHz，CDCl 3 -d)δ164.8，163.5，156.5，138.4，138.3，132.7，131.1， 130.4，128.7，128.0，128.0，127.5，127.1，126.4，126.1，124.4，107.9，52.3，38.5，34.4，20.1.HRMS (ESI)：calcd for C 23 H 23 N 4 O[M+H] + 371.1866，found 371.1868.
Synthesis of I-21: the synthesis method is the same as I-16. Pale yellow solid, yield 80%, melting point 176-177 ℃. 1 H NMR (400MHz，CDCl 3 -d)δ8.42(s，1H)，7.93(d，J＝8.0Hz，2H)，7.70(d，J＝8.1Hz，2H)，7.33(t，J＝ 7.2Hz，2H)，7.26(d，J＝7.3Hz，1H)，7.20-7.15(m，2H)，6.91(d，J＝2.9Hz，1H)，6.85(t，J＝4.0 Hz，2H)，5.63(s，2H)，3.43(q，J＝5.8Hz，2H)，3.20(dd，J＝6.6，4.2Hz，2H). 13 C NMR(100MHz， CDCl 3 )δ164.6，164.0，155.7，138.2，138.0，132.1(q，J＝32.0Hz)，128.7，128.4，128.1，127.6， 127.1，126.1，125.65(q，J＝4.0Hz)，123.9(q，J＝271.0Hz)，124.5，108.0，52.4，38.4，34.1.HRMS (ESI)：calcd for C 23 H 20 F 3 N 4 O[M+H] + 425.1584，found 425.1578.
Synthesis of I-22: the synthesis method is the same as I-16. Pale yellow solid, yield 83%, m.p. 205-207 ℃. 1 H NMR (400MHz，CDCl 3 -d)δ10.24(s，1H)，8.71(s，1H)，7.81(d，J＝7.8Hz，1H)，7.42-7.38(m，2H)， 7.35-7.29(m，3H)，7.25-7.17(m，3H)，6.94(d，J＝2.9Hz，1H)，6.89(d，J＝2.8Hz，1H)，6.67(t， J＝2.7Hz，1H)，6.24(s，1H)，5.64(s，2H)，3.53(q，J＝5.9Hz，2H)，3.32-3.25(m，2H). 13 C NMR (100MHz，CDCl 3 -d)δ164.8，162.4，159.9，138.3，133.5，128.7，128.3，128.1，127.6，127.1，126.5， 126.4，124.9，124.3，124.2，119.7，117.8，108.1，102.8，52.3，38.5，34.6.HRMS(ESI)：calcd for C 24 H 22 N 5 O[M+H] + 396.1819，found 396.1817.
Synthesis of I-23: the synthesis method is the same as I-16. Pale yellow solid, yield 59%, melting point 163-165 ℃. 1 H NMR (400MHz，CDCl 3 -d)δ9.72(s，1H)，8.98(dd，J＝4.2，1.8Hz，1H)，8.56(d，J＝1.1Hz，1H)，8.20 (dd，J＝8.3，1.7Hz，1H)，7.93(dd，J＝8.1，1.2Hz，1H)，7.64(t，J＝7.7Hz，1H)，7.46(dd，J＝8.3，4.2Hz，1H)，7.33(t，J＝7.2Hz，2H)，7.27(s，1H)，7.17(d，J＝7.0Hz，2H)，6.92(q，J＝2.8Hz，2H)， 6.49(t，J＝5.9Hz，1H)，5.64(s，2H)，3.44(td，J＝6.0，3.7Hz，2H)，3.31-3.22(m，2H). 13 C NMR (100MHz，CDCl 3 -d)δ164.6，162.3，154.4，150.2，146.6，138.3，136.2，132.1，130.3，128.6，128.3， 128.1，127.5，127.2，127.1，126.7，126.3，124.0，121.4，108.1，52.3，38.6，34.0.HRMS(ESI)：calcd for C 25 H 22 N 5 O[M+H] + 408.1819，found 408.1813.
