CN112079744A - Aromatic acylhydrazone derivatives and application thereof as NA (adenosine) inhibitor - Google Patents
Aromatic acylhydrazone derivatives and application thereof as NA (adenosine) inhibitor Download PDFInfo
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Abstract
The invention relates to aromatic acylhydrazone derivatives shown in a structural formula I, pharmaceutically acceptable salts thereof, a pharmaceutical composition and application thereof in preparation of influenza virus neuraminidase inhibitors:
Description
Technical Field
The invention relates to a novel compound, a preparation method and application thereof, in particular to an aromatic acylhydrazone derivative, a preparation method and application thereof in preparation of an influenza virus neuraminidase inhibitor.
Background
The aromatic acylhydrazone derivatives have antiviral, antitumor, antiinflammatory, analgesic, antipsychotic and antibacterial activities [ Drug discovery today,2016,21(6):868-872 ].
In 2005, Silva et al [ Bioorganic & Medicinal Chemistry,2005,13(10):3431-3437] described the dehydrocondensation of thiophene-2-carbaldehyde derivatives and 3, 4-methylenedioxybenzoyl hydrazine in ethanol to give a series of novel acylhydrazone derivatives, and evaluated their vasodilating activity.
In 2010, Cui et al [ European Journal of medicinal Chemistry,2010,45(12):5576-5584] described that benzaldehyde derivatives and furan hydrazide derivatives were refluxed in ethanol to prepare acylhydrazone derivatives containing furan rings, and evaluated for antitumor biological activity.
In 2010, Andrad et al [ Journal of combinatorial Chemistry,2010,12(2):245-247] describe the microwave-assisted organic preparation of isonicotinyl hydrazides and aldehydes or ketones to produce acylhydrazones.
In 2014, Filho et al [ European Journal of Organic Chemistry,2014 (29):6411-]Describes CeCl3·7H2Under the catalysis of O, the acylhydrazone derivative is obtained by condensation reaction of a hydrazide compound and an aldehyde compound。
In 2017, Oliveira et al [ Molecules,2017,22(9):1457] described that isonicotinyl hydrazide and formaldehyde derivatives containing various N-heterocyclic indoles, indazoles or imidazoles prepared a series of isonicotinyl hydrazone derivatives by mechanochemical method under catalysis of p-toluenesulfonic acid and tested their inhibitory activity on growth of Mycobacterium tuberculosis cells.
In 2017, Filho et al (Green Chemistry,2017,19(9): 2212-2224) describe aldehyde or ketone compounds and hydrazide compounds, and a series of acylhydrazone derivatives are prepared by a grinding chemical preparation method under the catalysis of acetic acid.
Disclosure of Invention
The invention aims to provide aromatic acylhydrazone derivatives, a preparation method, a pharmaceutical composition and application thereof.
In order to solve the technical problem, the invention provides the following technical scheme:
the first aspect of the technical scheme of the invention provides aromatic acylhydrazone derivatives shown as a structural formula I and pharmaceutically acceptable salts thereof:
wherein R is selected from: 3-trifluoromethyl, 4-trifluoromethyl, 5-trifluoromethyl, 6-trifluoromethyl, 3-nitro, 4-nitro, 5-nitro, 6-nitro, 3-methyl-4-nitro, 3-hydroxy-4-nitro, 3-nitro-4-hydroxy, 2-hydroxy, 3-hydroxy, 4-hydroxy, 2, 3-dihydroxy, 3, 5-dihydroxy, 2, 4-dihydroxy, 3, 5-dinitro, 3-methoxy-4-hydroxy or 3,4, 5-trihydroxy; y is selected from: 2-hydroxy group, 3-hydroxy group, 4-hydroxy group, 2, 4-dihydroxy group, 3, 4-dihydroxy group, 2, 5-dihydroxy group, 3, 5-dihydroxy group, 2, 6-dihydroxy group, 2-hydroxy-3-methoxy group, 2-hydroxy-4-methoxy group, 2-hydroxy-5-methoxy group, 2-hydroxy-6-methoxy group, 3-hydroxy-2-methoxy group, 3-hydroxy-4-methoxy group, 3-hydroxy-5-methoxy group, 3-hydroxy-6-methoxy group, 4-hydroxy-2-methoxy group, 4-hydroxy-3, 5-dimethoxy group, 2,3, 4-trihydroxy, 4-hydroxy-3-ethoxy or 4-hydroxy-3, 5-dimethyl; w is selected from: CH or N; z is selected from: CH or N.
Further, preferred compounds are selected from: 3-hydroxybenzaldehyde-3-nitrobenzoylhydrazone, 4-hydroxybenzaldehyde-3-nitrobenzoylhydrazone, 3-hydroxy-4-methoxybenzaldehyde-3-nitrobenzoylhydrazone, 4-hydroxy-3-ethoxybenzaldehyde-3-nitrobenzoylhydrazone, 2, 4-dihydroxybenzaldehyde-3-nitrobenzoylhydrazone, 3-hydroxybenzaldehyde-4-nitrobenzoylhydrazone, 4-hydroxybenzaldehyde-4-nitrobenzoylhydrazone, 3-hydroxy-4-methoxybenzaldehyde-4-nitrobenzoylhydrazone, 3-hydroxy-4-methoxybenzaldehyde-3-nitrobenzoylhydrazone, 4-nitrobenzoylhydrazone, and the like, 3-methoxy-4-hydroxybenzaldehyde-4-nitrobenzoylhydrazone, 3, 5-dimethyl-4-hydroxybenzaldehyde-4-nitrobenzoylhydrazone, 2, 4-dihydroxybenzaldehyde-4-nitrobenzoylhydrazone, 4-pyridinecarboxaldehyde-4-nitrobenzoylhydrazone, 4-hydroxybenzaldehyde-3-methyl-4-nitrobenzoylhydrazone, 3-methoxy-4-hydroxybenzaldehyde-3-methyl-4-nitrobenzoylhydrazone, 3, 4-dihydroxybenzaldehyde-3-methyl-4-nitrobenzoylhydrazone, 2, 4-dihydroxybenzaldehyde-3-methyl-4-nitrobenzoylhydrazone, 3-methoxy-4-nitrobenzoylhydrazone, 4-nitrobenzaldehyde-3-methyl-4-nitrobenzoylhydrazone, N-methyl-4, 4-hydroxybenzaldehyde-3-hydroxy-4-nitrobenzoylhydrazone, 4-hydroxy-3-methoxybenzaldehyde-3-hydroxy-4-nitrobenzoylhydrazone, 3, 4-dihydroxybenzaldehyde-3-hydroxy-4-nitrobenzoylhydrazone, 2, 4-dihydroxybenzaldehyde-3-hydroxy-4-nitrobenzoylhydrazone, 3-hydroxybenzaldehyde-3-hydroxybenzoylhydrazone, 4-hydroxybenzaldehyde-3-hydroxybenzoylhydrazone, 3-hydroxy-4-methoxybenzaldehyde-3-hydroxybenzoylhydrazone, 4-hydroxy-3-methoxybenzaldehyde-3-hydroxybenzoylhydrazone, 2, 4-dihydroxybenzaldehyde-3-hydroxybenzoylhydrazone, 3-hydroxybenzaldehyde-4-hydroxybenzoylhydrazone, 4-hydroxybenzaldehyde-4-hydroxybenzoylhydrazone, 3-hydroxy-4-methoxybenzaldehyde-4-hydroxybenzoylhydrazone, 4-hydroxy-3-methoxybenzaldehyde-4-hydroxybenzoylhydrazone, 3, 4-dihydroxybenzaldehyde-4-hydroxybenzoylhydrazone, 2, 4-dihydroxybenzaldehyde-4-hydroxybenzoylhydrazone, 4-pyridinecarboxaldehyde-4-hydroxybenzoylhydrazone, 4-hydroxybenzaldehyde-3, 5-dihydroxybenzoylformylhydrazone, 4-hydroxy-3-methoxybenzaldehyde-3, 5-dihydroxybenzoylhydrazone, 2, 4-dihydroxybenzaldehyde-3, 5-dihydroxybenzoylhydrazone, 4-pyridinecarboxaldehyde-3, 5-dihydroxybenzoylhydrazone, 3, 4-dihydroxybenzaldehyde-3, 5-dihydroxybenzoylhydrazone, 4-hydroxybenzaldehyde-4-trifluoromethylphenylacylhydrazone, 3-methoxy-4-hydroxybenzaldehyde-4-trifluoromethylphenylacylhydrazone, 2, 4-dihydroxybenzaldehyde-4-trifluoromethylphenylacylhydrazone, 4-hydroxybenzaldehyde-3, 5-dinitrophenylacylhydrazone, 4-hydroxy-3-methoxybenzaldehyde-3, 5-dinitrophenylacylhydrazone, 2, 4-dihydroxybenzaldehyde-3, 5-dinitrobenzoyl hydrazone, 4-hydroxybenzaldehyde-3-methoxy-4-hydroxybenzoyl hydrazone, 2, 4-dihydroxybenzaldehyde-3-methoxy-4-hydroxybenzoyl hydrazone, 4-hydroxybenzaldehyde-3, 4, 5-trihydroxybenzoyl hydrazone, 4-hydroxy-3-methoxybenzaldehyde-3, 4, 5-trihydroxybenzoyl hydrazone, 2, 4-dihydroxybenzaldehyde-3, 4, 5-trihydroxybenzoyl hydrazone, 4-hydroxybenzaldehyde-2, 4-dihydroxybenzoyl hydrazone, 4-hydroxy-3-methoxybenzaldehyde-2, 4-dihydroxybenzoylhydrazone, 2, 4-dihydroxybenzaldehyde-2, 4-dihydroxybenzoylhydrazone, 4-hydroxybenzaldehyde-3, 4-dihydroxybenzoylhydrazone, 4-hydroxy-3-methoxybenzaldehyde-3, 4-dihydroxybenzoylhydrazone, or 2, 4-dihydroxybenzaldehyde-3, 4-dihydroxybenzoylhydrazone.
The second aspect of the technical scheme of the invention provides a preparation method of aromatic acylhydrazone derivatives, which is characterized in that the preparation reaction is as follows:
wherein R is selected from: 3-trifluoromethyl, 4-trifluoromethyl, 5-trifluoromethyl, 6-trifluoromethyl, 3-nitro, 4-nitro, 5-nitro, 6-nitro, 3-methyl-4-nitro, 3-hydroxy-4-nitro, 3-nitro-4-hydroxy, 2-hydroxy, 3-hydroxy, 4-hydroxy, 2, 3-dihydroxy, 3, 5-dihydroxy, 2, 4-dihydroxy, 3, 5-dinitro, 3-methoxy-4-hydroxy or 3,4, 5-trihydroxy; y is selected from: 2-hydroxy group, 3-hydroxy group, 4-hydroxy group, 2, 4-dihydroxy group, 3, 4-dihydroxy group, 2, 5-dihydroxy group, 3, 5-dihydroxy group, 2, 6-dihydroxy group, 2-hydroxy-3-methoxy group, 2-hydroxy-4-methoxy group, 2-hydroxy-5-methoxy group, 2-hydroxy-6-methoxy group, 3-hydroxy-2-methoxy group, 3-hydroxy-4-methoxy group, 3-hydroxy-5-methoxy group, 3-hydroxy-6-methoxy group, 4-hydroxy-2-methoxy group, 4-hydroxy-3, 5-dimethoxy group, 2,3, 4-trihydroxy, 4-hydroxy-3-ethoxy or 4-hydroxy-3, 5-dimethyl; w is selected from: CH or N; z is selected from: CH or N.
According to a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the first aspect and a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition comprises a therapeutically effective amount of the aromatic acylhydrazone derivatives and pharmaceutically acceptable salts thereof of the present invention, and optionally a pharmaceutically acceptable carrier. Wherein the medicinal carrier refers to a medicinal carrier commonly used in the field of pharmacy; the pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compound of the present invention and the pharmaceutically acceptable salt thereof in the pharmaceutical composition thereof is usually 0.1 to 95% by weight.
The compounds of the present invention and their pharmaceutically acceptable salts or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ocular, pulmonary and respiratory, dermal, vaginal, rectal, and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound and the pharmaceutically acceptable salt thereof can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems.
For tableting the compounds of the present invention and pharmaceutically acceptable salts thereof, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
In order to encapsulate the administration unit, the active ingredient of the compound of the present invention and a pharmaceutically acceptable salt thereof may be mixed with a diluent and a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. Or the effective component of the compound and the pharmaceutically acceptable salt thereof can be prepared into granules or pellets with a diluent, an adhesive and a disintegrating agent, and then the granules or pellets are placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compounds of the present invention and their pharmaceutically acceptable salt tablets may also be used to prepare capsules of the compounds of the present invention and their pharmaceutically acceptable salts.
In order to prepare the compound and the pharmaceutically acceptable salt thereof into injection, water, ethanol, isopropanol, propylene glycol or a mixture of the water, the ethanol, the isopropanol and the propylene glycol can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The fourth aspect of the technical scheme of the invention is to provide the aromatic acylhydrazone derivatives and the pharmaceutically acceptable salts thereof, and the application of the pharmaceutical composition of the third aspect in the preparation of influenza virus neuraminidase inhibitors.
The beneficial technical effects are as follows:
the aromatic acylhydrazone derivatives are compounds with influenza virus neuraminidase inhibitory activity.
