Naringenin derivative containing 1, 3, 4-oxadiazole acylhydrazone structure and preparation method thereof

Abstract

The invention discloses a naringenin compound containing 1, 3, 4-oxadiazole acylhydrazone as shown in a formula A as well as a preparation method and application of the naringenin compound: # imgabs0 #, wherein R is alkyl, cycloalkyl, phenyl, substituted phenyl, heteroaromatic ring group or substituted heteroaromatic ring group.

Description

Technical field:

[0001] The invention relates to the field of organic synthesis, and in particular to a class of naringenin derivatives containing a 1,3,4-oxadiazole acylhydrazone structure and a preparation method thereof. Background technology:

[0002] Naringenin is a natural dihydroflavonoid compound, which is mainly present in the form of glycosides in grapefruit, tomatoes, grapes and citrus fruits of the Rutaceae family. It has antibacterial, anti-inflammatory, antioxidant, antiviral, lipid-lowering, anti-tumor and other biological activities. Due to its plant origin, wide range of pharmacological and physiological activities, mild effects, and relatively low toxicity to normal human cells, naringenin has been highly valued by scientists and researchers.

[0003] In 2019, Latif et al [Latif, AD; Gonda, T.; M.;Kúsz, N.;Kulmány, A.;Ocsovszki, I.;Zomborszki, Z.P;Zupkó, I.;Hunyadi, A.Synthesis and In Vitro Antitumor Activity of Naringenin Oxime and Oxime Ether Derivatives[J]. Int. J. Mol. Sci., 2019, 20, 2184.] reported that 8 oxime or oxime ether derivatives of naringenin were obtained by addition condensation between the 4-carbonyl group of naringenin and the amino group. The results of biological tests showed that tert-butyl oxime ether derivatives had a strong inhibitory effect on the growth of leukemia (HL-60) and cervical cancer (HeLa, Siha) and breast cancer (MCF-7, MDA-MB-231) cells.

[0004] In 2020, Duda-Madej et al. [Duda-Madej, A.; Kozlowska, J.; Krzyzek, P.; Aniol, M.; Seniuk, A.; Jermakow, K.; Dworniczek, E. Antimicrobial O-Alkyl Derivatives of Naringenin and Their Oximes Against Multidrug-Resistant Bacteria [J]. Molecules., 2020, 25, 3642.] reported 18 new O-alkyl derivatives of naringenin and its oxime. The results of antibacterial activity evaluation showed that naringenin oxime derivatives had higher antibacterial activity against Enterococcus faecalis, Staphylococcus aureus, Acinetobacter baumannii, Klebsiella pneumoniae and Helicobacter pylori than naringenin derivatives.

[0005] In 2022, Morimoto et al. [Morimoto, R.; Matsubara, C.; Hanada, A.; Omoe, Y.; Ogata, T.; Isegawa, Y. Effect of Structural Differences in Naringenin, Prenylated Naringenin, and Their Derivatives on the Anti-Influenza Virus Activity and Cellular Uptake of Their Flavanones [J]. Pharmaceuticals., 2022, 15, 1480.] reported the antiviral activity of naringenin, enoyl naringenin and its derivatives against influenza. The results showed that the spatial effect of the compound is an important factor affecting its antiviral activity. In the structure of naringenin, the substituent pentenyl can enhance its antiviral activity, and its structure and position have a significant effect on its cellular permeability.

[0006] Based on naringenin, the 1,3,4-oxadiazole structure and acylhydrazone structure with broad biological activity were introduced into the 4-position of naringenin to obtain a series of novel naringenin derivatives containing 1,3,4-oxadiazole acylhydrazone, which have not been reported so far. Summary of the invention:

[0007] The purpose of the present invention is to provide a naringenin derivative containing a 1,3,4-oxadiazole acylhydrazone structure and a preparation method and application thereof.

[0008] The present invention is achieved through the following technical solutions:

[0009] The naringenin compound containing 1,3,4-oxadiazole acylhydrazone shown in formula A:

[0010]

[0011] Wherein: R is an alkyl group, a cycloalkyl group, a phenyl group, a substituted phenyl group, an aromatic heterocyclic group or a substituted aromatic heterocyclic group.

[0012] Preferably, the substituted phenyl group is an alkyl group containing C1-C6, an alkoxy group containing C1-C6, a nitro group, a halogen atom or a hydrogen atom at the ortho, meta or para position on the benzene ring; the aromatic heterocyclic group is a thienyl group, a furyl group, a pyrrolyl group or a pyridyl group; and the substituent on the substituted aromatic heterocyclic group is an alkyl group containing C1-C6, an alkoxy group containing C1-C6, a nitro group, a halogen atom or a hydrogen atom at the ortho, meta or para position on the benzene ring.