Synthesis of I-24: the synthesis method is the same as I-16. Yellow solid, yield 78%, melting point 171-173 ℃. 1 H NMR(400 MHz，CDCl 3 -d)δ8.70-8.64(m，1H)，8.39(s，1H)，8.06(d，J＝8.0Hz，1H)，7.74(t，J＝7.6Hz， 1H)，7.30(t，J＝8.3Hz，4H)，7.14(d，J＝7.5Hz，2H)，6.91-6.82(m，3H)，5.60(s，2H)，3.39(q，J ＝5.8Hz，2H)，3.19-3.10(m，2H). 13 C NMR(100MHz，CDCl 3 -d)δ164.6，163.1，156.9，153.6， 149.8，138.2，136.4，128.6，128.1，127.5，127.1，126.1，124.6，124.4，121.7，108.1，52.4，38.4，34.1. HRMS(ESI)：calcd for C 21 H 20 N 5 O[M+H] + 358.1662，found 358.1662.
Synthesis of I-25: the synthesis method is the same as I-16. Yellow solid, yield 92%, m.p. 1159-161 ℃. 1 H NMR (400MHz，DMSO-d 6 )δ8.40(s，1H)，8.17(tt，J＝5.9，3.2Hz，1H)，7.90(s，1H)，7.80(d，J＝7.2Hz， 1H)，7.56-7.48(m，2H)，7.35-7.30(m，2H)，7.27-7.19(m，2H)，7.13(d，J＝7.0Hz，2H)，6.67 (d，J＝2.8Hz，1H)，5.62(s，2H)，3.23(q，J＝5.7Hz，2H)，3.09-2.96(m，2H). 13 C NMR(100MHz， DMSO-d 6 )δ163.8，163.6，155.4，139.5，137.1，134.1，131.2，130.8，128.9，128.9，128.4，127.7， 127.6，127.2，125.5，125.2，107.6，51.5，37.8，34.3.HRMS(ESI)：calcd for C 22 H 20 ClN 4 O[M+H] + 391.1320，found 391.1320.
Synthesis of I-26: the synthesis method is the same as I-16. Pale yellow solid, yield 85%, melting point 173-175 ℃. 1 H NMR (400MHz，CDCl 3 -d)δ8.36(s，1H)，7.74(d，J＝8.1Hz，2H)，7.45(d，J＝8.1Hz，2H)，7.30(t，J＝ 7.3Hz，2H)，7.23(d，J＝7.2Hz，1H)，7.14(d，J＝7.4Hz，2H)，6.85(dd，J＝19.7，2.8Hz，2H)，6.49 (t，J＝6.1Hz，1H)，5.60(s，2H)，3.40(q，J＝5.9Hz，2H)，3.25-3.14(m，2H)，1.34(s，9H). 13 C NMR(100MHz，CDCl 3 -d)δ164.8，163.0，157.2，154.3，138.4，132.0，128.6，128.1，128.0，127.5， 127.1，126.5，125.7，124.2，107.9，52.4，38.5，35.0，34.1，31.2.HRMS(ESI)：calcd for C 26 H 29 N 4 O [M+H] + 413.2336，found 413.2337.
Synthesis of I-27: the synthesis method is the same as I-16. Pale yellow solid, yield 83%, m.p. 179-180 ℃. 1 H NMR (400MHz，DMSO-d 6 )δ8.64(s，1H)，8.19-8.10(m，2H)，7.58(d，J＝7.9Hz，1H)，7.52(t，J＝7.6 Hz，1H)，7.46(t，J＝7.5Hz，1H)，7.33(t，J＝7.5Hz，2H)，7.24(dd，J＝18.7，5.0Hz，2H)，7.13(d，J ＝7.4Hz，2H)，6.70(d，J＝2.8Hz，1H)，5.62(s，2H)，3.23(d，J＝5.3Hz，2H)，3.04(t，J＝5.3Hz， 2H). 13 C NMR(100MHz，DMSO-d 6 )δ164.3，163.6，152.7，139.5，134.4，132.7，131.9，130.5， 128.9，128.5，128.5，128.0，127.7，127.2，125.6，125.1，107.7，51.5，37.8，34.4.HRMS(ESI)：calcd for C 22 H 20 ClN 4 O[M+H] + 391.1320，found 391.1320.
