CN112409231A - Acylthiourea neuraminidase inhibitor and preparation and application thereof - Google Patents
Acylthiourea neuraminidase inhibitor and preparation and application thereof Download PDFInfo
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- CN112409231A CN112409231A CN202011279783.3A CN202011279783A CN112409231A CN 112409231 A CN112409231 A CN 112409231A CN 202011279783 A CN202011279783 A CN 202011279783A CN 112409231 A CN112409231 A CN 112409231A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/24—Derivatives of thiourea containing any of the groups, X being a hetero atom, Y being any atom
- C07C335/26—Y being a hydrogen or a carbon atom, e.g. benzoylthioureas
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
Abstract
The invention relates to an acyl thiourea neuraminidase inhibitor and preparation and application thereof, wherein the inhibitor has a structure shown in a formula (I):
wherein Ar is
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an acylthiourea neuraminidase inhibitor, and preparation and application thereof.
Background
Neuraminidase is a glycoprotein distributed on an influenza virus envelope, and can assist mature influenza viruses to separate from original host cells to infect new cells, so that neuraminidase is one of important targets for development of anti-influenza virus medicines.
Anti-influenza drugs developed with neuraminidase as a target can be classified into the following classes according to structure: cyclohexenes, pyrans, pyrrolidines, benzoic acid derivatives, natural products, and the like. The most widely used anti-influenza drug is tamiflu at present, but with the wide use of the drug, the drug resistance of influenza virus to tamiflu also appears, and the production raw materials of tamiflu are extremely expensive and the synthesis process is complex. Therefore, it is urgent to develop a novel neuraminidase inhibitor having a better inhibitory effect.
Disclosure of Invention
The invention aims to solve the problems and provide an acylthiourea neuraminidase inhibitor and preparation and application thereof.
The purpose of the invention is realized by the following technical scheme:
an acylthiourea neuraminidase inhibitor having the structure of formula (I):
wherein Ar is
Ar is selected from
Any one of them.
Ar is
A preparation method of the acyl thiourea neuraminidase inhibitor is disclosed, and the formula of the preparation method is as follows:
the preparation method specifically comprises the following steps:
(1) forming a reaction system by substituted benzaldehyde and malonic acid, and carrying out post-treatment after reaction to obtain an intermediate of a formula (II);
(2) dissolving the intermediate of the formula (II) obtained in the step (1) and thionyl chloride in an organic solvent to form a reaction system, and removing thionyl chloride after reaction to obtain an intermediate of the formula (III);
(3) dissolving the intermediate of the formula (III) obtained in the step (2) and ammonium thiocyanate in an organic solvent to form a reaction system, and carrying out post-treatment after the reaction to obtain an intermediate of the formula (IV);
(4) dissolving the intermediate of the formula (IV) obtained in the step (3) and 3-amino-4-methoxy methyl benzoate in an organic solvent to form a reaction system, and performing post-treatment after reaction to obtain an intermediate of the formula (V);
(5) and (5) hydrolyzing the intermediate of the formula (V) obtained in the step (4), and carrying out post-treatment to obtain the inhibitor shown in the formula (I).
In the step (1), piperidine is used as a catalyst, and the organic solvent is ethanol.
In the step (1), the reaction system is placed in an oil bath for heating, the reaction temperature is 75-95 ℃, the reaction time is 85 ℃, and the reaction time is 1.5-2.5h, preferably 2 h.
In the step (1), the post-treatment process specifically comprises the following steps: and (3) taking out the reaction system (namely the reaction liquid in the embodiment) to cool, adjusting the pH of the reaction system to 3 by using hydrochloric acid, separating out a precipitate, and sequentially filtering, washing, drying and recrystallizing by using absolute ethyl alcohol to obtain the intermediate of the formula (II).
In the step (1), the adding amount ratio of the substituted benzaldehyde, malonic acid, piperidine and the organic solvent is (8-12) mmol, (8-12) mmol:1 drop of (15-25) mL, preferably 10mmol:10mmol:1 drop of 20 mL. One drop refers to one drop of a common pipette.
In the step (2), the reaction system is placed in an oil bath for heating, the reaction temperature is 70-90 ℃, the reaction time is preferably 80 ℃, and the reaction time is 3.5-5.5h, and the reaction time is preferably 4 h.