[0013] The present invention also protects a method for preparing the above-mentioned naringenin compounds containing 1,3,4-oxadiazole acylhydrazone, comprising the following steps:

[0014] (1) Using naringenin and dimethyl sulfate as raw materials, anhydrous potassium carbonate as catalyst, and acetone as solvent, a reflux reaction was performed to prepare intermediate 1: 4′,5,7-trimethoxynaringenin;

[0015]

[0016] (2) using carboxylic acid as raw material and H2SO4 as catalyst for reflux reaction to prepare intermediate 2: methyl carboxylate;

[0017]

[0018] (3) Using the intermediate 2 obtained in step (2): methyl carboxylate and hydrazine hydrate as raw materials, prepare intermediate 3: hydrazide:

[0019]

[0020] (4) Using the intermediate 3 obtained in step (3) as raw materials and methyl oxalyl chloride as a catalyst, and after the reaction is completed, p-toluenesulfonyl chloride and triethylamine are added to prepare intermediate 4: methyl oxadiazolecarboxylate:

[0021]

[0022] (5) Using the intermediate 4 obtained in step (4): methyl oxadiazolecarboxylate and hydrazine hydrate as raw materials, prepare intermediate 5: oxadiazolecarboxylic acid hydrazide:

[0023]

[0024] (6) Using the intermediate 1 obtained in step (1): 4′,5,7-trimethoxynaringenin and the intermediate 5 obtained in step (5): oxadiazole carboxylic acid hydrazide as raw materials, acetic acid as a catalyst, and ethanol as a solvent, the target compound A: a naringenin derivative containing 1,3,4-oxadiazole acylhydrazone is prepared:

[0025]

[0026] The present invention also protects the application of the above-mentioned naringenin compounds containing 1,3,4-oxadiazole acylhydrazone as Candida albicans inhibitors, which have a good inhibitory effect on Candida albicans and provide an important scientific basis for the research and development and creation of new antibacterial drugs.

[0027] The beneficial effects of the present invention are as follows: Based on naringenin, the present invention introduces 1,3,4-oxadiazole structure and acylhydrazone structure with broad biological activity into naringenin to obtain a series of novel naringenin derivatives containing 1,3,4-oxadiazole acylhydrazone, and it is found that the compounds have a good inhibitory effect on Candida albicans, providing an important scientific basis for the research and development and creation of new antibacterial drugs. Specific implementation method:

[0028] The following is a further description of the present invention, rather than a limitation of the present invention.

[0029] Example 1: A method for preparing N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-phenyl-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A1), comprising the following steps:

[0030] (1) Preparation of 4′,5,7-trimethoxynaringenin (Intermediate 1):

[0031]

[0032] 2 g (7.34 mmol) of naringenin and 4.06 g (29.4 mmol) of anhydrous potassium carbonate were added to 45 mL of acetone solution containing 3.71 g (29.4 mmol) of dimethyl sulfate, and the reaction was stopped after reflux reaction at 60°C for 9 h. The solvent was removed under reduced pressure, and then 60 mL of ethyl acetate was added for extraction. The mixture was washed with water, saturated sodium bicarbonate solution, and saturated NaCl. The organic layer was dried over anhydrous sodium sulfate, removed under reduced pressure, and purified by column chromatography to obtain an orange-yellow solid with a yield of 53.8%.

[0033] (2) Preparation of methyl benzoate (intermediate 2-1):

[0034] Add 2 g (16.38 mmol) of benzoic acid into 30 mL of methanol solution, stir to dissolve, then slowly drop 1 mL of 98% (19.16 mmol) concentrated sulfuric acid into the system. After the addition is complete, reflux at 70°C for 6 h to stop the reaction, desolventize under reduced pressure, disperse the system in 45 mL of distilled water, extract with ethyl acetate (3×20 mL), then wash with water, saturated NaHCO3, saturated NaCl, combine the ethyl acetate layers, dry over anhydrous sodium sulfate, desolventize under reduced pressure to obtain a colorless transparent liquid. Yield: 95.5%.

[0035] (3) Preparation of benzoyl hydrazide (intermediate 3-1):

[0036] Add 2 g (14.69 mmol) of methyl benzoate to 30 mL of methanol solution, then add 7.95 mL (146.9 mmol) of hydrazine hydrate, reflux at 70°C for 5 h, stop the reaction, desolventize under reduced pressure, disperse the system in 45 mL of distilled water, extract with dichloromethane (3×25 mL), wash with saturated NaCl, combine the dichloromethane layers, dry over anhydrous sodium sulfate, desolventize under reduced pressure to obtain a white solid with a yield of 78.2%.