Detailed Description
The following examples are intended to illustrate the invention without further limiting it.
Example 1
Preparation of 3-hydroxybenzaldehyde-3-nitrobenzoylhydrazone (I1)
(1) Preparation of methyl 3-nitrobenzoate
8.0mmol of 3-nitrobenzoic acid was dissolved in 12mL of methanol, 9.6mmol of thionyl chloride was slowly added with stirring at room temperature, the mixture was heated to reflux for 2h, and the reaction was monitored by TLC. Removing the solvent in the reaction liquid by reduced pressure rotary evaporation, adding 40mL of water, stirring for 20min, performing suction filtration, washing a filter cake by using water, and drying to obtain 3-methyl nitrobenzoate as a light yellow solid with m.p.73-74 ℃ and the yield of 93.7%;1H NMR(400MHz，CDCl3)：8.85(s，1H，C6H4)，8.40(d，J＝8.2Hz，1H，C6H4)，8.36(d，J＝7.7Hz，1H，C6H4)，7.65(t，J＝8.0Hz，1H，C6H4)，3.98(s，3H，CH3)；13C NMR(100MHz，CDCl3)：165.06，148.41，135.37，132.00，129.75，127.49，124.71，52.91。
(2) preparation of 3-nitrobenzyl hydrazide
6.0mmol of methyl 3-nitrobenzoate and 18.0mmol of 80% hydrazine hydrate were placed in 12mL of ethanol, refluxed for 2h and monitored by TLC for the reaction. Cooling the reaction mixture to room temperature, performing suction filtration, washing a filter cake with petroleum ether and ethanol, and drying to obtain 3-nitrobenzyl hydrazide which is a light yellow solid and has m.p.142-143 ℃ and the yield of 88.7%;1H NMR(400MHz，DMSO-d6)：10.15(s，1H，NH)，8.63(s，1H，C6H4)，8.36(d，J＝8.0Hz，1H，C6H4)，8.25(d，J＝7.7Hz，1H，C6H4)，7.76(t，J＝7.9Hz，1H，C6H4)，4.63(s，2H，NH2)；13C NMR(100MHz，DMSO-d6)：163.54，147.78，134.74，133.22，130.13，125.66，121.77。
(3) preparation of 3-hydroxybenzaldehyde-3-nitrobenzoylhydrazone (I1)
1.0mmol of 3-nitrobenzyl hydrazide, 1.05mmol of 3-hydroxybenzaldehyde and 2 drops of acetic acid were suspended in 12mL of ethanol, refluxed for 5h and monitored by TLC for the reaction. Cooling the reaction liquid to room temperature, carrying out suction filtration, washing a filter cake by using a mixed solution (1:1) of petroleum ether and ethyl acetate, and drying to obtain 3-hydroxybenzaldehyde-3-nitrobenzoylhydrazone (I1) as a yellow solid with m.p.255-256 ℃ and the yield of 82.2%;1H NMR(400MHz，DMSO-d6)：12.11(s，1H，NH)，9.66(s，1H，OH)，8.76(s，1H，C6H4)，8.44(d，J＝7.8Hz，1H，C6H4)，8.40(s，1H，CH)，8.37(d，J＝7.6Hz，1H，C6H4)，7.88～7.80(m，1H，C6H4)，7.31～7.21(m，2H，C6H4)，7.13(d，J＝7.2Hz，1H，C6H4)，6.86(d，J＝7.5Hz，1H，C6H4)；13C NMR(100MHz，DMSO-d6)：160.97，157.73，148.95，147.80，135.36，134.80，134.17，130.34，129.98，126.38，122.33，119.03，117.75，112.76。
example 2
Preparation of 4-hydroxybenzaldehyde-3-nitrobenzoylhydrazone (I2)
Prepared according to the method in (3) in the example 1, 1.0mmol of 3-nitrobenzyl hydrazide reacts with 1.05mmol of 4-hydroxybenzaldehyde for 5h to obtain 4-hydroxybenzaldehyde-3-nitrobenzoyl hydrazone (I2) which is yellow solid with m.p.278-279 ℃ and the yield of 84.5%;1H NMR(400MHz，DMSO-d6)：11.97(s，1H，NH)，9.98(s，1H，OH)，8.74(s，1H，C6H4)，8.43(d，J＝8.1Hz，1H，C6H4)，8.38(s，1H，CH)，8.35(d，J＝7.9Hz，1H，C6H4)，7.88～7.78(m，1H，C6H4)，7.59(d，J＝8.0Hz，2H，C6H4)，6.85(d，J＝8.0Hz，2H，C6H4)；13C NMR(100MHz，DMSO-d6)：160.96，159.69，149.43，147.96，135.04，134.24，130.53，129.35，126.46，125.26，122.42，115.90。
example 3
Preparation of 3-hydroxy-4-methoxybenzaldehyde-3-nitrobenzoylhydrazone (I3)
Prepared according to the method in (3) in the embodiment 1, 1.0mmol of 3-nitrobenzyl hydrazide reacts with 1.05mmol of 3-hydroxy-4-methoxybenzaldehyde for 5h to obtain 3-hydroxy-4-methoxybenzaldehyde-3-nitrobenzoylhydrazone (I3) which is light yellow solid with m.p.239-240 ℃ and the yield of 85.7%;1HNMR(400MHz，DMSO-d6)：11.99(s，1H，NH)，9.34(s，1H，OH)，8.75(s，1H，C6H4)，8.43(d，J＝8.0Hz，1H，C6H4)，8.35(d，J＝8.0Hz，1H，C6H4)，8.34(s，1H，CH)，7.88～7.79(m，1H，C6H4)，7.30(s，1H，C6H3)，7.09(d，J＝8.1Hz，1H，C6H3)，6.99(d，J＝8.1Hz，1H，C6H3)，3.82(s，3H，CH3)；13C NMR(100MHz，DMSO-d6)：160.76，150.05，149.02，147.80，146.93，134.97，134.11，130.32，126.90，126.27，122.28，120.63，112.38，111.87，55.61。
example 4
Preparation of 4-hydroxy-3-methoxybenzaldehyde-3-nitrobenzoylhydrazone (I4)
Prepared according to the method in (3) in the embodiment 1, 1.0mmol of 3-nitrobenzyl hydrazide reacts with 1.05mmol of 4-hydroxy-3-methoxybenzaldehyde for 5h to obtain 4-hydroxy-3-methoxybenzaldehyde-3-nitrobenzoylhydrazone (I4) which is light yellow solid with m.p.206-207 ℃ and the yield of 85.6%;1HNMR(400MHz，DMSO-d6)：11.99(s，1H，NH)，9.60(s，1H，OH)，8.74(s，1H，C6H4)，8.43(d，J＝8.1Hz，1H，C6H4)，8.37(s，1H，CH)，8.35(d，J＝8.0Hz，1H，C6H4)，7.88～7.80(m，1H，C6H4)，7.34(s，1H，C6H3)，7.12(d，J＝8.0Hz，1H，C6H3)，6.86(d，J＝8.0Hz，1H，C6H3)，3.84(s，3H，C6H3O)；13C NMR(100MHz，DMSO-d6)：160.72，149.39，149.29，148.10，147.79，135.01，134.10，130.32，126.25，125.45，122.49，122.26，115.48，108.99，55.59。
example 5
Preparation of 4-hydroxy-3-ethoxybenzaldehyde-3-nitrobenzoylhydrazone (I5)
Prepared according to the method in (3) in the example 1, 1.0mmol of 3-nitrobenzyl hydrazide reacts with 1.05mmol of 4-hydroxy-3-ethoxybenzaldehyde for 5h to obtain 4-hydroxy-3-ethoxybenzaldehyde-3-nitrobenzoylhydrazone (I5) which is light yellow solid with m.p.177-178 ℃ and the yield is 80.6%;1HNMR(400MHz，DMSO-d6)：11.98(s，1H，NH)，9.52(s，1H，OH)，8.74(s，1H，C6H4)，8.43(d，J＝8.5Hz，1H，C6H4)，8.36(s，1H，CH)，8.34(d，J＝8.2Hz，1H，C6H4)，7.83(m，1H，C6H4)，7.32(s，1H，C6H3)，7.12(d，J＝8.1Hz，1H，C6H3)，6.87(d，J＝8.1Hz，1H，C6H3)，4.08(q，J＝7.0Hz，2H，CH2)，1.37(t，J＝7.0Hz，3H，CH3)；13C NMR(100MHz，DMSO-d6)：160.73，149.52，149.42，147.79，147.26，135.01，134.10，130.32，126.24，125.44，122.39，122.26，115.57，110.34，63.91，14.77。
example 6
Preparation of 2, 4-dihydroxybenzaldehyde-3-nitrobenzoylhydrazone (I6)
Prepared according to the method of (3) in example 1, 1.0mmol of 3-nitrobenzoyl hydrazide was reacted with 1.05mmol of 2, 4-dihydroxybenzaldehyde for 5h to give 2, 4-dihydroxybenzaldehyde-3-nitrobenzoylhydrazone (I6) as a yellow solid, m.p.>The yield is 86.4 percent at 280 ℃;1H NMR(400MHz，DMSO-d6)：12.21(s，1H，NH)，11.29(s，1H，OH)，10.00(s，1H，OH)，8.77(s，1H，C6H4)，8.56(s，1H，CH)，8.43(d，J＝7.9Hz，1H，C6H4)，8.36(d，J＝7.5Hz，1H，C6H4)，7.88～7.80(m，1H，C6H4)，7.36(d，J＝8.4Hz，1H，C6H3)，6.37(d，J＝8.4Hz，1H，C6H3)，6.33(s，1H，C6H3)；13C NMR(100MHz，DMSO-d6)：161.02，160.36，159.53，149.74，147.82，134.45，134.12，131.19，130.37，126.40，122.23，110.53，107.87，102.67。
example 7
Preparation of 3, 4-dihydroxybenzaldehyde-3-nitrobenzoylhydrazone (I7)
Prepared according to the method of (3) in example 1, 1.0mmol of 3-nitrobenzyl hydrazide is reacted with 1.05mmol of 3, 4-dihydroxybenzaldehyde for 5 hours to obtain 3, 4-dihydroxybenzaldehyde-3-nitro benzaldehydeBenzoylhydrazone (I7), yellow solid, m.p. 269-270 ℃, yield 87.4%;1H NMR(400MHz，DMSO-d6)：11.93(s，1H，NH)，9.44(s，1H，OH)，9.30(s，1H，OH)，8.74(s，1H，C6H4)，8.42(d，J＝7.5Hz，1H，C6H4)，8.35(d，J＝7.5Hz，1H，C6H4)，8.30(s，1H，CH)，7.87～7.78(m，1H，C6H4)，7.27(s，1H，C6H3)，6.97(d，J＝7.8Hz，1H，C6H3)，6.80(d，J＝7.8Hz，1H，C6H3)；13C NMR(100MHz，DMSO-d6)：160.66，149.37，148.30，147.80，145.81，135.04，134.10，130.31，126.23，125.52，122.26，120.94，115.63，112.78。
example 8
Preparation of 3-hydroxybenzaldehyde-4-nitrobenzoylhydrazone (I8)
(1) Preparation of methyl 4-nitrobenzoate
Prepared according to the method in the step (1) in the embodiment 1, 8.0mmol of 4-nitrobenzoic acid and 9.6mmol of thionyl chloride react in 12mL of methanol for 2 hours to obtain 4-nitrobenzoic acid methyl ester as a light yellow solid with m.p.95-96 ℃ and the yield of 95.1%;1HNMR(400MHz，CDCl3)：8.28(d，J＝8.0Hz，2H，C6H4)，8.20(d，J＝8.0Hz，2H，C6H4)，3.97(s，3H，OCH3)；13C NMR(100MHz，CDCl3)：165.29，150.68，135.62，130.83，123.66，52.95。
(2) preparation of 4-nitrobenzyl hydrazide
Prepared by the method of (2) in example 1, 6.0mmol of methyl 4-nitrobenzoate was reacted with 18.0mmol of 80% hydrazine hydrateReacting for 2 hours to obtain 4-nitrobenzyl hydrazide which is a light yellow solid, wherein m.p.214-215 ℃ and the yield is 90.2%;1H NMR(400MHz，DMSO-d6)：10.12(s，1H，NH)，8.29(d，J＝8.5Hz，2H，C6H4)，8.04(d，J＝8.5Hz，2H，C6H4)，4.65(s，2H，NH2)；13C NMR(100MHz，DMSO-d6)：163.89，148.90，139.01，128.42，123.52。
(3) preparation of 3-hydroxybenzaldehyde-4-nitrobenzoylhydrazone (I8)
Prepared according to the method in (3) in the example 1, 1.0mmol of 4-nitrobenzyl hydrazide reacts with 1.05mmol of 3-hydroxybenzaldehyde for 5h to obtain 3-hydroxybenzaldehyde-4-nitrobenzyl hydrazone (I8) which is light yellow solid with the yield of 91.2 percent at the temperature of m.p.255-256 ℃;1H NMR(400MHz，DMSO-d6)：12.08(s，1H，NH)，9.66(s，1H，OH)，8.38(s，1H，CH)，8.37(d，J＝8.5Hz，2H，C6H4)，8.15(d，J＝8.5Hz，2H，C6H4)，7.31～7.24(m，1H，C6H4)，7.22(s，1H，C6H4)，7.12(d，J＝7.5Hz，1H，C6H4)，6.86(dd，J＝8.1，2.4Hz，1H，C6H4)；13C NMR(100MHz，DMSO-d6)：161.45，157.71，149.26，149.02，139.10，135.31，129.95，129.16，123.66，119.02，117.75，112.72。
