A nitrogen azole antifungal compound and its application

Abstract

The present invention discloses an azole antifungal compound, specifically an azole antifungal compound having the following chemical structural general formula (I) and (II) and an optical isomer and a pharmaceutically acceptable salt thereof, which can be used to prepare a new antifungal drug. Compared with the commonly used clinical drug fluconazole, the compound of the present invention has a strong antibacterial activity against the pathogenic fungus Candida albicans.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and specifically relates to an azole antifungal compound and application thereof. Background Art

[0002] In recent years, with the widespread development of organ transplantation and the continuous expansion of the HIV-infected population, the number of people with low immunity has increased. In addition, the use of invasive diagnostic and treatment equipment has led to the spread of invasive deep fungal infections around the world. Compared with the increasingly serious fungal infections, the development speed of new antifungal drugs is far slower than the speed at which fungi develop drug resistance. The increasingly serious fungal drug resistance is also one of the important reasons for the annual increase in the incidence and mortality of invasive fungal infections in immunodeficient patients. Currently, the varieties that can be used in clinical practice mainly include polyenes, azoles, and echinocandins. Triazole drugs are a class of drugs with the most development potential and advantages. Drugs such as itraconazole (1989), fluconazole (1990), voriconazole (2001), posaconazole (2006), and isavuconazole (2015) have been launched on the market and have become the first-line drugs for clinical antifungal infections. However, due to the long-term treatment and repeated administration of azole antifungal drugs, fungi have developed resistance to them, resulting in clinical treatment failure. Therefore, it is still very important to develop a new generation of antifungal drugs, especially drugs against resistant fungi. Summary of the invention

[0003] The purpose of the present invention is to provide an azole antifungal compound and its application.

[0004] The technical solution of the present invention to solve the above technical problems is as follows:

[0005] A nitrogen azole antifungal compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof, characterized in that the compound comprises the general formula (I) or (II), the compound of the general formula (I) or (II) contains the structure of triazole or tetrazole and difluorophenyl,

[0006]

[0007] wherein X is selected from a C atom or a N atom;

[0008] Y is selected from a methyl group or a H atom;

[0009] Z is selected from -NH- or an O atom;

[0010] R is selected from 3,4-(methylenedioxy)phenethyl, 3,4-(methylenedioxy)benzyl, 3,4-(methylenedioxy)phenyl, 3-[3,4-(methylenedioxy)phenyl]acryloyl, 3-[3,4-(methylenedioxy)phenyl]propionyl, 3-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)acryloyl, 1,4-benzodioxane-6-acryloyl, 3,4-(methylenedioxy)phenylacetyl, 3-piperanoyl, 2-piperanoyl, 2,3-dihydrobenzofuran-5-acetyl, 1-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)acryloyl, fluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl, (2,3-dihydro-benzo[1,4]dioxol-6)-acetyl, 2,3-dihydro-1,4-benzodioxane-6-yl, 2,3-dihydro-1,4-benzodioxane-5-yl, 3-(2,3-dihydrobenzofuran-5-yl)acryloyl, 3,4-dihydroxycinnamoyl, 3-hydroxy-4-methoxycinnamoyl, 4-hydroxy-3-methoxycinnamoyl, 3,4-dimethoxycinnamoyl; the carbon atom marked with * is a chiral carbon atom or an achiral carbon atom.

[0011] The preferred compound structures of the present invention are: 1 The HNMR and MS characterization data are shown in Table 1.

[0012] Table 1 Structure and characterization data of preferred compounds

[0013]

[0014]

[0015]

[0016]

[0017]

[0018]

[0019]

[0020] Preferably, the azole antifungal compound, its optical isomer or a pharmaceutically acceptable salt thereof, the compound (I) or (II) includes any one or a mixture of isomers.

[0021] Preferably, the azole antifungal compound, its optical isomer or a pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt is hydrochloride, acetate, oxalate, sulfate, bisulfate, hydrobromide, methanesulfonate or citrate.

[0022] The present invention also provides an application of an azole antifungal compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof in the preparation of an antifungal drug.

[0023] If there is a conflict between the Chinese name and the structural formula of the compound in the present invention, the structural formula shall prevail, unless there is an obvious error in the structural formula.