[0037] (4) Preparation of 5-phenyl-1,3,4-oxadiazole-2-carboxylic acid methyl ester (Intermediate 4-1):

[0038] 1.5 g (11.02 mmol) of benzoyl hydrazide and 2.23 g (22.04 mmol) of triethylamine were added to 35 mL of dichloromethane, and after stirring and dissolving at 0°C, 1.48 g (12.12 mmol) of methyl oxalyl chloride was dissolved in 10 mL of dichloromethane and then slowly added dropwise to the above system. After continuing to stir at 0°C for 30 min, the mixture was reacted at room temperature for 6 h. Then 1.12 g (11.02 mmol) of triethylamine and 2.10 g (11.02 mmol) of p-toluenesulfonyl chloride were added. After reacting at room temperature for 12 h, the reaction was stopped, 20 mL of dichloromethane was added, and the mixture was washed with water, saturated NaHCO3, and saturated NaCl. The organic layer was dried over anhydrous sodium sulfate, desolventized under reduced pressure, and anhydrous ethanol was added for recrystallization to precipitate a white solid. The mixture was filtered, washed with a small amount of anhydrous ethanol, and dried to obtain a white solid with a yield of 39.1%.

[0039] (5) Preparation of 5-phenyl-1,3,4-oxadiazole-2-carboxylic acid hydrazide (Intermediate 5-1):

[0040] 0.6 g (2.94 mmol) of 5-phenyl-1,3,4-oxadiazole-2-carboxylic acid methyl ester was added to 30 mL of methanol solution, and then 1.43 mL (29.4 mmol) of hydrazine hydrate was added. The reaction was stopped after reflux at 70°C for 2 h. The solvent was removed under reduced pressure. The system was dispersed in 10 mL of distilled water, extracted with dichloromethane (3×25 mL), washed with saturated NaCl, the dichloromethane layers were combined, dried over anhydrous sodium sulfate, and removed under reduced pressure to obtain a white solid with a yield of 83.7%.

[0041] (6) Preparation of N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-phenyl-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A1):

[0042] 150 mg (0.4772 mmol) of 4′,5,7-trimethoxynaringenin and 98 mg (0.4772 mmol) of 5-phenyl-1,3,4-oxadiazole-2-carboxylic acid hydrazide were added to 5 mL of anhydrous ethanol solution containing 47.7 μL of acetic acid. The reaction was stopped after reflux at 80°C for 8 h. The mixture was desolvated under reduced pressure, extracted with 20 mL of dichloromethane, washed with water, washed with saturated NaHCO3, washed with saturated NaCl, and the organic layer was dried over anhydrous sodium sulfate, desolvated under reduced pressure, and purified by column chromatography to obtain a yellow solid with a yield of 40.4%.

[0043] Example 2: A method for preparing N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(2-chlorophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A2), comprising the following steps:

[0044] (1) Preparation of 4′,5,7-trimethoxynaringenin (Intermediate 1):

[0045] As in step (1) of Example 1.

[0046] (2) Preparation of methyl 2-chlorobenzoate (intermediate 2-2):

[0047] As in step (2) of Example 1, except that benzoic acid is replaced by 2-chlorobenzoic acid.

[0048] (3) Preparation of 2-chlorobenzoylhydrazide (intermediate 3-2):

[0049] As in step (3) of Example 1, except that methyl benzoate is replaced by methyl 2-chlorobenzoate.

[0050] (4) Preparation of methyl 5-(2-chlorophenyl)-1,3,4-oxadiazole-2-carboxylate (Intermediate 4-2):

[0051] As in step (4) of Example 1, except that benzoyl hydrazide is replaced by 2-chlorobenzoyl hydrazide.

[0052] (5) Preparation of 5-(2-chlorophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide (Intermediate 5-2):

[0053] As in step (5) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester is replaced by 5-(2-chlorophenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester.

[0054] (6) Preparation of N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(2-chlorophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A2):

[0055] As in step (6) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide is replaced by 5-(2-chlorophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide.

[0056] Example 3: A method for preparing N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(3-chlorophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A3), comprising the following steps:

[0057] (1) Preparation of 4′,5,7-trimethoxynaringenin (Intermediate 1):

[0058] As in step (1) of Example 1.

[0059] (2) Preparation of methyl 3-chlorobenzoate (intermediate 2-3):

[0060] As in step (2) of Example 1, except that benzoic acid is replaced by 3-chlorobenzoic acid.