example 9
Preparation of 4-hydroxybenzaldehyde-4-nitrobenzoylhydrazone (I9)
Prepared according to the method of (3) in example 1, 1.0mmol of 4-nitrobenzyl hydrazide was reacted with 1.05mmol of 4-hydroxybenzaldehyde for 5h to give 4-hydroxybenzaldehyde-4-nitrobenzoylhydrazone (I9) as a yellow solid, m.p.>The yield is 91.9 percent at 280 ℃;1HNMR(400MHz，DMSO-d6)：11.94(s，1H，NH)，9.99(s，1H，OH)，8.37(d，J＝8.6Hz，2H，C6H4)，8.35(s，1H，CH)，8.14(d，J＝8.6Hz，2H，C6H4)，7.59(d，J＝8.4Hz，2H，C6H4)，6.85(d，J＝8.4Hz，2H，C6H4)；13C NMR(100MHz，DMSO-d6)：161.55，159.74，149.60，149.39，139.41，129.38，129.29，125.25，123.86，115.93。
example 10
Preparation of 3-hydroxy-4-methoxybenzaldehyde-4-nitrobenzoylhydrazone (I10)
Prepared according to the method in (3) in the embodiment 1, 1.0mmol of 4-nitrobenzyl hydrazide reacts with 1.05mmol of 3-hydroxy-4-methoxybenzaldehyde for 5h, and the 3-hydroxy-4-methoxybenzaldehyde-4-nitrobenzoylhydrazone (I10) is obtained after drying, and is yellow solid with m.p.235-236 ℃ and the yield of 92.1%;1HNMR(400MHz，DMSO-d6)：11.96(s，1H，NH)，9.35(s，1H，OH)，8.37(d，J＝8.6Hz，2H，C6H4)，8.32(s，1H，CH)，8.14(d，J＝8.6Hz，2H，C6H4)，7.30(d，J＝1.2Hz，1H，C6H3)，7.08(dd，J＝8.4Hz，J＝1.2Hz，1H，C6H3)，6.99(d，J＝8.4Hz，1H，C6H3)，3.81(s，3H，CH3O)；13C NMR(100MHz，DMSO-d6)：161.24，150.05，149.19，149.09，146.92，139.29，129.10，126.86，123.63，120.61，112.37，111.87，55.59。
example 11
Preparation of 3-methoxy-4-hydroxybenzaldehyde-4-nitrobenzoylhydrazone (I11)
Prepared according to the method in (3) in the embodiment 1, 1.0mmol of 4-nitrobenzyl hydrazide reacts with 1.05mmol of 3-methoxy-4-hydroxybenzaldehyde for 5h, and the 3-methoxy-4-hydroxybenzaldehyde-4-nitrobenzoyl hydrazone (I11) is obtained after drying, and is yellow solid with m.p.228-229 ℃ and the yield of 92.9%;1HNMR(400MHz，DMSO-d6)：11.95(s，1H，NH)，9.61(s，1H，OH)，8.40～8.32(m，3H，CH and C6H4)，8.14(d，J＝8.6Hz，2H，C6H4)，7.33(s，1H，C6H3)，7.12(d，J＝8.1Hz，1H，C6H3)，6.86(d，J＝8.1Hz，1H，C6H3)，3.84(s，3H，CH3O)；13C NMR(100MHz，DMSO-d6)：161.22，149.47，149.30，149.17，148.08，139.34，129.09，125.42，123.64，122.45，115.47，109.05，55.58。
example 12
Preparation of 3, 5-dimethyl-4-hydroxybenzaldehyde-4-nitrobenzoylhydrazone (I12)
Prepared according to the method of (3) in example 1, 1.0mmol of 4-nitrobenzoyl hydrazide was reacted with 1.05mmol of 3, 5-dimethyl-4-hydroxybenzaldehyde for 5h to give 3, 5-dimethyl-4-hydroxybenzaldehyde-4-nitrobenzoyl hydrazone (I12) as a yellow solid, m.p.>The yield is 94.5 percent at 280 ℃;1H NMR(400MHz，DMSO-d6)：11.92(s，1H，NH)，8.80(s，1H，OH)，8.36(d，J＝8.5Hz，2H，C6H4)，8.29(s，1H，CH)，8.13(d，J＝8.5Hz，2H，C6H4)，7.33(s，2H，C6H2)，2.21(s，6H，2×CH3)；13C NMR(100MHz，DMSO-d6)：161.17，155.71，149.34，149.14，139.36，129.09，127.65，124.95，124.63，123.60，16.56。
example 13
Preparation of 2, 4-dihydroxybenzaldehyde-4-nitrobenzoylhydrazone (I13)
Prepared according to the method of (3) in example 1, 1.0mmol of 4-nitrobenzoyl hydrazide was reacted with 1.05mmol of 2, 4-dihydroxybenzaldehyde for 5h, and dried to give 2, 4-dihydroxybenzaldehyde-4-nitrobenzoylhydrazone (I13) as a yellow solid, m.p.>The yield is 86.7 percent at 280 ℃;1H NMR(400MHz，DMSO-d6)：12.17(s，1H，OH)，11.29(s，1H，NH)，10.00(s，1H，OH)，8.54(s，1H，CH)，8.37(d，J＝8.2Hz，2H，C6H4)，8.16(d，J＝8.2Hz，2H，C6H4)，7.36(d，J＝8.5Hz，1H，C6H3)，6.37(d，J＝8.5Hz，1H，C6H3)，6.33(s，1H，C6H3)；13C NMR(100MHz，DMSO-d6)：161.00，160.80，159.52，149.89，149.26，138.71，131.21，129.07，123.65，110.45，107.83，102.64。
example 14
Preparation of 4-pyridinecarboxaldehyde-4-nitrobenzoylhydrazone (I14)
Prepared according to the method of (3) in example 1, 1.0mmol of 4-nitrobenzyl hydrazide is reacted with 1.05mmol of 4-pyridinecarboxaldehyde for 5h to obtain 4-pyridinecarboxaldehyde-4-nitrobenzoylhydrazone (I14) as a pale yellow solid, m.p.>The yield is 96.3 percent at 280 ℃;1HNMR(400MHz，DMSO-d6)：12.40(s，1H，NH)，8.68(d，J＝4.5Hz，2H，C5H4N)，8.47(s，1H，CH)，8.39(d，J＝8.1Hz，2H，C6H4)，8.17(d，J＝8.1Hz，2H，C6H4)，7.70(d，J＝4.5Hz，2H，C5H4N)；13C NMR(100MHz，DMSO-d6)：161.85，150.34，146.52，141.00，129.29，126.49，123.81，123.71，121.11。
example 15
Preparation of 4-hydroxybenzaldehyde-3-methyl-4-nitrobenzoylhydrazone (I15)
(1) Preparation of methyl 3-methyl-4-nitrobenzoate
Prepared according to the method in the step (1) in the embodiment 1, 8.0mmol of 3-methyl-4-nitrobenzoic acid and 9.6mmol of thionyl chloride react in 12mL of methanol for 2 hours to obtain 3-methyl-4-nitrobenzoic acid methyl ester which is light yellow solid and has the yield of 96.0 percent at the temperature of m.p.73-74 ℃;1HNMR(400MHz，CDCl3)：8.02(s，1H，C6H3)，8.00～7.94(m，2H，C6H3)，3.96(s，3H，CH3O)，2.62(s，3H，CH3)；13C NMR(100MHz，CDCl3)：165.45，151.98，134.12，133.85，133.60，128.17，124.69，52.85，20.20。
(2) preparation of 3-methyl-4-nitrobenzyl hydrazide
Prepared according to the method in the step (2) in the embodiment 1, 6.0mmol of 3-methyl-4-nitrobenzoic acid methyl ester reacts with 18.0mmol of 80% hydrazine hydrate for 2 hours to obtain 3-methyl-4-nitrobenzoic hydrazide which is light yellow solid and has the yield of 92.4% at the temperature of m.p.138-139 ℃;1H NMR(400MHz，DMSO-d6)：10.01(s，1H，NH)，8.03(d，J＝8.4Hz，1H，C6H3)，7.91(s，1H，C6H3)，7.83(d，J＝8.4Hz，1H，C6H3)，4.61(s，2H，NH2)，2.53(s，3H，CH3)；13C NMR(100MHz，DMSO-d6)：163.95，150.21，137.18，132.69，131.36，125.74，124.43，19.36。
(3) preparation of 4-hydroxybenzaldehyde-3-methyl-4-nitrobenzoylhydrazone (I15)
Prepared according to the method of (3) in the example 1, 1.0mmol of 3-methyl-4-nitrobenzyl hydrazide reacts with 1.05mmol of 4-hydroxybenzaldehyde for 5h to obtain 4-hydroxybenzaldehyde-3-methyl-4-nitrobenzoyl hydrazone (I15) which is yellow solid, m.p. 275-276 ℃ and has the yield of 93.6%;1H NMR(400MHz，DMSO-d6)：11.84(s，1H，NH)，9.97(s，1H，OH)，8.35(s，1H，CH)，8.10(d，J＝8.4Hz，1H，C6H3)，7.99(s，1H，C6H3)，7.92(d，J＝8.4Hz，1H，C6H3)，7.58(d，J＝8.3Hz，2H，C6H4)，6.85(d，J＝8.3Hz，2H，C6H4)，2.58(s，3H，CH3)；13C NMR(100MHz，DMSO-d6)：161.60，159.73，150.76，149.43，137.64，133.16，132.12，129.40，126.71，125.29，124.84，115.95，19.62。
example 16
Preparation of 3-methoxy-4-hydroxybenzaldehyde-3-methyl-4-nitrobenzoylhydrazone (I16)
Prepared according to the method of (3) in example 1, 1.0mmol of 3-methyl-4-nitrobenzyl hydrazide is reacted with 1.05mmol of 3-methoxy-4-hydroxybenzaldehyde for 5h to obtain 3-methoxy-4-hydroxybenzaldehyde-3-methyl-4-nitrobenzyl hydrazone (I16) as a yellow solid with m.p. 216-217 ℃ yield of 90.9%;1H NMR(400MHz，DMSO-d6)：11.86(s，1H，NH)，9.59(s，1H，OH)，8.34(s，1H，CH)，8.10(d，J＝8.4Hz，1H，C6H3)，7.98(s，1H，C6H3)，7.92(d，J＝8.4Hz，1H，C6H3)，7.33(s，1H，C6H3)，7.11(d，J＝8.1Hz，1H，C6H3)，6.85(d，J＝8.1Hz，1H，C6H3)，3.84(s，3H，CH3O)，2.58(s，3H，CH3)；13C NMR(100MHz，DMSO-d6)：161.27，150.51，149.29，149.28，148.09，137.59，132.88，131.93，126.48，125.44，124.60，122.45，115.48，109.00，55.59，19.42。
example 17
Preparation of 3, 4-dihydroxybenzaldehyde-3-methyl-4-nitrobenzoylhydrazone (I17)
Prepared according to the method of (3) in the example 1, 1.0mmol of 3-methyl-4-nitrobenzoyl hydrazide reacts with 1.05mmol of 3, 4-dihydroxybenzaldehyde for 5h to obtain 3, 4-dihydroxybenzaldehyde-3-methyl-4-nitrobenzoyl hydrazone (I17) which is yellow solid with m.p.271-272 ℃ and the yield of 90.6%;1HNMR(400MHz，DMSO-d6)：11.80(s，1H，NH)，9.35(s，2H，2OH)，8.26(s，1H，CH)，8.10(d，J＝8.4Hz，1H，C6H3)，7.99(s，1H，C6H3)，7.92(d，J＝8.4Hz，1H，C6H3)，7.26(s，1H，C6H3)，6.95(d，J＝8.0Hz，1H，C6H3)，6.80(d，J＝8.0Hz，1H，C6H3)，2.58(s，3H，CH3)；13C NMR(100MHz，DMSO-d6)：161.18，150.50，149.25，148.28，145.79，137.60，132.87，131.94，126.46，125.50，124.60，120.90，115.61，112.74，19.42。
example 18
Preparation of 2, 4-dihydroxybenzaldehyde-3-methyl-4-nitrobenzoylhydrazone (I18)
Prepared according to the method of (3) in example 1,1.0mmol of 3-methyl-4-nitrobenzoyl hydrazide is reacted with 1.05mmol of 2, 4-dihydroxybenzaldehyde for 5h to obtain 2, 4-dihydroxybenzaldehyde-3-methyl-4-nitrobenzoyl hydrazone (I18) as a yellow solid m.p.>The yield is 96.8 percent at 280 ℃;1HNMR(400MHz，DMSO-d6)：12.10(s，1H，OH)，11.29(s，1H，NH)，10.01(s，1H，OH)，8.53(s，1H，CH)，8.11(d，J＝8.4Hz，1H，C6H3)，8.01(s，1H，C6H3)，7.94(d，J＝8.4Hz，1H，C6H3)，7.35(d，J＝8.4Hz，1H，C6H3)，6.37(d，J＝8.5Hz，1H，C6H3)，6.33(s，1H，C6H3)，2.58(s，3H，CH3)；13C NMR(100MHz，DMSO-d6)：160.98，160.85，159.50，150.59，149.69，136.95，132.85，131.91，131.17，126.45，124.58，110.47，107.83，102.64，19.36。
example 19
Preparation of 4-hydroxybenzaldehyde-3-hydroxy-4-nitrobenzoylhydrazone (I19)
(1) Preparation of methyl 3-hydroxy-4-nitrobenzoate
Prepared according to the method in (1) in the example 1, 8.0mmol of 3-hydroxy-4-nitrobenzoic acid and 9.6mmol of thionyl chloride are reacted in 12mL of methanol for 2h to obtain 3-hydroxy-4-nitrobenzoic acid methyl ester as yellow solid with m.p.89-90 ℃ and the yield of 96.2%;1H NMR(400MHz，CDCl3)：10.48(s，1H，OH)，8.17(d，J＝8.8Hz，1H，C6H3)，7.82(s，1H，C6H3)，7.61(d，J＝8.8Hz，1H，C6H3)，3.96(s，3H，OCH3)；13C NMR(100MHz，CDCl3)：164.95，154.79，138.12，135.93，125.39，121.80，120.72，53.05。