In the step (2), the addition amount ratio of the intermediate of the formula (II) to thionyl chloride is (8-12) mmol, (5-15) mL, preferably 10mmol:10 mL.
In the step (3), the organic solvent is acetonitrile.
In the step (3), the reaction system is placed in an oil bath for heating, the reaction temperature is 55-80 ℃, the reaction time is preferably 80 ℃, and the reaction time is 2.0-4.5h, preferably 2 h.
In the step (3), the post-treatment process specifically comprises the following steps: and (3) taking out the reaction system, cooling, standing to separate out a precipitate, and sequentially filtering, washing, drying and recrystallizing with absolute ethyl alcohol to obtain the intermediate of the formula (IV).
In the step (3), the adding amount ratio of the intermediate of the formula (III), the ammonium thiocyanate and the organic solvent is 10mmol (9.5-11.5) mL, preferably 10mmol:10.05mmol:30 mL.
In the step (4), the organic solvent is absolute ethyl alcohol.
In the step (4), the reaction temperature is 75-90 ℃, preferably 80 ℃, and the reaction time is 1.5-4.5h, preferably 2 h.
In the step (4), the post-treatment process specifically comprises the following steps: and (3) cooling the reaction system after the reaction is finished, standing to separate out a precipitate, and then sequentially filtering, washing and drying the precipitate to obtain the intermediate of the formula (V).
In the step (4), the adding amount ratio of the intermediate of the formula (IV), the methyl 3-amino-4-methoxybenzoate and the organic solvent is 1mmol (1.0-1.1) mL, preferably 1mmol:1.1mmol:10 mL.
In the step (5), the hydrolysis is carried out under the alkaline condition, and the hydrolysis is carried out in an oil bath for heating, wherein the hydrolysis temperature is 65-80 ℃, preferably 75 ℃, and the hydrolysis time is 1.5-2.5h, preferably 2 h.
In the step (5), the post-treatment process specifically comprises the following steps: and (3) cooling the hydrolyzed intermediate shown in the formula (V), adjusting the pH value to 3 by using acid (hydrochloric acid), separating out a precipitate, and sequentially filtering, washing, drying and recrystallizing by using ethanol to obtain the inhibitor shown in the formula (I).
In the step (5), a methanol solution containing NaOH is adopted to form an alkaline condition, the mass fraction of the NaOH in the methanol solution is 40%, and methanol is used as a solvent.
The adding amount ratio of the intermediate shown in the formula (V) to the methanol solution containing NaOH is 10mmol:25 mL.
The application of the acylthiourea-containing neuraminidase inhibitor in preparing the medicine capable of inhibiting the neuraminidase activity.
The invention utilizes a receptor-based molecular docking virtual screening method to screen 6000000 compounds from a ZINC database and a SPECS database to obtain a compound theoretically having neuraminidase inhibitory activity, then modifies the structure of the compound, designs a more reasonable compound, performs neuraminidase test on one of the compounds, and takes Oseltamivir carboxlate (OSC) as a positive control, wherein IC of the OSC is IC50Value of 2.68. mu.M, IC of the synthesized Compound50The IC of the compound with the best inhibition effect is less than 2.68 mu M50The value is 0.69. mu.M, i.e., this compound has a very excellent neuraminidase inhibitory activity.
Compared with the prior art, the invention provides the neuraminidase inhibitor with the novel skeleton structure and the preparation method and application thereof, the synthesis method is simple, the prepared inhibitor has good neuraminidase inhibition activity and excellent neuraminidase inhibition effect, and can be applied to preparation of drugs for inhibiting the neuraminidase activity.
Detailed Description
The present invention is described in detail below with reference to specific examples, but the present invention is not limited thereto in any way.
An acylthiourea neuraminidase inhibitor having the structure of formula (I):
wherein Ar is
Specifically, Ar is selected from
Any one of them.