Synthesis of I-28: the synthesis method is the same as I-16. Yellow solid, yield 84%, melting point 199-201 ℃. 1 H NMR(400 MHz，DMSO-d 6 )δ8.41(d，J＝1.5Hz，1H)，8.14(s，1H)，7.86(d，J＝8.6Hz，2H)，7.58-7.52(m， 2H)，7.35-7.29(m，2H)，7.27-7.22(m，1H)，7.20(d，J＝2.3Hz，1H)，7.12(d，J＝7.5Hz，2H)， 6.67(t，J＝2.1Hz，1H)，5.61(s，2H)，3.22(q，J＝5.7Hz，2H)，3.02(t，J＝5.4Hz，2H). 13 C NMR (100MHz，DMSO-d 6 )δ163.7，163.6，163.6，155.8，139.5，135.8，133.9，130.1，129.4，128.9，128.4， 127.6，127.2，125.4，125.3，107.6，51.5，37.8，34.3.HRMS(ESI)：calcd for C 22 H 20 ClN 4 O[M+H] + 391.1320，found 391.1320.
Synthesis of I-29: the synthesis method is the same as I-16. Pale yellow solid, yield 58%, melting point 144-145 ℃. 1 H NMR (400MHz，CDCl 3 -d)δ8.09(s，1H)，7.60(d，J＝5.1Hz，1H)，7.41(d，J＝3.8Hz，1H)，7.37-7.29 (m，3H)，7.17(d，J＝7.7Hz，2H)，7.14-7.05(m，2H)，6.94(t，J＝2.7Hz，1H)，6.13(s，1H)，5.63(s， 2H)，3.42(q，J＝5.8Hz，2H)，3.07(s，2H). 13 C NMR(100MHz，CDCl 3 -d)δ164.7，160.6，145.6， 138.3，134.8，133.6，133.0，128.7，128.2，127.6，127.2，126.6，126.5，124.4，109.0，52.4，38.3，33.3. HRMS(ESI)：calcd for C 20 H 20 N 4 OS[M+H] + 363.1274，found 363.1273.
Synthesis of I-30: the synthesis method is the same as I-16. Yellow solid, yield 85%, melting point 170-172 ℃. 1 H NMR(400 MHz，DMSO-d 6 )δ8.36(s，1H)，8.10(t，J＝5.9Hz，1H)，7.79(d，J＝8.8Hz，2H)，7.31(t，J＝7.3 Hz，2H)，7.24(t，J＝7.3Hz，1H)，7.18(d，J＝2.8Hz，1H)，7.11(d，J＝7.1Hz，2H)，7.04(d，J＝8.8 Hz，2H)，6.64(d，J＝2.8Hz，1H)，5.59(s，2H)，3.82(s，3H)，3.21(q，J＝5.7Hz，2H)，3.08-2.99 (m，2H). 13 C NMR(100MHz，DMSO-d 6 )δ163.8，163.0，161.9，157.0，139.6，130.3，128.9，128.3， 127.6，127.6，127.2，125.6，125.2，114.8，107.4，55.8，51.5，37.9，34.2.HRMS(ESI)：calcd for C 23 H 23 N 4 O 2 [M+H] + 387.1816，found 387.1817.
Synthesis of I-31: the synthesis method is the same as I-16. Yellow solid, yield 84%, melting point 163-164 ℃. 1 H NMR(400 MHz，DMSO-d 6 )δ8.37(s，1H)，8.12(t，J＝5.9Hz，1H)，7.79(d，J＝8.4Hz，2H)，7.32(t，J＝7.4 Hz，2H)，7.25(t，J＝7.3Hz，1H)，7.20(d，J＝2.9Hz，1H)，7.12(d，J＝7.5Hz，2H)，7.03(d，J＝8.4 Hz，2H)，5.61(s，2H)，4.10(q，J＝6.9Hz，2H)，3.22(q，J＝5.5Hz，2H)，3.04(t，J＝5.3Hz，2H)， 1.36(t，J＝7.0Hz，3H). 13 C NMR(100MHz，DMSO-d 6 )δ163.2，162.5，160.7，156.5，139.1，129.8， 128.4，127.8，127.1，127.0，126.7，125.1，124.6，114.6，107.0，63.3，51.0，37.4，33.7，14.5.HRMS (ESI)：calcd for C 24 H 25 N 4 O 2 [M+H] + 401.1972，found 401.1972.