(2) preparation of 3-hydroxy-4-nitrobenzyl hydrazide
Prepared according to the method in (2) in the embodiment 1, 6.0mmol of 3-hydroxy-4-nitrobenzoic acid methyl ester reacts with 18.0mmol of 80% hydrazine hydrate for 2h to obtain 3-hydroxy-4-nitrobenzoic hydrazide which is yellow solid and has the yield of 93.2% at the temperature of m.p.207-208 ℃;1HNMR(400MHz，DMSO-d6)：10.04(s，2H，NH and OH)，7.92(d，J＝8.5Hz，1H，C6H3)，7.53(s，1H，C6H3)，7.34(d，J＝8.5Hz，1H，C6H3)，5.01(s，2H，NH2)；13C NMR(100MHz，DMSO-d6)：164.01，151.57，139.03，138.38，125.22，117.95，117.28。
(3) preparation of 4-hydroxybenzaldehyde-3-hydroxy-4-nitrobenzoylhydrazone (I19)
Prepared according to the method of (3) in the example 1, 1.0mmol of 3-hydroxy-4-nitrobenzyl hydrazide reacts with 1.05mmol of 4-hydroxybenzaldehyde for 5h to obtain 4-hydroxybenzaldehyde-3-hydroxy-4-nitrobenzoyl hydrazone (I19) as a brown yellow solid with m.p.277-278 ℃ and the yield of 88.3%;1H NMR(400MHz，DMSO-d6)：11.81(s，1H，NH)，11.30(s，1H，OH)，9.97(s，1H，OH)，8.34(s，1H，CH)，8.00(d，J＝8.5Hz，1H，C6H3)，7.60(s，1H，C6H3)，7.57(d，J＝8.4Hz，2H，C6H4)，7.45(d，J＝8.5Hz，1H，C6H3)，6.85(d，J＝8.4Hz，2H，C6H4)；13C NMR(100MHz，DMSO-d6)：161.66，159.75，151.71，149.57，139.47，138.92，129.45，125.74，125.32，118.52，118.29，115.98。
example 20
Preparation of 4-hydroxy-3-methoxybenzaldehyde-3-hydroxy-4-nitrobenzoylhydrazone (I20)
Prepared according to the method of (3) in example 1, 1.0mmol of 3-hydroxy-4-nitrobenzyl hydrazide reacts with 1.05mmol of 4-hydroxy-3-methoxybenzaldehyde for 5h to obtain 4-hydroxy-3-methoxybenzaldehyde-3-hydroxy-4-nitrobenzyl hydrazone (I20) which is a brownish red solid with m.p.246-247 ℃ and yield of 85.8%;1H NMR(400MHz，DMSO-d6)：11.83(s，1H，NH)，11.31(s，1H，OH)，9.59(s，1H，OH)，8.33(s，1H，CH)，8.00(d，J＝8.5Hz，1H，C6H3)，7.60(s，1H，C6H3)，7.45(d，J＝8.5Hz，1H，C6H3)，7.32(s，1H，C6H3)，7.10(d，J＝8.2Hz，1H，C6H3)，6.85(d，J＝8.2Hz，1H，C6H3)，3.83(s，3H，CH3)；13C NMR(100MHz，DMSO-d6)：161.71，152.03，149.78，149.70，148.51，139.73，139.19，125.90，125.85，122.87，118.87，118.35，115.91，109.44，56.01。13C NMR(100MHz，DMSO-d6)：161.28，151.60，149.35，149.27，148.08，139.30，138.76，125.47，125.41，122.43，118.44，117.92，115.48，109.01，55.58。
example 21
Preparation of 3, 4-dihydroxybenzaldehyde-3-hydroxy-4-nitrobenzoylhydrazone (I21)
Prepared according to the method of (3) in example 1, 1.0mmol of 3-hydroxy-4-nitrobenzoyl hydrazide reacts with 1.05mmol of 3, 4-dihydroxybenzaldehyde for 5h to obtain 3, 4-dihydroxybenzaldehyde-3-hydroxy-4-nitrobenzoyl hydrazone (I21) as a yellow solid with m.p. of 273-274 ℃ in yield89.7％；1H NMR(400MHz，DMSO-d6)：11.77(s，1H，NH)，11.30(s，1H，OH)，9.44(s，1H，OH)，9.29(s，1H，OH)，8.26(s，1H，CH)，8.00(d，J＝8.6Hz，1H，C6H3)，7.59(s，1H，C6H3)，7.44(d，J＝8.6Hz，1H，C6H3)，7.25(s，1H，C6H3)，6.95(d，J＝8.1Hz，1H，C6H3)，6.79(d，J＝8.1Hz，1H，C6H3)；13C NMR(100MHz，DMSO-d6)：161.21，151.62，149.34，148.27，145.79，139.35，138.73，125.52，125.41，120.91，118.44，117.92，115.61，112.74。
Example 22
Preparation of 2, 4-dihydroxybenzaldehyde-3-hydroxy-4-nitrobenzoylhydrazone (I22)
Prepared according to the method of (3) in the example 1, 1.0mmol of 3-hydroxy-4-nitrobenzyl hydrazide reacts with 1.05mmol of 2, 4-dihydroxybenzaldehyde for 5h to obtain 2, 4-dihydroxybenzaldehyde-3-hydroxy-4-nitrobenzoyl hydrazone (I22) which is orange red solid with m.p.273-274 ℃ and the yield of 91.5 percent;1H NMR(400MHz，DMSO-d6)：12.06(s，1H，NH)，11.31(s，2H，2×OH)，10.01(s，1H，OH)，8.52(s，1H，CH)，8.01(d，J＝8.5Hz，1H，C6H3)，7.62(s，1H，C6H3)，7.46(d，J＝8.5Hz，1H，C6H3)，7.34(d，J＝8.5Hz，1H，C6H3)，6.37(d，J＝8.5Hz，1H，C6H3)，6.33(s，1H，C6H3)；13C NMR(100MHz，DMSO-d6)：160.99，160.90，159.55，151.64，149.89，138.90，138.64，131.30，125.42，118.49，117.85，110.47，107.85，102.67。
example 23
Preparation of 3-hydroxybenzaldehyde-3-hydroxybenzoylhydrazone (I23)
(1) Preparation of 3-hydroxybenzoyl hydrazine
Prepared according to the method in the step (2) in the embodiment 1, 6.0mmol of methyl 3-hydroxybenzoate reacts with 18.0mmol of 80% hydrazine hydrate for 2h to obtain 3-hydroxybenzoyl hydrazine, white solid, m.p.242-243 ℃ with the yield of 91.3%;1H NMR(400MHz，DMSO-d6)：9.64(s，1H，NH)，9.52(s，1H，OH)，7.24～7.18(m，3H，C6H4)，6.92～6.85(m，1H，C6H4)，4.45(s，2H，NH2)；13C NMR(100MHz，DMSO-d6)：166.00，157.29，134.77，129.29，117.95，117.39，114.08。
(2) preparation of 3-hydroxybenzaldehyde-3-hydroxybenzoylhydrazone (I23)
The preparation method is as in (3) in example 1, 1.0mmol of 3-hydroxybenzoyl hydrazine reacts with 1.05mmol of 3-hydroxybenzaldehyde for 5h, and the 3-hydroxybenzaldehyde-3-hydroxybenzoyl hydrazone (I23) is dried to obtain a white solid with m.p.245-246 ℃ and the yield of 93.8%;1H NMR(400MHz，DMSO-d6)：11.71(s，1H，NH)，9.76(s，1H，OH)，9.63(s，1H，OH)，8.35(s，1H，CH)，7.34～7.26(m，3H，C6H4)，7.24(d，J＝7.8Hz，1H，C6H4)，7.19(s，1H，C6H4)，7.08(d，J＝7.4Hz，1H，C6H4)，7.00～6.94(m，1H，C6H4)，6.85～6.80(m，1H，C6H4)；13C NMR(100MHz，DMSO-d6)：163.10，157.67，157.41，147.73，135.65，134.85，129.88，129.53，118.79，118.67，118.09，117.40，114.51，112.59。
example 24
Preparation of 4-hydroxybenzaldehyde-3-hydroxybenzoylhydrazone (I24)
The preparation method is as in (3) in example 1, 1.0mmol of 3-hydroxybenzoyl hydrazine reacts with 1.05mmol of 4-hydroxybenzaldehyde for 5h, and the 4-hydroxybenzaldehyde-3-hydroxybenzoyl hydrazone (I24) is dried to obtain a light yellow solid with m.p.239-240 ℃ and the yield of 93.6%;1H NMR(400MHz，DMSO-d6)：11.57(s，1H，NH)，9.93(s，1H，OH)，9.74(s，1H，OH)，8.34(s，1H，CH)，7.55(d，J＝8.4Hz，2H，C6H4)，7.33～7.26(m，3H，C6H4)，6.99～6.93(m，1H，C6H4)，6.84(d，J＝8.4Hz，2H，C6H4)；13C NMR(100MHz，DMSO-d6)：163.30，159.46，157.43，148.46，135.10，129.87，129.21，125.61，118.80，118.36，115.90，114.58。
example 25
Preparation of 3-hydroxy-4-methoxybenzaldehyde-3-hydroxybenzoylhydrazone (I25)
Prepared according to the method of (3) in the embodiment 1, 1.0mmol of 3-hydroxybenzoyl hydrazine reacts with 1.05mmol of 3-hydroxy-4-methoxybenzaldehyde for 5h, and the 3-hydroxy-4-methoxybenzaldehyde-3-hydroxybenzoyl hydrazone (I25) is dried to obtain a white solid with m.p.246-247 ℃ and the yield of 95.5 percent;1HNMR(400MHz，DMSO-d6)：11.59(s，1H，NH)，9.75(s，1H，OH)，9.31(s，1H，OH)，8.29(s，1H，CH)，7.32～7.25(m，4H，C6H3and C6H4)，7.04(d，J＝8.2Hz，1H，C6H4)，6.99～6.94(m，2H，C6H3and C6H4)，3.80(s，3H，CH3O)；13C NMR(100MHz，DMSO-d6)：162.96，157.40，149.78，147.85，146.88，135.04，129.51，127.23，120.28，118.55，118.05，114.48，112.31，111.88，55.59。
example 26
Preparation of 4-hydroxy-3-methoxybenzaldehyde-3-hydroxybenzoylhydrazone (I26)
Prepared according to the method of (3) in the embodiment 1, 1.0mmol of 3-hydroxybenzoyl hydrazine reacts with 1.05mmol of 4-hydroxy-3-methoxybenzaldehyde for 5h, and the 4-hydroxy-3-methoxybenzaldehyde-3-hydroxybenzoyl hydrazone (I26) is obtained after drying, and the white solid is m.p. 222-223 ℃, and the yield is 90.9%;1HNMR(400MHz，DMSO-d6)：11.60(s，1H，NH)，9.75(s，1H，OH)，9.55(s，1H，OH)，8.33(s，1H，CH)，7.33～7.27(m，4H，C6H3and C6H4)，7.07(d，J＝8.0Hz，1H，C6H4)，6.99～6.93(m，1H，C6H4)，6.84(d，J＝8.1Hz，1H，C6H3)，3.83(s，3H，CH3O)；13C NMR(100MHz，DMSO-d6)：162.95，157.40，148.97，148.23，148.05，135.07，129.50，125.79，122.15，118.52，118.03，115.45，114.48，108.92，55.57。
example 27
Preparation of 2, 4-dihydroxybenzaldehyde-3-hydroxybenzoylhydrazone (I27)
The preparation method is as in (3) in example 1, 1.0mmol of 3-hydroxybenzoyl hydrazine reacts with 1.05mmol of 2, 4-dihydroxybenzaldehyde for 5h, and the 2, 4-dihydroxybenzaldehyde-3-hydroxybenzoyl hydrazone (I27) is dried to obtain 2, 4-dihydroxybenzaldehyde-3-hydroxybenzoyl hydrazone (I27) as a gray solid with m.p. 245-246 ℃ and the yield of 94.2%;1H NMR(400MHz，DMSO-d6)：11.85(s，1H，NH)，11.52(s，1H，OH)，9.86(s，2H，2×OH)，8.49(s，1H，CH)，7.36～7.26(m，4H，C6H3and C6H4)，6.98(d，J＝6.6Hz，1H，C6H4)，6.36(d，J＝8.5Hz，1H，C6H3)，6.32(s，1H，C6H3)；13C NMR(100MHz，DMSO-d6)：162.57，160.71，159.54，157.46，149.24，134.38，131.46，129.60，118.79，118.05，114.47，110.55，107.71，102.71。
example 28
Preparation of 3-hydroxybenzaldehyde-4-hydroxybenzoylhydrazone (I28)
(1) Preparation of 4-hydroxybenzoyl hydrazine
Prepared according to the method in the step (2) in the embodiment 1, 6.0mmol of methyl 4-hydroxybenzoate reacts with 18.0mmol of 80% hydrazine hydrate for 2h, and 4-hydroxybenzoyl hydrazine is obtained after drying, wherein the solid is white solid, the yield is 96.8% at m.p.267-268 ℃;1H NMR(400MHz，DMSO-d6)：9.92(s，1H，NH)，9.48(s，1H，OH)，7.68(d，J＝7.7Hz，2H，C6H4)，6.78(d，J＝7.7Hz，2H，C6H4)，4.38(s，2H，NH2)；13C NMR(100MHz，DMSO-d6)：165.93，159.98，128.81，123.98，114.82。
(2) preparation of 3-hydroxybenzaldehyde-4-hydroxybenzoylhydrazone (I28)