The preparation method of the acyl thiourea neuraminidase inhibitor is as follows:
the preparation method specifically comprises the following steps:
(1) forming a reaction system by substituted benzaldehyde and malonic acid, and carrying out post-treatment after reaction to obtain an intermediate of a formula (II);
(2) dissolving the intermediate of the formula (II) obtained in the step (1) and thionyl chloride in an organic solvent to form a reaction system, and reacting to obtain an intermediate of the formula (III);
(3) dissolving the intermediate of the formula (III) obtained in the step (2) and ammonium thiocyanate in an organic solvent to form a reaction system, and carrying out post-treatment after the reaction to obtain an intermediate of the formula (IV);
(4) dissolving the intermediate of the formula (IV) obtained in the step (3) and 3-amino-4-methoxy methyl benzoate in an organic solvent to form a reaction system, and performing post-treatment after reaction to obtain an intermediate of the formula (V);
(5) and (5) hydrolyzing the intermediate of the formula (V) obtained in the step (4), and carrying out post-treatment to obtain the inhibitor shown in the formula (I).
In the step (1), piperidine is used as a catalyst, ethanol is used as an organic solvent, the reaction system is placed in an oil bath for heating, the reaction temperature is 75-95 ℃, the reaction time is 1.5-2.5h, and the post-treatment process specifically comprises the following steps: and (3) taking out the reaction system, cooling, adjusting the pH of the reaction system to 3 by adopting acid, precipitating a precipitate, sequentially filtering, washing, drying and recrystallizing the precipitate by using absolute ethyl alcohol to obtain an intermediate shown in the formula (II), wherein the addition ratio of the substituted benzaldehyde, malonic acid, piperidine and the organic solvent is (8-12) mmol, (8-12) mmol:1 drop, (15-25) mL.
In the step (2), the reaction system is placed in an oil bath for heating, the reaction temperature is 70-90 ℃, the reaction time is 3.5-5.5h, and the adding amount ratio of the intermediate of the formula (II) to the thionyl chloride is (8-12) mmol (5-15) mL.
In the step (3), the organic solvent is acetonitrile, the reaction system is placed in an oil bath for heating, the reaction temperature is 55-80 ℃, the reaction time is 2.0-4.5h, and the post-treatment process specifically comprises the following steps: and (3) taking out the reaction system, cooling, standing to separate out a precipitate, sequentially filtering, washing, drying and recrystallizing the precipitate with absolute ethyl alcohol to obtain an intermediate shown in the formula (IV), wherein the addition ratio of the intermediate shown in the formula (III), ammonium thiocyanate and an organic solvent is 10mmol (9.5-11.5) mmol (25-35 mL).
In the step (4), the organic solvent adopts absolute ethyl alcohol, the reaction temperature is 75-90 ℃, the reaction time is 1.5-4.5h, and the post-treatment process specifically comprises the following steps: and (3) cooling the reaction system after the reaction is finished, standing to separate out a precipitate, and then sequentially filtering, washing and drying the precipitate to obtain the intermediate shown in the formula (V), wherein the adding amount ratio of the intermediate shown in the formula (IV), the methyl 3-amino-4-methoxybenzoate and the organic solvent is 1mmol (1.0-1.1): (25-35) mL and 1:1 (25-35) mL.
In the step (5), the hydrolysis is carried out under the alkaline condition, the hydrolysis temperature is 65-80 ℃, the hydrolysis time is 1.5-2.5h, and the post-treatment process specifically comprises the following steps: and (3) cooling the hydrolyzed intermediate shown as the formula (V), adjusting the pH value to 3 by adopting acid, separating out a precipitate, and sequentially filtering, washing, drying and recrystallizing by using ethanol to obtain the inhibitor shown as the formula (I). The adding amount ratio of the intermediate shown in the formula (V) to the methanol solution containing NaOH is 10mmol:25mL, and the mass fraction of NaOH in the methanol solution containing NaOH is 40%. The steps of filtering, washing, drying and absolute ethyl alcohol recrystallization, which are involved in each step, are all conventional operations, and the operation parameters are selected according to parameters commonly adopted in laboratories to reach the required target values.
The application of the acylthiourea-containing neuraminidase inhibitor in preparing the medicine capable of inhibiting the neuraminidase activity.