Synthesis of I-32: the synthesis method is the same as I-16. Yellow solid, yield 82%, melting point 145-147 ℃. 1 H NMR(400 MHz，CDCl 3 -d)δ8.36(s，1H)，7.74(d，J＝8.7Hz，2H)，7.30(t，J＝7.2Hz，2H)，7.24(d，J＝7.4Hz， 1H)，7.14(d，J＝7.0Hz，2H)，6.93(d，J＝8.7Hz，2H)，6.88(d，J＝2.9Hz，1H)，6.83(d，J＝2.9Hz， 1H)，6.19(t，J＝6.1Hz，1H)，5.60(s，2H)，3.97(t，J＝6.6Hz，2H)，3.42(q，J＝5.9Hz，2H)，3.23 (dd，J＝6.5，4.2Hz，2H)，1.83(q，J＝7.0Hz，2H)，1.05(t，J＝7.4Hz，3H). 13 C NMR(101MHz， CDCl 3 -d)δ164.8，162.9，161.4，157.3，138.4，129.9，128.6，128.0，127.5，127.3，127.1，126.6，124.2， 114.7，107.8，69.6，52.3，38.5，34.1，22.5，10.5.HRMS(ESI)：calcd for C 25 H 27 N 4 O 2 [M+H] + 415.2129，found 415.2130.
Synthesis of I-33: the synthesis method is the same as I-16. Yellow colourSolid, yield 85%, melting point 145-147 deg.C. 1 H NMR(400 MHz，CDCl 3 -d)δ8.39(s，1H)，7.77(d，J＝8.4Hz，2H)，7.34(t，J＝7.3Hz，2H)，7.27(d，J＝7.4Hz， 1H)，7.18(d，J＝7.4Hz，2H)，6.96(d，J＝8.4Hz，2H)，6.91(d，J＝2.8Hz，1H)，6.86(d，J＝2.9Hz， 1H)，6.30(t，J＝6.2Hz，1H)，5.64(s，2H)，4.04(t，J＝6.5Hz，2H)，3.44(q，J＝5.8Hz，2H)，3.29- 3.18(m，2H)，1.82(dd，J＝8.5，6.2Hz，2H)，1.54(q，J＝7.5Hz，2H)，1.02(t，J＝7.4Hz，3H). 13 C NMR(100MHz，CDCl 3 -d)δ164.8，162.9，161.4，157.3，138.4，129.9，128.6，128.0，127.5，127.3， 127.1，126.6，124.2，114.7，107.8，67.8，52.3，38.5，34.1，31.2，19.2，13.9.HRMS(ESI)：calcd for C 26 H 29 N 4 O 2 [M+H] + 429.2285，found 429.2287.
Synthesis of I-34: the synthesis method is the same as I-16. Yellow solid, yield 86%, m.p. 151-153 ℃. 1 H NMR(400 MHz，DMSO-d 6 )δ8.36(s，1H)，8.11(t，J＝5.9Hz，1H)，7.76(d，J＝8.6Hz，2H)，7.31(t，J＝7.3 Hz，2H)，7.24(t，J＝7.3Hz，1H)，7.19(d，J＝2.8Hz，1H)，7.09(dd，J＝15.8，7.9Hz，4H)，6.65(d， J＝2.8Hz，1H)，5.60(s，2H)，3.21(q，J＝5.7Hz，2H)，3.09-2.98(m，2H)，1.35(s，9H). 13 C NMR (100MHz，DMSO-d 6 )δ163.2，162.6，157.7，156.1，139.1，129.1，129.0，128.4，127.8，127.1，126.7， 125.0，124.7，123.0，107.0，78.8，51.0，37.4，33.8，28.5.HRMS(ESI)：calcd for C 26 H 29 N 4 O 2 [M+H] + 429.2285，found 429.2288.