The preparation method is as in (3) in example 1, 1.0mmol of 4-hydroxybenzoyl hydrazine reacts with 1.05mmol of 3-hydroxybenzaldehyde for 5h, and the 3-hydroxybenzaldehyde-4-hydroxybenzoyl hydrazone (I28) is obtained after drying, and the white solid is m.p.255-256 ℃, and the yield is 95.1%;1H NMR(400MHz，DMSO-d6)：11.59(s，1H，NH)，10.13(s，1H，OH)，9.62(s，1H，OH)，8.34(s，1H，CH)，7.81(d，J＝7.0Hz，2H，C6H4)，7.27～7.21(m，1H，C6H4)，7.19(s，1H，C6H4)，7.08(d，J＝7.2Hz，1H，C6H4)，6.86(d，J＝7.0Hz，2H，C6H4)，6.82(d，J＝8.0Hz，1H，C6H4)；13C NMR(100MHz，DMSO-d6)：162.74，160.68，157.67，146.93，135.81，129.87，129.67，123.90，118.69，117.24，115.03，112.52。
example 29
Preparation of 4-hydroxybenzaldehyde-4-hydroxybenzoylhydrazone (I29)
The preparation method is as in (3) in example 1, 1.0mmol of 4-hydroxybenzoyl hydrazine reacts with 1.05mmol of 4-hydroxybenzaldehyde for 5h, and the 4-hydroxybenzaldehyde-4-hydroxybenzoyl hydrazone (I29) is dried to obtain a white solid with m.p.259-260 ℃ and the yield of 90.2%;1H NMR(400MHz，DMSO-d6)：11.44(s，1H，NH)，10.06(s，1H，OH)，9.93(s，1H，OH)，8.32(s，1H，CH)，7.79(d，J＝8.4Hz，2H，C6H4)，7.54(d，J＝8.0Hz，2H，C6H4)，6.85(d，J＝8.4Hz，2H，C6H4)，6.83(d，J＝8.0Hz，2H，C6H4)；13C NMR(100MHz，DMSO-d6)：162.93，160.62，159.32，147.64，129.80，129.06，125.74，124.19，115.87，115.21。
example 30
Preparation of 3-hydroxy-4-methoxybenzaldehyde-4-hydroxybenzoylhydrazone (I30)
Prepared according to the method of (3) in example 1, 1.0mmol of 4-hydroxybenzoyl hydrazine was reacted with 1.05mmol of 3-hydroxy-4-methoxybenzaldehyde for 5 hours, and dried to give 3-hydroxy-4-methoxybenzaldehyde-4-hydroxybenzoylhydrazone (I30) as a white solidSolid, m.p.278-279 ℃, yield 94.4%;1H NMR(400MHz，DMSO-d6)：11.46(s，1H，NH)，10.09(s，1H，OH)，9.29(s，1H，OH)，8.28(s，1H，CH)，7.79(d，J＝8.5Hz，2H，C6H4)，7.26(s，1H，C6H3)，7.03(d，J＝8.2Hz，1H，C6H3)，6.96(d，J＝8.2Hz，1H，C6H3)，6.85(d，J＝8.5Hz，2H，C6H4)，3.80(s，3H，CH3)；13C NMR(100MHz，DMSO-d6)：162.58，160.57，149.63，147.06，146.88，129.59，127.40，124.09，120.10，115.01，112.26，111.88，55.59。
example 31
Preparation of 4-hydroxy-3-methoxybenzaldehyde-4-hydroxybenzoylhydrazone (I31)
The preparation method is as in (3) in example 1, 1.0mmol of 4-hydroxybenzoyl hydrazine reacts with 1.05mmol of 4-hydroxy-3-methoxybenzaldehyde for 5 hours, and the 4-hydroxy-3-methoxybenzaldehyde-4-hydroxybenzoyl hydrazone (I31) is dried to obtain a light yellow solid with m.p.108-109 ℃ and the yield of 83.9%;1H NMR(400MHz，DMSO-d6)：11.47(s，1H，NH)，10.10(s，1H，OH)，9.52(s，1H，OH)，8.31(s，1H，CH)，7.79(d，J＝8.1Hz，2H，C6H4)，7.30(s，1H，C6H3)，7.06(d，J＝7.9Hz，1H，C6H3)，6.88～6.81(m，3H，C6H4and C6H3)，3.82(s，3H，CH3O)；13C NMR(100MHz，DMSO-d6)：162.61，160.56，148.83，148.05，147.50，129.59，125.96，124.11，122.02，115.45，115.01，108.89，55.56。
example 32
Preparation of 3, 4-dihydroxybenzaldehyde-4-hydroxybenzoylhydrazone (I32)
The preparation method is as in (3) in example 1, 1.0mmol of 4-hydroxybenzoyl hydrazine reacts with 1.05mmol of 3, 4-dihydroxybenzaldehyde for 5h, and the reaction product is dried to obtain 3, 4-dihydroxybenzaldehyde-4-hydroxybenzoyl hydrazone (I32) which is gray solid with m.p.275-276 ℃ and the yield of 93.2%;1H NMR(400MHz，DMSO-d6)：11.39(s，1H，NH)，10.07(s，1H，OH)，9.34(s，1H，OH)，9.25(s，1H，OH)，8.23(s，1H，CH)，7.78(d，J＝8.4Hz，2H，C6H4)，7.23(s，1H，C6H3)，6.91(d，J＝8.0Hz，1H，C6H3)，6.85(d，J＝8.4Hz，2H，C6H4)，6.78(d，J＝8.0Hz，1H，C6H3)；13C NMR(100MHz，DMSO-d6)：162.49，160.49，147.77，147.43，145.70，129.53，125.99，124.16，120.39，115.57，114.98，112.63。
example 33
Preparation of 2, 4-dihydroxybenzaldehyde-4-hydroxybenzoylhydrazone (I33)
Prepared according to the method of (3) in example 1, 1.0mmol of 4-hydroxybenzoyl hydrazine was reacted with 1.05mmol of 2, 4-dihydroxybenzaldehyde for 5h and dried to give 2, 4-dihydroxybenzaldehyde-4-hydroxybenzoylhydrazone (I33), grey solid, m.p.>The yield is 96.4 percent at 280 ℃;1H NMR(400MHz，DMSO-d6)：11.72(s，1H，NH)，11.61(s，1H，OH)，10.02(s，2H，2×OH)，8.47(s，1H，CH)，7.80(d，J＝8.1Hz，2H，C6H4)，7.26(d，J＝8.5Hz，1H，C6H3)，6.87(d，J＝8.1Hz，2H，C6H4)，6.35(d，J＝8.5Hz，1H，C6H3)，6.31(s，1H，C6H3)；13C NMR(100MHz，DMSO-d6)：162.17，160.76，160.52，159.46，148.51，131.38，129.59，123.41，115.09，110.61，107.60，102.69。
example 34
Preparation of 4-pyridinecarboxaldehyde-4-hydroxybenzoylhydrazone (I34)
The preparation method is as in (3) in example 1, 1.0mmol of 4-hydroxybenzoyl hydrazine reacts with 1.05mmol of 4-pyridinecarboxaldehyde for 5 hours, and the 4-pyridinecarboxaldehyde-4-hydroxybenzoyl hydrazone (I34) is obtained after drying, and the white solid is m.p. 276-277 ℃, and the yield is 95.8%;1H NMR(400MHz，DMSO-d6)：11.90(s，1H，OH)，10.18(s，1H，NH)，8.64(d，J＝5.1Hz，2H，C5H4N)，8.41(s，1H，CH)，7.82(d，J＝8.2Hz，2H，C6H4)，7.64(d，J＝5.1Hz，2H，C5H4N)，6.88(d，J＝8.2Hz，2H，C6H4)；13C NMR(100MHz，DMSO-d6)：162.97，160.90，150.23，144.28，141.69，129.90，123.48，120.87，115.06。
example 35
Preparation of 4-hydroxybenzaldehyde-3, 5-dihydroxybenzoylhydrazone (I35)
(1) Preparation of 3, 5-dihydroxybenzoylhydrazine
Prepared according to the method in the step (2) in the embodiment 1, 6.0mmol of methyl 3, 5-dihydroxybenzoate reacts with 18.0mmol of 80% hydrazine hydrate for 2h to obtain 3, 5-dihydroxybenzoyl hydrazine, gray solid, m.p.265-266 ℃, and the yield is 90.8%;1H NMR(400MHz，DMSO-d6)：9.51(s，1H，NH)，9.40(s，2H，2×OH)，6.63(s，2H，C6H3)，6.33(s，1H，C6H3)，4.39(s，2H，NH2)；13C NMR(100MHz，DMSO-d6)：166.26，158.22，135.50，105.25，104.98。
(2) preparation of 4-hydroxybenzaldehyde-3, 5-dihydroxybenzoylhydrazone (I35)
The preparation method is as in (3) in example 1, 1.0mmol of 3, 5-dihydroxybenzoylhydrazine reacts with 1.05mmol of 4-hydroxybenzaldehyde for 5h, and the 4-hydroxybenzaldehyde-3, 5-dihydroxybenzoylhydrazone (I35) is obtained after drying, wherein the solid is gray solid, m.p.213-214 ℃, and the yield is 93.1%;1H NMR(400MHz，DMSO-d6)：11.47(s，1H，NH)，9.90(s，1H，OH)，9.55(s，2H，2×OH)，8.32(s，1H，CH)，7.53(d，J＝8.1Hz，2H，C6H4)，6.83(d，J＝8.1Hz，2H，C6H4)，6.73(s，2H，C6H3)，6.41(s，1H，C6H3)；13C NMR(100MHz，DMSO-d6)：163.12，159.35，158.37，147.85，135.73，128.80，125.43，115.71，105.72，105.48。
example 36
Preparation of 4-hydroxy-3-methoxybenzaldehyde-3, 5-dihydroxybenzoylhydrazone (I36)
Prepared according to the method of (3) in the example 1, 1.0mmol of 3, 5-dihydroxybenzoylhydrazine reacts with 1.05mmol of 4-hydroxy-3-methoxybenzaldehyde for 5h, and is dried to obtain 4-hydroxy-3-methoxybenzaldehyde-3, 5-dihydroxybenzoylhydrazone (I36) which is yellow solid with m.p.101-102 ℃ and the yield of 93.8 percent;1H NMR(400MHz，DMSO-d6)：11.49(s，1H，NH)，9.55(s，2H，2×OH)，9.52(s，1H，OH)，8.30(s，1H，CH)，7.29(s，1H，C6H3)，7.05(d，J＝8.1Hz，1H，C6H3)，6.83(d，J＝8.1Hz，1H，C6H3)，6.72(s，2H，C6H3)，6.41(s，1H，C6H3)，3.82(s，3H，CH3)；13C NMR(100MHz，DMSO-d6)：163.14，158.36，148.91，148.05，148.04，135.72，125.86，122.08，115.44，108.96，105.72，105.47，55.57。
example 37
Preparation of 2, 4-dihydroxybenzaldehyde-3, 5-dihydroxybenzoylhydrazone (I37)
The preparation method is as in (3) in example 1, 1.0mmol of 3, 5-dihydroxybenzoylhydrazine reacts with 1.05mmol of 2, 4-dihydroxybenzaldehyde for 5h to obtain 2, 4-dihydroxybenzaldehyde-3, 5-dihydroxybenzoylhydrazone (I37), gray solid, and the yield is 90.6% at m.p.273-274 ℃;1H NMR(400MHz，DMSO-d6)：11.76(s，1H，NH)，11.54(s，1H，OH)，9.92(s，1H，OH)，9.63(s，1H，OH)，9.62(s，1H，OH)，8.46(s，1H，CH)，7.26(d，J＝8.4Hz，1H，C6H3)，6.74(s，2H，C6H3)，6.42(s，1H，C6H3)，6.35(d，J＝8.4Hz，1H，C6H3)，6.31(s，1H，C6H3)；13C NMR(100MHz，DMSO-d6)：162.75，160.66，159.55，158.46，149.20，135.01，131.53，110.56，107.69，105.73，102.77，102.71。
example 38
Preparation of 4-pyridinecarboxaldehyde-3, 5-dihydroxybenzoylhydrazone (I38)
According toPrepared by the method of (3) in example 1, 1.0mmol of 3, 5-dihydroxybenzoylhydrazine reacted with 1.05mmol of 4-pyridinecarboxaldehyde for 5h to give 4-pyridinecarboxaldehyde-3, 5-dihydroxybenzoylhydrazone (I38) as a white solid, m.p.>The yield is 91.8 percent at 280 ℃;1H NMR(400MHz，DMSO-d6)：11.95(s，1H，NH)，9.62(s，2H，2×OH)，8.64(d，J＝4.6Hz，2H，C5H4N)，8.42(s，1H，CH)，7.64(d，J＝4.6Hz，2H，C5H4N)，6.76(s，2H，C6H3)，6.44(s，1H，C6H3)；13C NMR(100MHz，DMSO-d6)：163.59，158.45，150.27，145.05，145.03，141.61，135.08，120.97，105.89。
example 39
Preparation of 3, 4-dihydroxybenzaldehyde-3, 5-dihydroxybenzoylhydrazone (I39)
Prepared according to the method of (3) in the example 1, 1.0mmol of 3, 5-dihydroxybenzoylhydrazine reacts with 1.05mmol of 3, 4-dihydroxybenzaldehyde for 5h to obtain 3, 4-dihydroxybenzaldehyde-3, 5-dihydroxybenzoylhydrazone (I39) which is white solid with m.p. 241-242 ℃ and the yield of 92.9%;1H NMR(400MHz，DMSO-d6)：11.42(s，1H，NH)，9.53(s，2H，2×OH)，9.33(s，2H，2×OH)，8.22(s，1H，CH)，7.21(s，1H，C6H3)，6.90(d，J＝8.0Hz，1H，C6H3)，6.77(d，J＝8.0Hz，1H，C6H3)，6.71(s，2H，C6H3)，6.40(s，1H，C6H3)；13C NMR(100MHz，DMSO-d6)：163.04，158.36，148.04，147.89，145.71，135.78，125.89，120.51，115.57，112.68，105.70，105.45。
example 40