Examples
A preparation method of acyl thiourea neuraminidase inhibitor is disclosed, the structural formula is shown as formula A:
The specific synthesis steps are as follows:
(1) 1.67g (10mmol) of 3-hydroxy-4-nitrobenzaldehyde and 1.04g (10mmol) of malonic acid were accurately weighed into a 50mL round-bottomed flask, 20mL of absolute ethanol was added, and a catalytic amount (1 drop) of piperidine was added dropwise. After the dropwise addition, taking out the round-bottom flask, putting the round-bottom flask in a constant-temperature oil bath kettle, heating and stirring at 85 ℃ for reacting for 2 hours, taking out the round-bottom flask, cooling the reaction solution, adjusting the pH value to 3 by using hydrochloric acid, standing to separate out a large amount of precipitate, filtering the precipitate to obtain a filter cake, washing the filter cake with a large amount of ice water for many times,then drying in a vacuum drying oven, and recrystallizing by ethanol to obtain an intermediate (II) (wherein Ar is
)。
(2) 2.09g (10mmol) of the intermediate of formula (II) was accurately weighed into a 50mL round-bottomed flask, 10mL of thionyl chloride was added, and the mixture was put in an oil bath and reacted at 80 ℃ for 4 hours. After the reaction is finished, removing thionyl chloride in vacuum to obtain an intermediate (wherein Ar is
)。
(3) Taking 2.27g (10mmol) of the intermediate of the formula (III) into a 50mL round-bottom flask, adding 0.76g (10.05mmol) and 30mL acetonitrile, placing the mixture into a constant-temperature oil bath, reacting for 2 hours at 80 ℃, taking out the reaction solution, cooling, standing to separate out a precipitate, filtering the precipitate to obtain a filter cake, washing the filter cake for multiple times by using water, drying, and recrystallizing by using ethanol to obtain the intermediate of the formula (IV) (wherein Ar is Ar)
)。
(4) Taking 2.5g (10mmol) of intermediate of formula (IV) and 1.81g (10mmol) of methyl 3-amino-4-methoxybenzoate in a 25mL round-bottom flask, adding 10mL of absolute ethanol, heating and refluxing at 80 ℃ in an oil bath for 2 hours, taking out reaction liquid, cooling, precipitating, filtering the precipitate to obtain a filter cake, washing the filter cake for multiple times by using distilled water, drying, recrystallizing by using ethanol to obtain the intermediate of formula (V) (wherein Ar is Ar)
)。
(5) Taking 4.3g (10mmol) of intermediate shown in the formula (V) and 25mL of methanol solution of NaOH with the mass fraction of 40% in a 50mL round-bottom flask, heating and refluxing for 2 hours at 75 ℃ in an oil bath kettle, taking out hydrolysate, cooling, adjusting the pH to 3 by using hydrochloric acid, standing to separate out precipitate, filtering the precipitate to obtain a filter cake, washing the filter cake by using distilled water, drying, recrystallizing by using ethanol to obtain the inhibitor shown in the formula (I), wherein the specific structural formula is shown in the formulaA shows that the (Z) -3- (3- (3- (4-hydroxy-3-nitro) acryloyl) thiourea) -4-methoxybenzoic acid is yellow solid with the yield of 89%.1H NMR(500MHz,Chloroform-d)δ8.45(dd,J＝2.0,1.0Hz,1H),8.42(s,1H),7.92(dd,J＝7.5,2.0Hz,1H),7.81–7.75(m,2H),7.52(dt,J＝15.3,1.2Hz,1H),7.06(dd,J＝24.5,7.5Hz,2H),6.71(d,J＝15.2Hz,1H),3.86(s,3H).13C NMR(125MHz,Chloroform-d)δ179.61,167.42,167.00,153.20,146.60,140.90,136.43,132.11,130.03,129.22,128.56,126.48,125.91,124.51,119.21,117.66,110.94,56.31.
The prepared inhibitor is tested for inhibiting the activity of neuraminidase:
1. laboratory instruments and materials
A multifunctional fluorescent microplate reader, model SP-Max 3500FL, Shanghai flash spectrum Biotech limited;
an ultra-clean bench;
bond A3Pipette manual single-channel adjustable pipettor, 0.5-10ul, 10-100ul, Tantan technology;
96-well plate (black), sterilized, kangning;
neuraminidase inhibitor screening kit, P0309, picnic biotechnology, comprising: 10mL of neuraminidase detection buffer; 1mL of neuraminidase; 1mL of neuraminidase fluorogenic substrate; Milli-Q water, 1.2 mL;
a positive control drug, Oseltamivir acid (abbreviated as OSC), shanghai haokang biotechnology limited.