[0061] (3) Preparation of 3-chlorobenzoylhydrazide (Intermediate 3-3):

[0062] As in step (3) of Example 1, except that methyl benzoate is replaced by methyl 3-chlorobenzoate.

[0063] (4) Preparation of methyl 5-(3-chlorophenyl)-1,3,4-oxadiazole-2-carboxylate (Intermediate 4-3):

[0064] As in step (4) of Example 1, except that benzoyl hydrazide is replaced by 3-chlorobenzoyl hydrazide.

[0065] (5) Preparation of 5-(3-chlorophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide (Intermediate 5-3):

[0066] As in step (5) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester is replaced by 5-(3-chlorophenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester.

[0067] (6) Preparation of N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(3-chlorophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A3):

[0068] As in step (6) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide is replaced by 5-(3-chlorophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide.

[0069] Example 4: A method for preparing N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(4-chlorophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A4), comprising the following steps:

[0070] (1) Preparation of 4′,5,7-trimethoxynaringenin (Intermediate 1):

[0071] As in step (1) of Example 1.

[0072] (2) Preparation of methyl 4-chlorobenzoate (intermediate 2-4):

[0073] As in step (2) of Example 1, except that benzoic acid is replaced by 4-chlorobenzoic acid.

[0074] (3) Preparation of 4-chlorobenzoylhydrazide (Intermediate 3-4):

[0075] As in step (3) of Example 1, except that methyl benzoate is replaced by methyl 4-chlorobenzoate.

[0076] (4) Preparation of methyl 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-carboxylate (Intermediate 4-4):

[0077] As in step (4) of Example 1, except that benzoyl hydrazide is replaced by 4-chlorobenzoyl hydrazide.

[0078] (5) Preparation of 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide (Intermediate 5-4):

[0079] As in step (5) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester is replaced by 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester.

[0080] (6) Preparation of N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(4-chlorophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A4):

[0081] As in step (6) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide is replaced by 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide.

[0082] Example 5: A method for preparing N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(2-methylphenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A5), comprising the following steps:

[0083] (1) Preparation of 4′,5,7-trimethoxynaringenin (Intermediate 1):

[0084] As in step (1) of Example 1.

[0085] (2) Preparation of methyl 2-methylbenzoate (intermediate 2-5):

[0086] As in step (2) of Example 1, except that benzoic acid is replaced by 2-methylbenzoic acid.

[0087] (3) Preparation of 2-methylbenzoylhydrazide (Intermediate 3-5):

[0088] As in step (3) of Example 1, except that methyl benzoate is replaced by methyl 2-methylbenzoate.

[0089] (4) Preparation of methyl 5-(2-methylphenyl)-1,3,4-oxadiazole-2-carboxylate (Intermediate 4-5):

[0090] As in step (4) of Example 1, except that benzoyl hydrazide is replaced by 2-methylbenzoyl hydrazide.

[0091] (5) Preparation of 5-(2-methylphenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide (Intermediate 5-5):

[0092] As in step (5) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester is replaced by 5-(2-methylphenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester.

[0093] (6) Preparation of N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(2-methylphenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A5):

[0094] As in step (6) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide is replaced by 5-(2-methylphenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide.

[0095] Example 6: A method for preparing N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(3-methylphenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A6), comprising the following steps:

[0096] (1) Preparation of 4′,5,7-trimethoxynaringenin (Intermediate 1):

[0097] As in step (1) of Example 1.

[0098] (2) Preparation of methyl 3-methylbenzoate (intermediate 2-6):

[0099] As in step (2) of Example 1, except that benzoic acid is replaced by 3-methylbenzoic acid.

[0100] (3) Preparation of 3-methylbenzoylhydrazide (Intermediate 3-6):

[0101] As in step (3) of Example 1, except that methyl benzoate is replaced by methyl 3-methylbenzoate.

[0102] (4) Preparation of methyl 5-(3-methylphenyl)-1,3,4-oxadiazole-2-carboxylate (Intermediate 4-6):

[0103] As in step (4) of Example 1, except that benzoyl hydrazide is replaced by 3-methylbenzoyl hydrazide.

[0104] (5) Preparation of 5-(3-methylphenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide (Intermediate 5-6):

[0105] As in step (5) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester is replaced by 5-(3-methylphenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester.

[0106] (6) Preparation of N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(3-methylphenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A6):

[0107] As in step (6) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide is replaced by 5-(3-methylphenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide.

[0108] Example 7: A method for preparing N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(4-methylphenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A7), comprising the following steps:

[0109] (1) Preparation of 4′,5,7-trimethoxynaringenin (Intermediate 1):

[0110] As in step (1) of Example 1.