Synthesis of I-35: the synthesis method is the same as I-16. Yellow solid, yield 79%, melting point 160-162 ℃. 1 H NMR(400 MHz，DMSO-d 6 )δ8.39(s，1H)，8.11(t，J＝5.9Hz，1H)，7.90-7.81(m，2H)，7.49-7.41(m，2H)， 7.31(t，J＝7.3Hz，2H)，7.24(dd，J＝12.8，7.3Hz，2H)，7.19(d，J＝2.7Hz，1H)，7.15-7.03(m， 6H)，6.65(d，J＝2.8Hz，1H)，5.60(s，2H)，3.21(q，J＝5.8Hz，2H)，3.06-2.95(m，2H). 13 C NMR (100MHz，DMSO-d 6 )δ163.7，163.2，159.5，156.3，156.2，139.55，130.7，130.5，130.0，128.9， 128.4，127.6，127.2，125.5，125.2，124.6，119.8，118.7，107.5，51.5，37.9，34.3.HRMS(ESI)：calcd for C 28 H 25 N 4 O 2 [M+H] + 449.1972，found 449.1974.
Synthesis of I-36: the synthesis method is the same as I-16. White solid, yield 83%, melting point 164-165 ℃. 1 H NMR(400 MHz，DMSO-d 6 )δ8.30(s，1H)，8.12(t，J＝5.9Hz，1H)，7.32(t，J＝7.3Hz，2H)，7.24(t，J＝7.3Hz， 1H)，7.20(d，J＝2.8Hz，1H)，7.11(d，J＝7.1Hz，2H)，7.01(d，J＝2.3Hz，2H)，6.64(d，J＝2.8Hz， 1H)，6.61(t，J＝2.2Hz，1H)，5.60(s，2H)，3.79(s，6H)，3.21(q，J＝6.1，5.7Hz，2H)，3.05-2.95(m， 2H). 13 C NMR(100MHz，DMSO-d 6 )δ163.1，162.7，160.6，156.1，139.0，136.4，128.4，127.9， 127.2，126.7，124.9，124.8，107.0，105.8，102.8，55.3，51.0，37.4，33.7.HRMS(ESI)：calcd for C 24 H 25 N 4 O 3 [M+H] + 417.1921，found 417.1923.
Synthesis of I-37: the synthesis method is the same as I-16. Pale yellow solid, yield 50%, melting point 202-204 ℃. 1 H NMR (400MHz，CDCl 3 -d)δ8.36(s，1H)，7.64(d，J＝1.9Hz，2H)，7.34-7.29(m，2H)，7.27(s，1H)， 7.15(d，J＝6.9Hz，2H)，6.89(d，J＝2.8Hz，1H)，6.84(s，1H)，6.08(t，J＝6.1Hz，1H)，5.61(s，2H)， 3.43(q，J＝6.0Hz，2H)，3.20(dd，J＝6.6，4.3Hz，2H)，1.36(s，18H). 13 C NMR(100MHz， CDCl 3 -d)δ164.6，162.4，158.0，151.2，138.3，134.0，128.6，128.0，127.5，127.1，126.5，125.2，124.1， 122.6，107.9，52.3，38.6，34.9，34.0，31.4.HRMS(ESI)：calcd for C 30 H 37 N 4 O[M+H] + 469.2962， found 469.2958.
Example 5: the activity against tobacco mosaic virus was determined by the following procedure:
1. virus purification and concentration determination:
virus purification and concentration determination were performed according to the tobacco mosaic virus SOP specifications compiled by the institute of elements institute of university of south kaki. 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:
after weighing, the compound and ribavirin are dissolved in DMF to obtain 1 × 10 solution 5 Mu 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 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.
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.
TABLE 1 anti-Tobacco Mosaic Virus (TMV) Activity test results of Aldisin derivatives
5. In vivo inactivation:
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.
Inhibition (%) = [ (control number of scorched spots-number of treated scorched spots)/control number of scorched spots ]. Times.100%
Firstly, the in-vivo inactivation activity of all compounds under the condition of a treatment dose of 500 mu g/mL is tested, and the in-vivo treatment and activity protection activity test under the condition of a treatment dose of 500 mu g/mL is carried out on the compounds with the relative inhibition rate of more than 40%. The positive control is commercial anti-plant virus agent ribavirin.
As can be seen from the data in Table 1, at 500. Mu.g/mL, some derivatives of the alkaloid Aldisin exhibited good anti-TMV activity, where compound I-19 exhibited anti-TMV activity comparable to commercial ribavirin, while compounds I-3, I-4, I-20, I-23 and I-24 exhibited anti-TMV activity superior to ribavirin.