Preparation of 4-hydroxybenzaldehyde-4-trifluoromethylbenzoylhydrazone (I40)
(1) Preparation of methyl 4-trifluoromethylbenzoate
Prepared according to the method in the (1) in the example 1, 8.0mmol of 4-trifluoromethylbenzoic acid and 9.6mmol of thionyl chloride are reacted in 12mL of methanol for 2h to obtain methyl 4-trifluoromethylbenzoate as a white solid with m.p.46-47 ℃ and the yield of 91.9%;1H NMR(400MHz，CDCl3)：8.14(d，J＝8.2Hz，2H，C6H4)，7.69(d，J＝8.2Hz，2H，C6H4)，3.95(s，3H，CH3)；13C NMR(100MHz，CDCl3)：165.86，134.41(q，J＝32.72Hz)，133.31，129.97，125.39(q，J＝3.7Hz)，122.27，52.52。
(2) preparation of 4-trifluoromethylbenzoyl hydrazine
Prepared according to the method in the step (2) in the embodiment 1, 6.0mmol of methyl 4-trifluoromethylbenzoate reacts with 18.0mmol of 80% hydrazine hydrate for 2h to obtain 4-trifluoromethylbenzoyl hydrazine as a white solid with the m.p.122-123 ℃ and the yield of 93.8%;1HNMR(400MHz，DMSO-d6)：10.01(s，1H，NH)，8.01(d，J＝8.0 Hz，2H，C6H4)，7.82(d，J＝8.0 Hz，2H，C6H4)，4.59(s，2H，NH2)；13C NMR(100 MHz，DMSO-d6)：164.51，137.11，130.99(q，J＝31.9 Hz)，127.84，125.31(q，J＝3.6 Hz)，122.56。
(3) preparation of 4-hydroxybenzaldehyde-4-trifluoromethylbenzoylhydrazone (I40)
Prepared according to the method of (3) in example 1, 1.0mmol of 4-trifluoromethylbenzoyl hydrazine is reacted with 1.05mmol of 4-hydroxybenzaldehyde for 5 hours to obtain 4-hydroxybenzaldehyde-4-trifluoromethylbenzylAcylhydrazone (I40), white solid, m.p.247-248 ℃, yield 90.9%;1H NMR(400 MHz，DMSO-d6)：11.84(s，1H，NH)，9.96(s，1H，OH)，8.37(s，1H，CH)，8.10(d，J＝8.0 Hz，2H，C6H4)，7.90(d，J＝8.0 Hz，2H，C6H4)，7.58(d，J＝8.1Hz，2H，C6H4)，6.85(d，J＝8.1 Hz，2H，C6H4)；13C NMR(100 MHz，DMSO-d6)：161.65，159.62，148.94，137.46，131.36(q，J＝32.2 Hz)，128.99，128.45，125.39(q，J＝3.6 Hz)，125.09，122.54，115.74。
EXAMPLE 41
Preparation of 3-methoxy-4-hydroxybenzaldehyde-4-trifluoromethylphenylcarbonylhydrazone (I41)
Prepared according to the method in (3) in the embodiment 1, 1.0mmol of 4-trifluoromethyl benzoyl hydrazine reacts with 1.05mmol of 3-methoxy-4-hydroxybenzaldehyde for 5h to obtain 3-methoxy-4-hydroxybenzaldehyde-4-trifluoromethyl benzoyl hydrazone (I41) which is light yellow solid with m.p. 185-186 ℃ and the yield of 94.6%;1H NMR(400 MHz，DMSO-d6)：11.86(s，1H，NH)，9.58(s，1H，OH)，8.35(s，1H，CH)，8.10(d，J＝8.0 Hz，2H，C6H4)，7.91(d，J＝8.0 Hz，2H，C6H4)，7.33(s，1H，C6H3)，7.11(d，J＝8.1 Hz，1H，C6H3)，6.86(d，J＝8.1 Hz，1H，C6H3)，3.84(s，3H，CH3)；13C NMR(100 MHz，DMSO-d6)：161.69，149.19(d，J＝4.1 Hz)，148.06，137.47，131.24(q，J＝31.82 Hz)，130.28，128.46，125.43(q，J＝4.6 Hz)，125.25，122.54，122.32，115.46，109.09，55.58。
example 42
Preparation of 2, 4-dihydroxybenzaldehyde-4-trifluoromethylbenzoylhydrazone (I42)
The preparation method is as in (3) in example 1, 1.0mmol of 4-trifluoromethylbenzoyl hydrazine reacts with 1.05mmol of 2, 4-dihydroxybenzaldehyde for 5h to obtain 2, 4-dihydroxybenzaldehyde-4-trifluoromethylbenzoyl hydrazone (I42) which is gray solid, m.p. 278-279 ℃ and the yield is 92.6%;1H NMR(400MHz，DMSO-d6)：12.10(s，1H，OH)，11.35(s，1H，NH)，10.00(s，1H，OH)，8.53(s，1H，CH)，8.12(d，J＝8.0Hz，2H，C6H4)，7.92(d，J＝8.0Hz，2H，C6H4)，7.35(d，J＝8.5Hz，1H，C6H3)，6.37(d，J＝8.5Hz，1H，C6H3)，6.33(s，1H，C6H3)；13C NMR(100MHz，DMSO-d6)：161.32，160.94，159.54，149.72，136.86，131.28，128.49，125.53，125.50，110.48，107.81，102.66。
example 43
Preparation of 4-hydroxybenzaldehyde-3, 5-dinitrobenzoylhydrazone (I43)
(1) Preparation of 3, 5-dinitrobenzoyl hydrazine
Prepared according to the method in the step (2) in the embodiment 1, 6.0mmol of methyl 3, 5-dinitrobenzoate reacts with 18.0mmol of 80% hydrazine hydrate for 2h to obtain 3, 5-dinitrobenzoyl hydrazine, yellow solid, m.p. 272-273 ℃, and the yield is 95.6%.
(2) Preparation of 4-hydroxybenzaldehyde-3, 5-dinitrobenzoylhydrazone (I43)
Prepared according to the method of (3) in example 1, 1.0mmol of 3, 5-dinitrobenzoyl hydrazine is reacted with 1.05mmol of 4-hydroxybenzaldehyde for 5 hours to obtain 4-hydroxybenzeneFormaldehyde-3, 5-dinitrobenzoylhydrazone (I43), yellow solid, m.p.>The yield is 90.9 percent at 280 ℃;1H NMR(400MHz，DMSO-d6)：12.21(s，1H，NH)，10.01(s，1H，OH)，9.11(s，2H，C6H3)，8.98(s，1H，C6H3)，8.39(s，1H，CH)，7.60(d，J＝8.0Hz，2H，C6H4)，6.85(d，J＝8.0Hz，2H，C6H4)；13C NMR(100MHz，DMSO-d6)：159.87，158.67，149.95，148.18，136.18，129.22，127.80，124.82，121.10，115.79。
example 44
Preparation of 4-hydroxy-3-methoxybenzaldehyde-3, 5-dinitrobenzoylhydrazone (I44)
Prepared according to the method of (3) in example 1, 1.0mmol of 3, 5-dinitrobenzoyl hydrazine was reacted with 1.05mmol of 4-hydroxy-3-methoxybenzaldehyde for 5h and dried to give 4-hydroxy-3-methoxybenzaldehyde-3, 5-dinitrobenzoyl hydrazone (I44) as a yellow solid, m.p.>The yield is 91.7 percent at 280 ℃;1H NMR(400MHz，DMSO-d6)：12.22(s，1H，NH)，9.62(s，1H，OH)，9.11(s，2H，C6H3)，8.98(s，1H，C6H3)，8.38(s，1H，CH)，7.33(s，1H，C6H3)，7.13(d，J＝8.1Hz，1H，C6H3)，6.85(d，J＝8.1Hz，1H，C6H3)，3.84(s，3H，CH3)；13C NMR(100MHz，DMSO-d6)：158.64，150.16，149.47，148.15，148.07，136.15，127.76，125.19，122.65，121.07，115.46，109.08，55.58。
example 45
Preparation of 2, 4-dihydroxybenzaldehyde-3, 5-dinitrobenzoylhydrazone (I45)
Prepared according to the method of (3) in example 1, 1.0mmol of 3, 5-dinitrobenzoyl hydrazine was reacted with 1.05mmol of 2, 4-dihydroxybenzaldehyde for 5h to give 2, 4-dihydroxybenzaldehyde-3, 5-dinitrobenzoyl hydrazone (I45) as a yellow solid, m.p.>The yield is 94.3 percent at 280 ℃;1H NMR(400MHz，DMSO-d6)：12.41(s，1H，NH)，11.09(s，1H，OH)，10.01(s，1H，OH)，9.12(s，2H，C6H3)，8.98(s，1H，C6H3)，8.58(s，1H，CH)，7.39(d，J＝8.5Hz，1H s，2H，C6H3)，6.36(d，J＝8.5Hz，1H s，2H，C6H3)，6.32(s，1H s，2H，C6H3)；13C NMR(100MHz，DMSO-d6)：161.18，159.45，158.31，150.03，148.17，135.68，130.87，127.75，121.14，110.44，107.92，102.57。
example 46
Preparation of 4-hydroxybenzaldehyde-3-methoxy-4-hydroxybenzoylhydrazone (I46)
(1) Preparation of 3-methoxy-4-hydroxybenzoyl hydrazine
The preparation method is as in (2) in the embodiment 1, 6.0mmol of methyl 3-methoxy-4-hydroxybenzoate reacts with 18.0mmol of 80% hydrazine hydrate for 2h, and the reaction product is dried to obtain 3-methoxy-4-hydroxybenzoyl hydrazine as a white solid with the m.p. of 205-206 ℃ and the yield of 91.5%;1H NMR(400MHz，DMSO-d6)：9.51(s，2H，NH and OH)，7.41(s，1H，C6H3)，7.31(d，J＝8.2Hz，1H，C6H3)，6.79(d，J＝8.2Hz，1H，C6H3)，4.39(s，2H，NH2)，3.80(s，3H，OCH3)；13C NMR(100MHz，DMSO-d6)：165.84，149.32，147.10，124.24，120.44，114.86，110.94，55.62。
(2) preparation of 4-hydroxybenzaldehyde-3-methoxy-4-hydroxybenzoylhydrazone (I46)
Prepared according to the method of (3) in the example 1, 1.0mmol of 3-methoxy-4-hydroxybenzoyl hydrazine reacts with 1.05mmol of 4-hydroxybenzaldehyde for 5h, and is dried to obtain 4-hydroxybenzaldehyde-3-methoxy-4-hydroxybenzoyl hydrazone (I46) as a white solid with m.p.247-248 ℃ and the yield of 90.9%;1HNMR(400MHz，DMSO-d6)：11.42(s，1H，NH)，9.80(s，2H，2×OH)，8.34(s，1H，CH)，7.54(d，J＝8.0Hz，2H，C6H4)，7.48(s，1H，C6H3)，7.43(d，J＝8.0Hz，1H，C6H3)，6.86(d，J＝8.0Hz，1H，C6H3)，6.84(d，J＝8.0Hz，2H，C6H4)，3.84(s，3H，CH3)；13C NMR(100MHz，DMSO-d6)：162.47，159.25，149.95，147.31，128.69，125.49，124.39，121.25，121.19，115.69，114.93，111.59，55.73。
example 47
Preparation of 3-methoxy-4-hydroxybenzaldehyde-3-methoxy-4-hydroxybenzoylhydrazone (I47)
Prepared according to the method of (3) in example 1, 1.0mmol of 3-methoxy-4-hydroxybenzoyl hydrazine reacts with 1.05mmol of 3-methoxy-4-hydroxybenzaldehyde for 5h to obtain 3-methoxy-4-hydroxybenzaldehyde-3-methoxy-4-hydroxybenzoyl hydrazone (I47) as a light yellow solid with m.p.242-243 ℃ yield of 93.7%;1HNMR(400MHz，DMSO-d6)：11.45(s，1H，NH)，9.61(s，2H，2×OH)，8.34(s，1H，CH)，7.48(s，1H，C6H3)，7.44(d，J＝8.4Hz，1H，C6H3)，7.30(s，1H，C6H3)，7.07(d，J＝8.0Hz，1H，C6H3)，6.86(d，J＝8.0Hz，1H，C6H3)，6.84(d，J＝8.4Hz，1H，C6H3)，3.84(s，3H，CH3)，3.82(s，3H，CH3)；13C NMR(100MHz，DMSO-d6)：162.52，149.99，148.85，148.04，147.60，147.26，125.90，124.37，121.97，121.24，115.46，114.95，111.58，108.93，55.74，55.55。
example 48
Preparation of 2, 4-dihydroxybenzaldehyde-3-methoxy-4-hydroxybenzoylhydrazone (I48)
Prepared according to the method of (3) in the example 1, 1.0mmol of 3-methoxy-4-hydroxybenzoyl hydrazine reacts with 1.05mmol of 2, 4-dihydroxybenzaldehyde for 5h to obtain 2, 4-dihydroxybenzaldehyde-3-methoxy-4-hydroxybenzoyl hydrazone (I48) which is gray solid with m.p.215-216 ℃ and the yield of 96.8%;1H NMR(400MHz，DMSO-d6)：11.71(s，1H，NH)，11.59(s，1H，OH)，9.84(s，2H，2×OH)，8.49(s，1H，CH)，7.49(s，1H，C6H3)，7.45(d，J＝8.2Hz，1H)，7.28(d，J＝8.4Hz，1H，C6H3)，6.88(d，J＝8.4Hz，1H，C6H3)，6.36(d，J＝8.2Hz，1H，C6H3)，6.32(s，1H，C6H3)，3.85(s，3H，CH3)；13C NMR(100MHz，DMSO-d6)：162.14，160.54，159.45，150.20，148.48，147.34，131.30，123.69，121.26，115.03，111.57，110.63，107.62，102.69，55.75。
example 49