[0111] (2) Preparation of methyl 4-methylbenzoate (intermediate 2-7):

[0112] As in step (2) of Example 1, except that benzoic acid is replaced by 4-methylbenzoic acid.

[0113] (3) Preparation of 4-methylbenzoylhydrazide (Intermediate 3-7):

[0114] As in step (3) of Example 1, except that methyl benzoate is replaced by methyl 4-methylbenzoate.

[0115] (4) Preparation of methyl 5-(4-methylphenyl)-1,3,4-oxadiazole-2-carboxylate (Intermediate 4-7):

[0116] As in step (4) of Example 1, except that benzoyl hydrazide is replaced by 4-methylbenzoyl hydrazide.

[0117] (5) Preparation of 5-(4-methylphenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide (Intermediate 5-7):

[0118] As in step (5) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester is replaced by 5-(4-methylphenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester.

[0119] (6) Preparation of N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(4-methylphenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A7):

[0120] As in step (6) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide is replaced by 5-(4-methylphenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide.

[0121] Example 8: A method for preparing N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(3-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A8), comprising the following steps:

[0122] (1) Preparation of 4′,5,7-trimethoxynaringenin (Intermediate 1):

[0123] As in step (1) of Example 1.

[0124] (2) Preparation of methyl 3-methoxybenzoate (intermediate 2-8):

[0125] As in step (2) of Example 1, except that benzoic acid is replaced by 3-methoxybenzoic acid.

[0126] (3) Preparation of 4-methoxybenzoylhydrazide (Intermediate 3-8):

[0127] As in step (3) of Example 1, except that methyl benzoate is replaced by methyl 3-methoxybenzoate.

[0128] (4) Preparation of methyl 5-(3-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (Intermediate 4-8):

[0129] As in step (4) of Example 1, except that benzoyl hydrazide is replaced by 3-methoxybenzoyl hydrazide.

[0130] (5) Preparation of 5-(3-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide (Intermediate 5-8):

[0131] As in step (5) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester is replaced by 5-(3-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester.

[0132] (6) Preparation of N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(3-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A8):

[0133] As in step (6) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide is replaced by 5-(3-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide.

[0134] Example 9: A method for preparing N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(2-nitrophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A9), comprising the following steps:

[0135] (1) Preparation of 4′,5,7-trimethoxynaringenin (Intermediate 1):

[0136] As in step (1) of Example 1.

[0137] (2) Preparation of methyl 2-nitrobenzoate (intermediate 2-9):

[0138] As in step (2) of Example 1, except that benzoic acid is replaced by 2-nitrobenzoic acid.

[0139] (3) Preparation of 2-nitrobenzoylhydrazide (Intermediate 3-9):

[0140] As in step (3) of Example 1, except that methyl benzoate is replaced by methyl 2-nitrobenzoate.

[0141] (4) Preparation of 5-(2-nitrophenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester (Intermediate 4-9):

[0142] As in step (4) of Example 1, except that benzohydrazide is replaced by 2-nitrobenzohydrazide.

[0143] (5) Preparation of 5-(2-nitrophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide (Intermediate 5-9):

[0144] As in step (5) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester is replaced by 5-(2-nitrophenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester.

[0145] (6) Preparation of N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(2-nitrophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A9):

[0146] As in step (6) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide is replaced by 5-(2-nitrophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide.

[0147] Example 10: A method for preparing N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(3-nitrophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A10), comprising the following steps:

[0148] (1) Preparation of 4′,5,7-trimethoxynaringenin (Intermediate 1):

[0149] As in step (1) of Example 1.

[0150] (2) Preparation of methyl 3-nitrobenzoate (intermediate 2-10):

[0151] As in step (2) of Example 1, except that benzoic acid is replaced by 3-nitrobenzoic acid.

[0152] (3) Preparation of 3-nitrobenzoylhydrazide (Intermediate 3-10):

[0153] As in step (3) of Example 1, except that methyl benzoate is replaced by methyl 3-nitrobenzoate.

[0154] (4) Preparation of 5-(3-nitrophenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester (Intermediate 4-10):

[0155] As in step (4) of Example 1, except that benzohydrazide is replaced by 3-nitrobenzohydrazide.

[0156] (5) Preparation of 5-(3-nitrophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide (Intermediate 5-10):

[0157] As in step (5) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester is replaced by 5-(3-nitrophenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester.

[0158] (6) Preparation of N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(3-nitrophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A10):

[0159] As in step (6) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide is replaced by 5-(3-nitrophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide.