[0024] The beneficial effects of the present invention are as follows: the present invention discloses a nitrogen azole antifungal compound, specifically a nitrogen azole antifungal compound having chemical structural general formula (I) and (II) and optical isomers and pharmaceutically acceptable salts thereof, which can be used to prepare new antifungal drugs. Compared with the commonly used clinical drug fluconazole, the compound of the present invention has a strong antibacterial activity against the pathogenic fungus Candida albicans. Pharmacophore fusion is an important strategy for discovering new drugs. The present invention fuses the key pharmacophore of berberine derivatives, piperonyl and its analogs, with the pharmacophore of nitrogen azole antifungal drugs, and designs and synthesizes a series of compounds that can be used for antifungal. Most of the compounds of the present invention have good antifungal activity characteristics, and some compounds have better inhibition on Candida albicans than the positive drug fluconazole, and have excellent antifungal activity. DETAILED DESCRIPTION

[0025] The present invention is described below with reference to examples, but the present invention is not limited thereto. In the art, simple replacement or improvement made by technicians in the field to the present invention belongs to the technical solution protected by the present invention.

[0026] The method examples provided below are used to promote further understanding of the preparation method of the present invention. The specific substances, types and conditions used are determined to further illustrate the present invention and are not intended to limit the reasonable scope thereof. The raw materials and reagents used in the following description may be purchased from the market or may be easily prepared by a person of ordinary skill in the art.

[0027] Some compounds of the general formula (I) of the present invention can be prepared according to the method of synthetic route (1).

[0028] Synthesis route (1):

[0029]

[0030] Example 1: Preparation of 1-((2-(Benzo[d][1,3]dioxolan-5-yl)ethyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazolyl-1-yl)propan-2-ol [(I)a Compound 1]

[0031] Step 1: Preparation of 2-(1H-1,2,3,4-tetrazolyl-1-yl)-2',4'-difluoroacetophenone [Intermediate (2)]

[0032] 2.74 g (0.065 mol) of 1H-tetrazole was dissolved in a 100 mL round-bottom flask of N,N-dimethylformamide (DMF), and the mixture was stirred in an ice-water bath at 0°C. Then, 1.56 g (0.065 mol) of 60% NaH was added in batches. After stirring in an ice-water bath for 0.5 h, 5.7 g (0.05 mol) of raw material (1) 2'-chloro-2,4-difluoroacetophenone was added. The reaction was stirred at room temperature for 2 h. The reaction solution was poured into ice water to precipitate a large amount of solid. The yellow solid was filtered to obtain the filtrate. The filtrate was extracted twice with ethyl acetate (100 mL*2). The organic layers were combined, washed three times with saturated brine (150 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a solid. The solids obtained twice were combined and purified by silica gel column (eluent: EA:PE=1:1.5) to obtain 7.2 g of off-white solid with a yield of 64.2%. The structure of the compound was confirmed by H NMR spectroscopy ( 1 H NMR) and LC-MS identification, the data are as follows: 1 H NMR(400MHz, DMSO-d6)δ9.33(s,1H),8.08(td,J=8.7,6.6Hz,1H),7.58(ddd,J=11.7,9.3, 2.5Hz,1H),7.34(td,J=8.5,2.5Hz,1H),6.18(d,J=3.0Hz,2H).MS(ESI)m / z:225.20[M+H] + ,223.10[MH] - .

[0033] Step 2: Preparation of 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,3,4-tetrazolyl [(3) intermediate]

[0034] To a 10 mL dichloromethane solution of 2-(1H-1,2,3,4-tetrazolyl-1-yl)-2',4'-difluoroacetophenone [(2) intermediate] (1.12 g, 5 mmol), 2.01 g (5 mmol) of trimethylsulfoxide iodide and 10 mL of 20% sodium hydroxide (2 g, 50 mmol) solution were added. The mixture was subjected to microwave reaction for 5 h. The microwave reactor was set to a temperature of 40°C and a maximum output power of 50 W. After the reaction, the mixture was extracted with ethyl acetate (20 mL*3), and the organic layer was washed three times with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oil. The product was purified by silica gel column (eluent: EA:PE=1:1.5) to obtain 0.9 g of a light red oil (yield: 75%). The structure of the compound was confirmed by H NMR ( 1 H NMR) and LC-MS identification, the data are as follows: 1H NMR(400MHz, DMSO-d6)δ9.35(s,1H),7.32(d,J=11.0Hz,1H),7.22(td,J=8.5,6.7Hz,1H),7.04(td,J=8.5,2.0Hz,1H),5 .12(d,J=14.9Hz,1H),4.89(d,J=14.9Hz,1H),3.20(d,J=4.6Hz,1H),3.04(d,J=4.6Hz,1H).MS(ESI),m / z:239.20[M+H] + ,237.10[MH] - .