2. Experimental methods
Dissolving a positive control drug and a target compound (namely prepared (Z) -3- (3- (3- (4-hydroxy-3-nitro) acryloyl) thiourea) -4-methoxybenzoic acid) in DMSO, preparing the initial concentration into 200um/l, diluting the initial concentration into 5 concentration gradients according to a multiple ratio, sequentially preparing three groups, namely 40 mu m/l, 8 mu m/l, 1.6 mu m/l, 0.32 mu m/l and 0.064 mu m/l;
2.1 sample preparation for detection
a. Adding 70 mu L of neuraminidase detection buffer solution into a 96-hole enzyme label plate in each hole;
b. adding 10 mu L of neuraminidase into each hole;
c. 10. mu.L of neuraminidase substrate per well;
d. each hole is added with 10 microliter of a prepared neuraminidase inhibitor sample to be detected or a positive control drug sample, three groups of blank test controls are arranged at the same time, and the positive control drug is used as a non-blank control group.
2.2 detection
a. Placing the 96-well plate in a multifunctional fluorescent microplate reader, and shaking and uniformly mixing for 1 minute;
b. setting the temperature to be 37 ℃, and incubating for 2 minutes to ensure that the neuraminidase and the sample to be detected are fully mixed and interacted;
c. taking out the 96-well plate, and adding 10 microliters of neuraminidase fluorescent substrate into each well;
d. placing the mixture in a multifunctional fluorescent microplate reader again, and shaking and uniformly mixing for 1 minute;
e. incubating at 37 ℃ for 45 minutes, setting the excitation wavelength to be 322nm and the emission wavelength to be 440nm, and starting fluorescence intensity (RFU) measurement after the incubation is finished;
f. repeating the above steps, and detecting in parallel for 3 times.
Note: the first three wells of the 96-well plate were used as blanks, and 10. mu.l of DMSO solution was added without adding the sample to be tested.
The inhibition rate of each sample was calculated and the corresponding IC was fitted by Origin50The value is obtained.
2.3 results of the experiment
IC of (Z) -3- (3- (3- (4-hydroxy-3-nitro) acryloyl) thiourea) -4-methoxybenzoic acid50Value of 0.69. mu.M, IC of positive control50The value was 2.68. mu.M, and the specific results are shown in Table 1.
The positive control drug and the target compound are prepared into mixed solution with the initial concentration of 200 mu m/L by DMSO solution, and the two mixed solutions are diluted into 5 concentration gradients according to the multiple ratio, wherein the concentration gradients are 40 mu m/L, 8 mu m/L, 1.6 mu m/L, 0.32 mu m/L and 0.064 mu m/L in sequence, and 3 groups are prepared (so as to reduce experimental error). 70 mu L of neuraminidase buffer solution, 10 mu L of neuraminidase, Milli-Q water and a sample of neuraminidase inhibitor to be detected are added into a 96-hole black fluorescent enzyme label plate, and simultaneouslyThree sets of blank controls were set. Shaking uniformly at room temperature, incubating at 37 ℃ for 2min, adding 10 mu L of neuraminidase substrate into each well, shaking uniformly, incubating at 37 ℃ for 45min, and performing fluorescence measurement. Setting excitation wavelength of 322nm and emission wavelength of 450nm for a fluorescence microplate reader, starting to test fluorescence intensity (RFU) after incubation is finished, calculating inhibition rate of each sample, and fitting by Origin to obtain corresponding IC50The values and specific results are shown in table 1.
TABLE 1 summary of neuraminidase Activity test results for the Experimental group and the control group
Wherein, the calculation formula of the inhibition rate is as follows: inhibition rate of 1/((A)0-A1)/(A2-A1))*100％，A0: fluorescence absorbance readings for positive controls at different concentrations; a. the1: fluorescence absorbance readings for the blank; a. the2: for the fluorescence absorbance readings of inhibitors at different concentrations, reference is made to the patent publication CN109776354A for a specific formula.