Preparation of 4-hydroxybenzaldehyde-3, 4, 5-trihydroxyphenylcarbonylhydrazone (I49)
(1) Preparation of 3,4, 5-trihydroxy benzoyl hydrazine
Prepared according to the method of (2) in example 1, 6.0mmol of methyl 3,4, 5-trihydroxybenzoate andreacting 18.0mmol of 80% hydrazine hydrate for 2h to obtain 3,4, 5-trihydroxy benzoyl hydrazine, white solid, m.p.276-277 ℃, and the yield is 89.8%;1H NMR(400MHz，DMSO-d6)：9.32(s，1H，NH)，8.88(s，3H，3×OH)，6.78(s，2H，C6H2)，4.32(s，2H，NH2)；13C NMR(100MHz，DMSO-d6)：166.43，145.43，136.16，123.60，106.51。
(2) preparation of 4-hydroxybenzaldehyde-3, 4, 5-trihydroxyphenylcarbonylhydrazone (I49)
Prepared according to the method of (3) in the embodiment 1, 1.0mmol of 3,4, 5-trihydroxybenzoyl hydrazine reacts with 1.05mmol of 4-hydroxybenzaldehyde for 5h to obtain 4-hydroxybenzaldehyde-3, 4, 5-trihydroxybenzoyl hydrazone (I49) which is light yellow solid, m.p. 262-263 ℃ and has the yield of 96.5 percent;1H NMR(400MHz，DMSO-d6)：11.32(s，1H，NH)，9.86(s，1H，OH)，9.08(s，3H，3×OH)，8.30(s，1H，CH)，7.51(d，J＝8.0Hz，2H，C6H4)，6.90(s，2H，C6H2)，6.82(d，J＝8.0Hz，2H，C6H4)；13C NMR(100MHz，DMSO-d6)：162.95，159.16，146.97，145.53，136.76，128.64，125.62，123.64，115.67，107.08。
example 50
Preparation of 4-hydroxy-3-methoxybenzaldehyde-3, 4, 5-trihydroxybenzoylhydrazone (I50)
Prepared according to the method of (3) in example 1, 1.0mmol of 3,4, 5-trihydroxybenzoyl hydrazine was reacted with 1.05mmol of 4-hydroxy-3-methoxybenzaldehyde to give 5h, obtaining 4-hydroxy-3-methoxybenzaldehyde-3, 4, 5-trihydroxybenzoyl hydrazone (I50) as a white solid with m.p. 244-245 ℃ and the yield of 96.8%;1H NMR(400MHz，DMSO-d6)：11.36(s，1H，NH)，9.13(s，4H，4×OH)，8.29(s，1H，CH)，7.28(s，1H，C6H3)，7.04(d，J＝8.1Hz，1H，C6H3)，6.90(s，2H，C6H2)，6.83(d，J＝8.1Hz，1H，C6H3)，3.82(s，3H，CH3)；13C NMR(100MHz，DMSO-d6)：162.99，148.73，148.03，147.21，145.54，136.80，126.05，123.61，121.89，115.43，108.88，107.10，55.55。
example 51
Preparation of 2, 4-dihydroxybenzaldehyde-3, 4, 5-trihydroxybenzoylhydrazone (I51)
Prepared according to the method of (3) in example 1, 1.0mmol of 3,4, 5-trihydroxybenzoyl hydrazine was reacted with 1.05mmol of 2, 4-dihydroxybenzaldehyde for 5h to give 2, 4-dihydroxybenzaldehyde-3, 4, 5-trihydroxybenzoyl hydrazone (I51) as a light yellow solid, m.p.>The yield is 96.7 percent at 280 ℃;1H NMR(400MHz，DMSO-d6)：11.66(s，1H，OH)，11.63(s，1H，NH)，9.92(s，1H，OH)，9.17(s，2H，2×OH)，8.89(s，1H，OH)，8.44(s，1H，CH)，7.23(d，J＝8.5Hz，1H，C6H3)，6.91(s，2H，C6H2)，6.35(d，J＝8.5Hz，1H，C6H3)，6.30(s，1H，C6H3)；13C NMR(100MHz，DMSO-d6)：162.56，160.42，159.47，148.47，145.60，137.05，131.45，122.87，110.61，107.54，107.08，102.68。
example 52
Preparation of 4-hydroxybenzaldehyde-2, 4-dihydroxybenzoylhydrazone (I52)
(1) Preparation of 2, 4-dihydroxybenzoylhydrazine
Prepared according to the method in the step (2) in the embodiment 1, 6.0mmol of methyl 2, 4-dihydroxybenzoate reacts with 18.0mmol of 80% hydrazine hydrate for 2h to obtain 2, 4-dihydroxybenzoyl hydrazine, white solid, m.p.242-243 ℃, and the yield is 85.2%;1H NMR(400MHz，DMSO-d6)：9.67(s，1H，NH)，8.20(s，1H，OH)，7.61(d，J＝8.8Hz，1H，C6H3)，7.40(s，1H，OH)，6.66(s，2H，NH2)，6.21(d，J＝8.8Hz，1H，C6H3)，6.20(s，1H，C6H3)；13CNMR(100MHz，DMSO-d6)：168.55，162.59，162.21，128.55，106.63，106.07，102.92。
(2) preparation of 4-hydroxybenzaldehyde-2, 4-dihydroxybenzoylhydrazone (I52)
Prepared according to the method in the step (3) in the embodiment 1, 1.0mmol of 2, 4-dihydroxybenzoylhydrazine reacts with 1.05mmol of 4-hydroxybenzaldehyde for 5 hours to obtain 4-hydroxybenzaldehyde-2, 4-dihydroxybenzoylhydrazone (I52) which is light yellow solid, m.p. is 275-276 ℃ and the yield is 87.3%;1H NMR(400MHz，DMSO-d6)：12.48(s，1H，OH)，11.52(s，1H，NH)，10.19(s，1H，OH)，9.94(s，1H，OH)，8.33(s，1H，CH)，7.79(d，J＝8.8Hz，1H，C6H3)，7.56(d，J＝8.1Hz，2H，C6H4)，6.84(d，J＝8.1Hz，2H，C6H4)，6.35(d，J＝8.8Hz，1H，C6H3)，6.30(s，1H，C6H3)；13C NMR(100MHz，DMSO-d6)：165.31，162.55，159.50，148.40，130.07，129.43，128.93，125.17，115.72，107.30，106.15，102.85。
example 53
Preparation of 4-hydroxy-3-methoxybenzaldehyde-2, 4-dihydroxybenzoylhydrazone (I53)
Prepared according to the method of (3) in the example 1, 1.0mmol of 2, 4-dihydroxybenzoylhydrazine reacts with 1.05mmol of 4-hydroxy-3-methoxybenzaldehyde for 5h to obtain 4-hydroxy-3-methoxybenzaldehyde-2, 4-dihydroxybenzoylhydrazone (I53) which is yellow solid with m.p. of 220-221 ℃ and the yield of 83.3%;1H NMR(400MHz，DMSO-d6)：12.48(s，1H，OH)，11.55(s，1H，NH)，10.20(s，1H，OH)，9.57(s，1H，OH)，8.32(s，1H，CH)，7.79(d，J＝8.8Hz，1H，C6H3)，7.31(s，1H，C6H3)，7.10(d，J＝8.1Hz，1H，C6H3)，6.85(d，J＝8.1Hz，1H，C6H3)，6.36(d，J＝8.8Hz，1H，C6H3)，6.31(s，1H，C6H3)，3.83(s，3H，CH3)；13C NMR(100MHz，DMSO-d6)：165.26，162.55，162.33，149.08，148.58，148.03，129.48，125.58，122.24，115.45，109.02，107.29，106.22，102.86，55.55。
example 54
Preparation of 2, 4-dihydroxybenzaldehyde-2, 4-dihydroxybenzoylhydrazone (I54)
Prepared according to the method of (3) in example 1, 1.0mmol of 2, 4-dihydroxybenzoylhydrazine was reacted with 1.05mmol of 2, 4-dihydroxybenzaldehyde for 5h to give 2, 4-dihydroxybenzaldehyde-2, 4-dihydroxybenzoylhydrazone (I54) as a yellow solid, m.p.>The yield is 85.8 percent at 280 ℃;1H NMR(400MHz，DMSO-d6)：11.77(s，2H，2×OH)，11.43(s，1H，NH)，10.15(s，2H，2×OH)，8.51(s，1H，CH)，7.78(d，J＝8.5Hz，1H，C6H3)，7.31(d，J＝8.5Hz，1H，C6H3)，6.36(d，J＝8.5Hz，2H，C6H3)，6.32(s，2H，C6H3)；13C NMR(100MHz，DMSO-d6)：164.91，162.72，162.31，160.79，159.49，149.28，131.33，129.50，110.52，107.73，107.44，105.89，102.88，102.66。
example 55
Preparation of 4-hydroxybenzaldehyde-3, 4-dihydroxybenzoylhydrazone (I55)
(1) Preparation of 3, 4-dihydroxybenzoylhydrazine
Prepared according to the method in the step (2) in the embodiment 1, 6.0mmol of methyl 3, 4-dihydroxybenzoate reacts with 18.0mmol of 80% hydrazine hydrate for 2h to obtain 3, 4-dihydroxybenzoyl hydrazine, white solid, m.p.261-262 ℃, and the yield is 82.3%;1H NMR(400MHz，DMSO-d6)：9.40(s，1H，NH)，9.01(s，2H，2×OH)，7.25(s，1H，C6H3)，7.15(d，J＝8.3Hz，1H，C6H3)，6.73(d，J＝8.3Hz，1H，C6H3)，4.36(s，2H，NH2)；13C NMR(100MHz，DMSO-d6)：166.13，148.22，144.83，124.52，118.62，114.90，114.90。
(2) preparation of 4-hydroxybenzaldehyde-3, 4-dihydroxybenzoylhydrazone (I55)
Prepared according to the method in the step (3) in the embodiment 1, 1.0mmol of 3, 4-dihydroxybenzoylhydrazine reacts with 1.05mmol of 4-hydroxybenzaldehyde for 5 hours to obtain 4-hydroxybenzaldehyde-3, 4-dihydroxybenzoylhydrazone (I55) which is light yellow solid, m.p. 263-264 ℃ and has the yield of 92.5 percent;1H NMR(400MHz，DMSO-d6)：11.37(s，1H，NH)，9.58(s，3H，3×OH)，8.31(s，1H，CH)，7.52(d，J＝7.9Hz，2H，C6H4)，7.35(s，1H，C6H3)，7.27(d，J＝8.2Hz，1H，C6H3)，6.83(d，J＝7.9Hz，2H，C6H4)，6.81(d，J＝8.2Hz，1H，C6H3)；13C NMR(100MHz，DMSO-d6)：159.19，148.83，147.07，145.00，128.64，125.56，124.58，119.41，115.67，115.34，114.95。
example 56
Preparation of 4-hydroxy-3-methoxybenzaldehyde-3, 4-dihydroxybenzoylhydrazone (I56)
Prepared according to the method of (3) in the example 1, 1.0mmol of 3, 4-dihydroxybenzoylhydrazine reacts with 1.05mmol of 4-hydroxy-3-methoxybenzaldehyde for 5h to obtain 4-hydroxy-3-methoxybenzaldehyde-3, 4-dihydroxybenzoylhydrazone (I56) which is yellow solid with m.p.259-260 ℃ and the yield of 89.4%;1HNMR(400MHz，DMSO-d6)：11.40(s，1H，NH)，9.58(s，1H，OH)，9.49(s，1H，OH)，9.21(s，1H，OH)，8.30(s，1H，CH)，7.35(s，1H，C6H3)，7.29(s，1H，C6H3)，7.27(d，J＝8.4Hz，1H，C6H3)，7.05(d，J＝8.1Hz，1H，C6H3)，6.83(d，J＝8.1Hz，1H，C6H3)，6.81(d，J＝8.4Hz，1H，C6H3)，3.82(s，3H，CH3)；13C NMR(100MHz，DMSO-d6)：162.72，148.83，148.75，148.02，147.28，145.00，126.00，124.58，121.91，119.42，115.42，115.35，114.95，108.87，55.54。
example 57
Preparation of 2, 4-dihydroxybenzaldehyde-3, 4-dihydroxybenzoylhydrazone (I57)
Prepared according to the method of (3) in example 1, 1.0mmol of 3, 4-dihydroxybenzoylhydrazine was reacted with 1.05mmol of 2, 4-dihydroxybenzaldehyde for 5 hours to give 24-dihydroxybenzaldehyde-3, 4-dihydroxybenzoylhydrazone (I57) as a yellow solid with m.p.257-258 ℃ and the yield of 97.6 percent;1H NMR(400MHz，DMSO-d6)：11.66(s，1H，NH)，11.41(s，1H，OH)，9.64(s，2H，2×OH)，9.40(s，1H，OH)，8.45(s，1H，CH)，7.35(s，1H，C6H3)，7.28(d，J＝8.2Hz，1H，C6H3)，7.25(d，J＝8.3Hz，1H，C6H3)，6.82(d，J＝8.3Hz，1H，C6H3)，6.35(d，J＝8.2Hz，1H，C6H3)，6.30(s，1H，C6H3)；13C NMR(100MHz，DMSO-d6)：162.30，160.46，159.46，149.10，148.45，145.08，131.40，123.86，119.50，115.29，115.04，110.61，107.56，102.68。
example 58
Anti-influenza virus neuraminidase activity of aromatic acylhydrazone derivatives
1. Principle of experiment
The compound MUNANA is a specific substrate of neuraminidase, metabolites generated under the action of neuraminidase can generate 450nm fluorescence under the irradiation and excitation of 360nm, and the change of fluorescence intensity can sensitively reflect neuraminidase activity. The enzymes were all from the A/PR/8/34(H1N1) virus strain.