[0160] Example 11: A method for preparing N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(4-nitrophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A11), comprising the following steps:

[0161] (1) Preparation of 4′,5,7-trimethoxynaringenin (Intermediate 1):

[0162] As in step (1) of Example 1.

[0163] (2) Preparation of methyl 4-nitrobenzoate (intermediate 2-11):

[0164] As in step (2) of Example 1, except that benzoic acid is replaced by 4-nitrobenzoic acid.

[0165] (3) Preparation of 4-nitrobenzoylhydrazide (Intermediate 3-11):

[0166] As in step (3) of Example 1, except that methyl benzoate is replaced by methyl 4-nitrobenzoate.

[0167] (4) Preparation of 5-(4-nitrophenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester (Intermediate 4-11):

[0168] As in step (4) of Example 1, except that benzohydrazide is replaced by 4-nitrobenzohydrazide.

[0169] (5) Preparation of 5-(4-nitrophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide (Intermediate 5-11):

[0170] As in step (5) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester is replaced by 5-(4-nitrophenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester.

[0171] (6) Preparation of N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(4-nitrophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A11):

[0172] As in step (6) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide is replaced by 5-(4-nitrophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide.

[0173] Example 12: A method for preparing N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(3-fluorophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A12), comprising the following steps:

[0174] (1) Preparation of 4′,5,7-trimethoxynaringenin (Intermediate 1):

[0175] As in step (1) of Example 1.

[0176] (2) Preparation of methyl 3-fluorobenzoate (intermediate 2-12):

[0177] As in step (2) of Example 1, except that benzoic acid is replaced by 3-fluorobenzoic acid.

[0178] (3) Preparation of 3-fluorobenzoylhydrazide (Intermediate 3-12):

[0179] As in step (3) of Example 1, except that methyl benzoate is replaced by methyl 3-fluorobenzoate.

[0180] (4) Preparation of methyl 5-(3-fluorophenyl)-1,3,4-oxadiazole-2-carboxylate (Intermediate 4-12):

[0181] As in step (4) of Example 1, except that benzoyl hydrazide is replaced by 3-fluorobenzoyl hydrazide.

[0182] (5) Preparation of 5-(3-fluorophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide (Intermediate 5-12):

[0183] As in step (5) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester is replaced by 5-(3-fluorophenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester.

[0184] (6) Preparation of N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(3-fluorophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A12):

[0185] As in step (6) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide is replaced by 5-(3-fluorophenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide.

[0186] Example 13: A method for preparing N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(pyridin-2-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A13), comprising the following steps:

[0187] (1) Preparation of 4′,5,7-trimethoxynaringenin (Intermediate 1):

[0188] As in step (1) of Example 1.

[0189] (2) Preparation of methyl 2-pyridinecarboxylate (intermediate 2-13):

[0190] As in step (2) of Example 1, except that benzoic acid is replaced by 2-pyridinecarboxylic acid.

[0191] (3) Preparation of 2-pyridinecarboxylic acid hydrazide (intermediate 3-13):

[0192] As in step (3) of Example 1, except that methyl benzoate is replaced by methyl 2-pyridinecarboxylate.

[0193] (4) Preparation of methyl 5-(pyridin-2-yl)-1,3,4-oxadiazole-2-carboxylate (Intermediate 4-13):

[0194] As in step (4) of Example 1, except that benzoyl hydrazide is replaced by 2-pyridinecarboxylic acid hydrazide.

[0195] (5) Preparation of 5-(pyridin-2-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide (Intermediate 5-13):

[0196] As in step (5) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester is replaced by 5-(pyridin-2-yl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester.

[0197] (6) Preparation of N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(pyridin-2-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A13):

[0198] As in step (6) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide is replaced by 5-(pyridin-2-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide.

[0199] Example 14: A method for preparing N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(3-chloropyridin-2-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A14), comprising the following steps:

[0200] (1) Preparation of 4′,5,7-trimethoxynaringenin (Intermediate 1):

[0201] As in step (1) of Example 1.

[0202] (2) Preparation of 3-chloro-2-pyridinecarboxylic acid methyl ester (Intermediate 2-14):

[0203] As in step (2) of Example 1, except that benzoic acid is replaced by 3-chloro-2-pyridinecarboxylic acid.

[0204] (3) Preparation of 3-chloro-2-pyridinecarboxylic acid hydrazide (Intermediate 3-14):

[0205] As in step (3) of Example 1, except that methyl benzoate is replaced by methyl 3-chloro-2-pyridinecarboxylate.