Example 6: insecticidal activity test, the procedure for determination was as follows:
TABLE 2 insecticidal Activity test results of Aldisin derivatives against armyworm and Helicoverpa armigera
Pest sticking: the test method was the leaf dipping method. Soaking corn leaf in the liquid medicine prepared from acetone for 5-6 s, taking out, inoculating 10-head armyworm larvae of 3 years old after the liquid medicine is dried, mainly performing stomach toxicity and contact killing, and observing feeding phenomenon of the larvae. Mortality was checked after 72 hours.
Diamondback moth larvae, cotton bollworms and corn borers are treated by the same method as armyworms. Each compound was tested twice (plutella xylostella was tested in triplicate) and averaged.
Mosquito larvae: culex pipiens pallor subspecies, normal population raised indoors. 10 larvae of culex 3 th instar were selected and placed in a 100mL beaker containing the test solution at the desired concentration. The cells were placed in a standard treatment room and checked for mortality after 72 hours and each compound was tested twice and averaged. An aqueous solution containing 1mL of test solvent was used as a blank.
Mortality (%) = [ (number of control insects-number of surviving insects)/number of control insects ]. Times.100%
TABLE 3 insecticidal Activity test results of Aldisin derivatives against corn borer and diamond back moth
As can be seen from the data in Table 2, most of the Aldisin derivatives showed insecticidal activity against armyworm and Helicoverpa armigera, wherein the compounds I-1, I-3, I-4, I-6, I-14 to I-15, I-17 to I-20, I-25 and I-32 had excellent insecticidal activity against armyworm.
As can be seen from the data in Table 3, most of the Aldisin derivatives show insecticidal activity on corn borer and diamond back moth under the condition of 600 mug/mL, wherein the compounds I-6, I-7, I-9, I-15, I-19, I-24, I-27 to I-29, I-31, I-36 and I-37 have excellent insecticidal activity on corn borer and diamond back moth.
TABLE 4 insecticidal Activity of Aldisin derivatives against mosquito larvae test results
As can be seen from the data in Table 4, most of the Aldisin derivatives had insecticidal activity against mosquito larvae at 10. Mu.g/mL, with compounds I-1, I-3 to I-6, I-16 to I-18 and I-22 having excellent insecticidal activity against mosquito larvae.
Example 7: antibacterial activity test, the determination procedure is as follows:
cell growth rate measurement method (plate method): the test compound was dissolved in acetone and 200. Mu.g/mL aqueous emulsifier solution was added to prepare the desired concentration of test solution. 1mL of the solution to be tested was pipetted into a petri dish, 9mL of the culture medium was added, the mixture was stirred uniformly to prepare a 50. Mu.g/mL drug-containing plate, and a plate containing 1mL of sterile water was prepared as a blank control. The plate was cut along the outer edge of the hyphae with a punch of 4mm diameter and transferred to the drug-containing plate and the control plate. The same operation was repeated 3 times. Finally, the culture dish is placed in a constant-temperature incubator, the colony diameter is measured after 48 hours, the average value of 3 times of measurement is compared with that of a blank control, and the relative inhibition rate is calculated.
Relative inhibition (%) = [ (control colony diameter-test colony diameter)/control colony diameter ] × 100%
TABLE 5 in vitro bactericidal Activity test results for Aldisin derivatives
As can be seen from the data in Table 5, under the condition of 50 mu g/mL, the Aldisin derivatives I-1 to I-37 show broad-spectrum inhibitory activity on 14 tested bacteria, wherein the inhibition rates of the compound I-6 on gibberellic capsicum, sclerotium napellum and apple ring rot are respectively 78+2%, 80 +/-1% and 76 +/-2%; the inhibitory activity of the compound I-21 on wheat sharp eyespot is 74 +/-2%; the inhibitory activity of the compound I-25 on sclerotium of colza is 71 +/-2%; the inhibitory activity of the compound I-30 on gibberella tritici is 73 +/-2%; the inhibitory activity of the compound I-31 on wheat sharp eyespot is 79 +/-2%; the inhibitory activities of the compound I-32 on phytophthora capsici and sclerotium rolfsii are respectively 70 +/-2% and 65 +/-1%; the inhibitory activities of the compound I-33 on sclerotium of colza and wheat sharp eyespot are 65 +/-2% and 86 +/-1% respectively.