2. Experimental methods
In an enzyme reaction system, a sample with a certain concentration and influenza virus RNA are suspended in a reaction buffer solution (pH 6.5), a fluorescent substrate MUNANA is added to start the reaction system, and after incubation for 40 minutes at 37 ℃, a reaction termination solution is added to terminate the reaction. The fluorescence intensity values were determined under the parameters of an excitation wavelength of 360nm and an emission wavelength of 450 nm. The fluorescence intensity of the reaction system may reflect the activity of the enzyme. The inhibition rate of the compound on the NA activity can be calculated according to the reduction of the fluorescence intensity.
3. Detecting a sample: EXAMPLES Compounds
4. Active results
Inhibition rate and IC of compound on neuraminidase when concentration of compound in reaction system is detected to be 40.0 mu g/mL50The values are shown in Table 1.
TABLE 1 inhibitory Activity of aromatic acylhydrazone derivatives on neuraminidase H1N1 and IC50
Continue to watch
The aromatic acylhydrazone derivatives have the activity of resisting influenza virus neuraminidase and can be used for preparing influenza virus neuraminidase inhibitors.
Claims (5)
1. A class of aromatic acylhydrazone derivatives represented by the chemical structural formula I:
wherein R is selected from: 3-trifluoromethyl, 4-trifluoromethyl, 5-trifluoromethyl, 6-trifluoromethyl, 3-nitro, 4-nitro, 5-nitro, 6-nitro, 3-methyl-4-nitro, 3-hydroxy-4-nitro, 3-nitro-4-hydroxy, 2-hydroxy, 3-hydroxy, 4-hydroxy, 2, 3-dihydroxy, 3, 5-dihydroxy, 2, 4-dihydroxy, 3, 5-dinitro, 3-methoxy-4-hydroxy or 3,4, 5-trihydroxy; y is selected from: 2-hydroxy group, 3-hydroxy group, 4-hydroxy group, 2, 4-dihydroxy group, 3, 4-dihydroxy group, 2, 5-dihydroxy group, 3, 5-dihydroxy group, 2, 6-dihydroxy group, 2-hydroxy-3-methoxy group, 2-hydroxy-4-methoxy group, 2-hydroxy-5-methoxy group, 2-hydroxy-6-methoxy group, 3-hydroxy-2-methoxy group, 3-hydroxy-4-methoxy group, 3-hydroxy-5-methoxy group, 3-hydroxy-6-methoxy group, 4-hydroxy-2-methoxy group, 4-hydroxy-3, 5-dimethoxy group, 2,3, 4-trihydroxy, 4-hydroxy-3-ethoxy or 4-hydroxy-3, 5-dimethyl; w is selected from: CH or N; z is selected from: CH or N.
2. A kind of aromatic acylhydrazone derivatives and their pharmaceutically acceptable salts are selected from the following compounds:
3-hydroxybenzaldehyde-3-nitrobenzoylhydrazone,
4-hydroxybenzaldehyde-3-nitrobenzoylhydrazone,
3-hydroxy-4-methoxybenzaldehyde-3-nitrobenzoylhydrazone,
4-hydroxy-3-methoxybenzaldehyde-3-nitrobenzoylhydrazone,
4-hydroxy-3-ethoxybenzaldehyde-3-nitrobenzoylhydrazone,
2, 4-dihydroxybenzaldehyde-3-nitrobenzoylhydrazone,
3, 4-dihydroxybenzaldehyde-3-nitrobenzoylhydrazone,
3-hydroxybenzaldehyde-4-nitrobenzoylhydrazone,
4-hydroxybenzaldehyde-4-nitrobenzoylhydrazone,
3-hydroxy-4-methoxybenzaldehyde-4-nitrobenzoylhydrazone,
3-methoxy-4-hydroxybenzaldehyde-4-nitrobenzoylhydrazone,
3, 5-dimethyl-4-hydroxybenzaldehyde-4-nitrobenzoylhydrazone,
2, 4-dihydroxybenzaldehyde-4-nitrobenzoylhydrazone,
4-pyridinecarboxaldehyde-4-nitrobenzoylhydrazone,
4-hydroxybenzaldehyde-3-methyl-4-nitrobenzoylhydrazone,
3-methoxy-4-hydroxybenzaldehyde-3-methyl-4-nitrobenzoylhydrazone,
3, 4-dihydroxybenzaldehyde-3-methyl-4-nitrobenzoylhydrazone,
2, 4-dihydroxybenzaldehyde-3-methyl-4-nitrobenzoylhydrazone,
4-hydroxybenzaldehyde-3-hydroxy-4-nitrobenzoylhydrazone,
4-hydroxy-3-methoxybenzaldehyde-3-hydroxy-4-nitrobenzoylhydrazone,
3, 4-dihydroxybenzaldehyde-3-hydroxy-4-nitrobenzoylhydrazone,
2, 4-dihydroxybenzaldehyde-3-hydroxy-4-nitrobenzoylhydrazone,
3-hydroxybenzaldehyde-3-hydroxybenzoylhydrazone,
4-hydroxybenzaldehyde-3-hydroxybenzoylhydrazone,
3-hydroxy-4-methoxybenzaldehyde-3-hydroxybenzoylhydrazone,
4-hydroxy-3-methoxybenzaldehyde-3-hydroxybenzoylhydrazone,
2, 4-dihydroxybenzaldehyde-3-hydroxybenzoylhydrazone,
3-hydroxybenzaldehyde-4-hydroxybenzoylhydrazone,
4-hydroxybenzaldehyde-4-hydroxybenzoylhydrazone,
3-hydroxy-4-methoxybenzaldehyde-4-hydroxybenzoylhydrazone,
4-hydroxy-3-methoxybenzaldehyde-4-hydroxybenzoylhydrazone,
3, 4-dihydroxybenzaldehyde-4-hydroxybenzoylhydrazone,
2, 4-dihydroxybenzaldehyde-4-hydroxybenzoylhydrazone,
4-pyridylaldehyde-4-hydroxybenzoylhydrazone,
4-hydroxybenzaldehyde-3, 5-dihydroxybenzoylhydrazone,
4-hydroxy-3-methoxybenzaldehyde-3, 5-dihydroxybenzoylhydrazone,
2, 4-dihydroxybenzaldehyde-3, 5-dihydroxybenzoylhydrazone,
4-pyridylaldehyde-3, 5-dihydroxybenzoylhydrazone,
3, 4-dihydroxybenzaldehyde-3, 5-dihydroxybenzoylhydrazone,
4-hydroxybenzaldehyde-4-trifluoromethylphenylcarbonylhydrazone,
3-methoxy-4-hydroxybenzaldehyde-4-trifluoromethylphenylcarbonylhydrazone,
2, 4-dihydroxybenzaldehyde-4-trifluoromethylphenylcarbonylhydrazone,
4-hydroxybenzaldehyde-3, 5-dinitrobenzoyl hydrazone,
4-hydroxy-3-methoxybenzaldehyde-3, 5-dinitrobenzoylhydrazone,
2, 4-dihydroxybenzaldehyde-3, 5-dinitrobenzoyl hydrazone,
4-hydroxybenzaldehyde-3-methoxy-4-hydroxybenzoylhydrazone,
3-methoxy-4-hydroxybenzaldehyde-3-methoxy-4-hydroxybenzoylhydrazone,
2, 4-dihydroxybenzaldehyde-3-methoxy-4-hydroxybenzoylhydrazone,
4-hydroxybenzaldehyde-3, 4, 5-trihydroxyphenylcarbonylhydrazone,
4-hydroxy-3-methoxybenzaldehyde-3, 4, 5-trihydroxybenzoylhydrazone,
2, 4-dihydroxybenzaldehyde-3, 4, 5-trihydroxyphenylcarbonylhydrazone,
4-hydroxybenzaldehyde-2, 4-dihydroxybenzoylhydrazone,
4-hydroxy-3-methoxybenzaldehyde-2, 4-dihydroxybenzoylhydrazone,
2, 4-dihydroxybenzaldehyde-2, 4-dihydroxybenzoylhydrazone,
4-hydroxybenzaldehyde-3, 4-dihydroxybenzoylhydrazone,
4-hydroxy-3-methoxybenzaldehyde-3, 4-dihydroxybenzoylhydrazone or
2, 4-dihydroxybenzaldehyde-3, 4-dihydroxybenzoylhydrazone.
3. The process for producing an aromatic acylhydrazone derivative according to claim 1, characterized in that it is produced by the following reaction:
wherein R, W, Z and Y are as defined in claim 1.
4. The use of the aromatic acylhydrazone derivatives and the pharmaceutically acceptable salts thereof according to claim 1 or 2 for the preparation of influenza virus neuraminidase inhibitors.
5. A pharmaceutical composition comprising at least one compound of claim 1 or 2 and a pharmaceutically acceptable carrier.
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|---|---|---|---|---|
| CN109651189A (en) * | 2019-01-31 | 2019-04-19 | 上海应用技术大学 | A kind of benzoyl hydrazone class neuraminidase inhibitor and its preparation method and application |
| CN109776354A (en) * | 2019-01-04 | 2019-05-21 | 上海应用技术大学 | A kind of dihydroxybenzoyl hydrazone class neuraminidase inhibitor and its preparation and application |
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| CN109776354A (en) * | 2019-01-04 | 2019-05-21 | 上海应用技术大学 | A kind of dihydroxybenzoyl hydrazone class neuraminidase inhibitor and its preparation and application |
| CN109651189A (en) * | 2019-01-31 | 2019-04-19 | 上海应用技术大学 | A kind of benzoyl hydrazone class neuraminidase inhibitor and its preparation method and application |
Non-Patent Citations (3)
| Title |
|---|
| ERIC CHEN 等: "Computation-Guided Discovery of Influenza Endonuclease Inhibitors", 《MEDICINAL CHEMISTRY LETTERS》 * |
| MAURO CARCELLI 等: "N-acylhydrazone inhibitors of influenza virus PA endonuclease with versatile metal binding modes", 《SCIENTIFIC REPORTS》 * |
| STN REGISTRY DATABASE: "CAS RN2218395-99-2化合物", 《STN REGISTRY DATABASE》 * |
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