[0206] (4) Preparation of 5-(3-chloropyridin-2-yl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester (Intermediate 4-14):

[0207] As in step (4) of Example 1, except that benzoyl hydrazide is replaced by 3-chloro-2-pyridinecarboxylic acid hydrazide.

[0208] (5) Preparation of 5-(3-chloropyridin-2-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide (Intermediate 5-14):

[0209] As in step (5) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester is replaced by 5-(3-chloropyridin-2-yl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester.

[0210] (6) Preparation of N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(3-chloropyridin-2-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A14):

[0211] As in step (6) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide is replaced by 5-(3-chloropyridin-2-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide.

[0212] Example 15: A method for preparing N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(pyridin-4-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A15), comprising the following steps:

[0213] (1) Preparation of 4′,5,7-trimethoxynaringenin (Intermediate 1):

[0214] As in step (1) of Example 1.

[0215] (2) Preparation of methyl 4-pyridinecarboxylate (intermediate 2-15):

[0216] As in step (2) of Example 1, except that benzoic acid is replaced by 4-pyridinecarboxylic acid.

[0217] (3) Preparation of 4-pyridinecarboxylic acid hydrazide (intermediate 3-15):

[0218] As in step (3) of Example 1, except that methyl benzoate is replaced by methyl 4-pyridinecarboxylate.

[0219] (4) Preparation of methyl 5-(pyridin-4-yl)-1,3,4-oxadiazole-2-carboxylate (Intermediate 4-15):

[0220] As in step (4) of Example 1, except that benzoyl hydrazide is replaced by 4-pyridinecarboxylic acid hydrazide.

[0221] (5) Preparation of 5-(pyridin-4-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide (Intermediate 5-15):

[0222] As in step (5) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester is replaced by 5-(pyridin-4-yl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester.

[0223] (6) Preparation of N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(pyridin-4-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A15):

[0224] As in step (6) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide is replaced by 5-(pyridin-4-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide.

[0225] Example 16: A method for preparing N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(2-chloropyridin-4-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A16), comprising the following steps:

[0226] (1) Preparation of 4′,5,7-trimethoxynaringenin (Intermediate 1):

[0227] As in step (1) of Example 1.

[0228] (2) Preparation of methyl 2-chloropyridine-4-carboxylate (Intermediate 2-16):

[0229] As in step (2) of Example 1, except that benzoic acid is replaced by 2-chloropyridine-4-carboxylic acid.

[0230] (3) Preparation of 2-chloropyridine-4-carboxylic acid hydrazide (Intermediate 3-16):

[0231] As in step (3) of Example 1, except that methyl benzoate is replaced by methyl 2-chloropyridine-4-carboxylate.

[0232] (4) Preparation of methyl 5-(2-chloropyridin-4-yl)-1,3,4-oxadiazole-2-carboxylate (Intermediate 4-16):

[0233] As in step (4) of Example 1, except that benzohydrazide is replaced by 2-chloropyridine-4-carboxyhydrazide.

[0234] (5) Preparation of 5-(2-chloropyridin-4-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide (Intermediate 5-16):

[0235] As in step (5) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester is replaced by 5-(2-chloropyridin-4-yl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester.

[0236] (6) Preparation of N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(2-chloropyridin-4-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A16):

[0237] As in step (6) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide is replaced by 5-(2-chloropyridin-4-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide.

[0238] Example 17: A method for preparing N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(3-chloropyridin-4-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A17), comprising the following steps:

[0239] (1) Preparation of 4′,5,7-trimethoxynaringenin (Intermediate 1):

[0240] As in step (1) of Example 1.

[0241] (2) Preparation of methyl 3-chloropyridine-4-carboxylate (Intermediate 2-17):

[0242] As in step (2) of Example 1, except that benzoic acid is replaced by 3-chloropyridine-4-carboxylic acid.

[0243] (3) Preparation of 3-chloropyridine-4-carboxylic acid hydrazide (Intermediate 3-17):

[0244] As in step (3) of Example 1, except that methyl benzoate is replaced by methyl 3-chloropyridine-4-carboxylate.

[0245] (4) Preparation of methyl 5-(3-chloropyridin-4-yl)-1,3,4-oxadiazole-2-carboxylate (Intermediate 4-17):

[0246] As in step (4) of Example 1, except that benzoyl hydrazide is replaced by 3-chloropyridine-4-carboxyhydrazide.

[0247] (5) Preparation of 5-(3-chloropyridin-4-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide (Intermediate 5-17):

[0248] As in step (5) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester is replaced by 5-(3-chloropyridin-4-yl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester.