Claims (10)
1. An Aldisin derivative containing a hydrazone structure, which is a compound shown as a general formula I:
wherein R represents hydrogen, substituted or unsubstituted benzyl; the substituent of the substituted benzyl is independently selected from one or more of hydroxyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, dioxymethylene and dioxyethylene;
R 1 、R 2 each represents hydrogen or R 1 、R 2 Are combined into
R 3 Represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted quinolyl group, a substituted or unsubstituted indolyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted thienyl group; the substituent of the substituted phenyl, the substituted quinolyl, the substituted indolyl, the substituted pyridyl and the substituted thienyl is independently selected from one or more of halogen, C1-C6 alkyl, C1-C6 alkoxy and phenoxy.
2. The hydrazone structure-containing Aldisin derivative according to claim 1, wherein R represents hydrogen, a substituted or unsubstituted benzyl group; the substituents of the substituted benzyl groups are each independently selected from one or more of hydroxyl, F, cl, br, I, cyano, nitro, trifluoromethyl, trifluoromethoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy;
R 1 、R 2 each represents hydrogen or R 1 、R 2 Are combined into
R 3 Represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted quinolyl group, a substituted or unsubstituted indolyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted thienyl group; the substituent of the substituted phenyl, the substituted quinolyl, the substituted indolyl, the substituted pyridyl and the substituted thienyl is respectively and independently selected from one or more of F, cl, br, I, cyano, nitro, trifluoromethyl, trifluoromethoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy and phenoxy.
3. The hydrazone structure-containing Aldisin derivative of claim 1 or 2, which is one of the compounds represented by the following formulae:
4. a process for the preparation of the hydrazone structure-containing Aldisin derivative of any one of claims 1 to 3, comprising, in the first process: taking Aldisin as a raw material and ethanol as a solvent, and carrying out condensation reaction with hydrazine hydrate under the condition of heating reflux to obtain the derivative containing hydrazone
5. A process for producing an Aldisin derivative containing a hydrazone structure according to any one of claims 1 to 3, comprising, in the second process: taking Aldisin as a raw material and ethanol as a solvent, and carrying out condensation reaction with hydrazine hydrate under the condition of heating reflux to obtain a hydrazone-containing derivative; ethanol is used as a solvent to perform addition elimination reaction with aromatic aldehyde at room temperature to obtain hydrazone with a diimine structure
6. A process for the preparation of an Aldisin derivative containing a hydrazone structure as claimed in any one of claims 1 to 3, which comprises, by process three: taking Aldisin and benzyl bromide as reactants, sodium carbonate as alkali, acetonitrile as solvent, and heating under reflux to obtain a compound A; taking a compound A as a raw material and ethanol as a solvent, and carrying out condensation reaction with hydrazine hydrate under the condition of heating reflux to obtain the hydrazone derivative protected on pyrrole nitrogen
7. A process for the preparation of the hydrazone structure-containing Aldisin derivative of any one of claims 1 to 3, comprising, process four: taking hydrazone derivative protected on pyrrole nitrogen as a raw material, taking ethanol as a solvent, and carrying out addition elimination reaction with aromatic aldehyde at room temperature to obtain hydrazone with a diimine structure of the hydrazone derivative protected on pyrrole nitrogen
8. Use of hydrazone structure-containing Aldisin derivatives in the treatment of plant viral diseases as claimed in any of claims 1-3, characterized in that the series of derivatives have activity against tobacco mosaic virus.
9. Use of an Aldisin derivative containing a hydrazone structure according to any one of claims 1 to 3 for insecticidal purposes, characterized in that the series of derivatives has insecticidal activity against one or more of armyworm, cotton bollworm, corn borer, diamondback moth and mosquito larvae.
10. The use of the hydrazone structure-containing Aldisin derivative of any one of claims 1 to 3, wherein the series of derivatives has inhibitory activity against one or more of cucumber wilt, peanut brown spot, apple ring rot, wheat sharp spot, corn small spot, watermelon anthracnose, rice bakanae disease, tomato early blight, wheat gibberella, rice blast, phytophthora capsici, rape sclerotium, cucumber gray mold, and rice sheath blight.
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