IC50Values were obtained by simulation of inhibition values in OrginPro8 software, IC of inhibitors50IC with value of 0.69 μ M, OSC50The value was 2.68. mu.M. As can be seen from Table 1, at the same concentration, the inhibition rate of the target compound is substantially greater than that of the positive control drug, and the IC of the target compound is obtained50IC less than Positive control drug (OSC)50The inhibitor prepared by the invention has very excellent inhibitory effect on neuraminidase.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Claims (10)
1. An acylthiourea neuraminidase inhibitor having the structure of formula (I):
wherein Ar is
2. The acylthiourea neuraminidase inhibitor according to claim 1,
ar is selected from
Any one of them.
3. The acylthiourea neuraminidase inhibitor according to claim 2,
ar is
4. A process for the preparation of an acylthiourea neuraminidase inhibitor according to any one of claims 1 to 3, which comprises the following equation:
the preparation method specifically comprises the following steps:
(1) forming a reaction system by substituted benzaldehyde and malonic acid, and carrying out post-treatment after reaction to obtain an intermediate of a formula (II);
(2) dissolving the intermediate of the formula (II) obtained in the step (1) and thionyl chloride in an organic solvent to form a reaction system, and reacting to obtain an intermediate of the formula (III);
(3) dissolving the intermediate of the formula (III) obtained in the step (2) and ammonium thiocyanate in an organic solvent to form a reaction system, and carrying out post-treatment after the reaction to obtain an intermediate of the formula (IV);
(4) dissolving the intermediate of the formula (IV) obtained in the step (3) and 3-amino-4-methoxy methyl benzoate in an organic solvent to form a reaction system, and performing post-treatment after reaction to obtain an intermediate of the formula (V);
(5) and (5) hydrolyzing the intermediate of the formula (V) obtained in the step (4), and carrying out post-treatment to obtain the inhibitor shown in the formula (I).
5. The method for preparing acyl thiourea neuraminidase inhibitor according to claim 4, wherein in the step (1), the reaction temperature is 75-95 ℃, the reaction time is 1.5-2.5h, and the post-treatment process comprises: and (3) taking out the reaction system, cooling, adjusting the pH value of the reaction system to 3 by adopting acid, separating out a precipitate, and sequentially filtering, washing, drying and recrystallizing with absolute ethyl alcohol to obtain the intermediate of the formula (II).
6. The method for preparing acylthiourea neuraminidase inhibitor according to claim 4, wherein in the step (2), the reaction temperature is 70-90 ℃ and the reaction time is 3.5-5.5 h.
7. The method for preparing an acylthiourea neuraminidase inhibitor according to claim 4, wherein in the step (3), the reaction temperature is 55-80 ℃, the reaction time is 2.0-4.5h, and the post-treatment process comprises: and (3) taking out the reaction system, cooling, standing to separate out a precipitate, and sequentially filtering, washing, drying and recrystallizing with absolute ethyl alcohol to obtain the intermediate of the formula (IV).
8. The method for preparing an acylthiourea neuraminidase inhibitor according to claim 4, wherein in the step (4), the reaction temperature is 75-90 ℃, the reaction time is 1.5-4.5h, and the post-treatment process comprises the following specific steps: and (3) cooling the reaction system after the reaction is finished, standing to separate out a precipitate, and then sequentially filtering, washing and drying the precipitate to obtain the intermediate of the formula (V).
9. The method for preparing acyl thiourea neuraminidase inhibitor according to claim 4, wherein in the step (5), the hydrolysis is carried out under alkaline condition, the hydrolysis temperature is 65-80 ℃, the hydrolysis time is 1.5-2.5h, and the post-treatment process comprises: and (3) cooling the hydrolyzed intermediate shown as the formula (V), adjusting the pH value to 3 by adopting acid, separating out a precipitate, and sequentially filtering, washing, drying and recrystallizing by using ethanol to obtain the inhibitor shown as the formula (I).
10. Use of an acylthiourea-containing neuraminidase inhibitor as defined in any of claims 1 to 3 for the preparation of a medicament capable of inhibiting neuraminidase activity.
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