[0249] (6) Preparation of N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(3-chloropyridin-4-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A17):

[0250] As in step (6) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide is replaced by 5-(3-chloropyridin-4-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide.

[0251] Example 18: A method for preparing N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(2-methoxypyridin-4-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A18), comprising the following steps:

[0252] (1) Preparation of 4′,5,7-trimethoxynaringenin (Intermediate 1):

[0253] As in step (1) of Example 1.

[0254] (2) Preparation of methyl 2-methoxypyridine-4-carboxylate (Intermediate 2-18):

[0255] As in step (2) of Example 1, except that benzoic acid is replaced by 2-methoxypyridine-4-carboxylic acid.

[0256] (3) Preparation of 2-methoxypyridine-4-carboxylic acid hydrazide (Intermediate 3-18):

[0257] As in step (3) of Example 1, except that methyl benzoate is replaced by methyl 2-methoxypyridine-4-carboxylate.

[0258] (4) Preparation of methyl 5-(2-methoxypyridin-4-yl)-1,3,4-oxadiazole-2-carboxylate (Intermediate 4-18):

[0259] As in step (4) of Example 1, except that benzoyl hydrazide is replaced by 2-methoxypyridine-4-carboxyhydrazide.

[0260] (5) Preparation of 5-(2-methoxypyridin-4-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide (Intermediate 5-18):

[0261] As in step (5) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester is replaced by 5-(2-methoxypyridin-4-yl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester.

[0262] (6) Preparation of N′-(5,7-dimethoxy-2-(4-methoxyphenyl)chroman)-5-(2-methoxypyridin-4-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazone (target compound A18):

[0263] As in step (6) of Example 1, except that 5-(phenyl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide is replaced by 5-(2-methoxypyridin-4-yl)-1,3,4-oxadiazole-2-carboxylic acid hydrazide.

[0264] The structure and H NMR, C NMR and F NMR data of the synthesized naringenin derivative containing 1,3,4-oxadiazole acylhydrazone are shown in Table 1, and the physicochemical properties are shown in Table 2.

[0265] Table 1 H NMR and C NMR data of the compounds

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272] Table 2 Physicochemical properties of target compounds

[0273]

[0274]

[0275] The embodiments described above are only descriptions of the preferred modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. Naringenin compounds containing 1,3,4-oxadiazole acylhydrazone as shown in formula A: in: R is an alkyl group, a cycloalkyl group, a phenyl group, a substituted phenyl group, an aromatic heterocyclic group, or a substituted aromatic heterocyclic group.

2. The compound according to claim 1, characterized in that The substituted phenyl group is an alkyl group containing C1-C6, an alkoxy group containing C1-C6, a nitro group, a halogen atom or a hydrogen atom at the ortho, meta or para position of the benzene ring; the aromatic heterocyclic group is a thienyl group, a furyl group, a pyrrolyl group or a pyridyl group; the substituent on the substituted aromatic heterocyclic group is an alkyl group containing C1-C6, an alkoxy group containing C1-C6, a nitro group, a halogen atom or a hydrogen atom at the ortho, meta or para position of the benzene ring.

3. The method for preparing naringenin compounds containing 1,3,4-oxadiazole acylhydrazone according to claim 1, characterized in that: The steps include: (1) 4′,5,7-trimethoxynaringenin was prepared by reflux reaction using naringenin and dimethyl sulfate as raw materials, anhydrous potassium carbonate as catalyst, and acetone as solvent; (2) using carboxylic acid as a raw material and H2SO4 as a catalyst for reflux reaction to prepare methyl carboxylate; (3) Using the methyl carboxylate obtained in step (2) and hydrazine hydrate as raw materials, preparing hydrazide: (4) Using the hydrazide obtained in step (3) and methyl oxalyl chloride as raw materials and triethylamine as a catalyst, after the reaction is completed, p-toluenesulfonyl chloride and triethylamine are added to prepare methyl oxadiazolecarboxylate: (5) Using the methyl oxadiazolecarboxylate obtained in step (4) and hydrazine hydrate as raw materials, preparing oxadiazolecarboxylic acid hydrazide: (6) Using the 4′,5,7-trimethoxynaringenin obtained in step (1) and the oxadiazole carboxylic acid hydrazide obtained in step (5) as raw materials, acetic acid as a catalyst, and ethanol as a solvent, a naringenin derivative containing 1,3,4-oxadiazole acylhydrazone is prepared:

4. The use of the naringenin compounds containing 1,3,4-oxadiazole acylhydrazone according to claim 1, characterized in that: Used as an inhibitor of Candida albicans.

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