[0035] Step 3: Preparation of 1-((2-(benzo[d][1,3]dioxolan-5-yl)ethyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazolyl-1-yl)propan-2-ol [(I)a Compound 1]

[0036] In a 50 mL round-bottom flask, 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,3,4-tetrazolyl [(3) intermediate] (70 mg, 2.95 mmol), K2CO3 (53 mg, 3.8 mmol) and 10 mL of N-methylpyrrolidone (NMP) were added, stirred and mixed, and 3,4-methylenedioxyphenylethylamine solution (49 mg, 3.54 mmol) was added dropwise. The mixture was reacted at 80°C for 5 h. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature. The mixture was extracted with ethyl acetate (10 mL*3) three times, and the organic layer was washed with saturated brine (10 mL*3) three times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The product was purified by silica gel column (eluent: DCM:MeOH=15:1) to obtain 71 mg of a white solid (yield: 60%). The compound was analyzed by hydrogen nuclear magnetic resonance spectrum ( 1 H NMR) and LC-MS characterization data are shown in Table 1.

[0037] (I)a Compound 2 was prepared by referring to the third step of Example 1 except that 3,4-methylenedioxybenzylamine was substituted for 3,4-methylenedioxyphenethylamine. The H NMR spectrum of the compound was ( 1 The characterization data of HNMR and LC-MS are shown in Table 1.

[0038] (I) a Compound 3 was prepared by referring to Specific Example 1 except that 1H-1,2,4-triazole was substituted for 1H-tetrazolyl in the first step and the subsequent steps were replaced with the corresponding intermediates according to Specific Example 1. The compound had a hydrogen nuclear magnetic resonance spectrum ( 1 The characterization data of HNMR and LC-MS are shown in Table 1.

[0039] Example 2: Preparation of (E)-3-(Benzo[d][1,3]dioxolan-5-yl)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-tetrazolyl-1-yl))propyl)acrylamide [(I)b Compound 4]

[0040] Step 1: Preparation of 1-amino-2-(2,4-difluorophenyl)-3-(1H-tetrazolyl-1-yl)propan-2-ol [(4) intermediate]

[0041] 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,3,4-tetrazolyl (0.9 g, 3.8 mmol) [(3) intermediate] and 8 mL of 7 M ammonia in methanol were added to a pressure tube and reacted at 85°C for 2 h. After cooling, the mixture was concentrated under reduced pressure and purified by silica gel column (eluent DCM:MeOH=10:1) to obtain 0.87 g of solid (yield 90%). The structure of the compound was confirmed by H NMR ( 1 H NMR) and LC-MS identification, the data are as follows: 1 H NMR(400MHz, DMSO-d6)δ9.13(s,1H),7.28(td,J=9.0,6.8Hz,1H),7.25–7.18(m,1H),6.95(td,J=8 .5,2.6Hz,1H),4.84(q,J=14.3Hz,2H),3.04–2.94(m,2H),1.91(s,3H).MS(ESI),m / z:256.31[M+H] + ,254.25[MH] - .

[0042] Step 2: Preparation of (E)-3-(benzo[d][1,3]dioxolan-5-yl)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-tetrazolyl-1-yl))propyl)acrylamide [(I)b Compound 4]

[0043] 1-amino-2-(2,4-difluorophenyl)-3-(1H-tetrazolyl-1-yl)propan-2-ol [(4) intermediate] (80 mg, 3.1 mmol), 3,4-(methylenedioxy)cinnamic acid (66 mg, 3.4 mmol) and 5 mL of DMF were added to a 25 mL round-bottom flask and stirred. HATU (155 mg, 4.0 mmol) was added and N,N-diisopropylethylamine (DIEA, 150 μL, 9.3 mmol) was added dropwise. The mixture was stirred at room temperature for 4 h. After the reaction was completed, the mixture was extracted three times with ethyl acetate (10 mL*3), and the organic layer was washed three times with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The product was purified by silica gel column (eluent: EA:PE=2:1) ​​to obtain 87 mg of a white solid (yield: 65%). The compound was analyzed by hydrogen nuclear magnetic resonance spectrum ( 1 H NMR) and LC-MS characterization data are shown in Table 1.

[0044] (I)b Compounds 5-21 can be prepared by amide condensation using the corresponding carboxylic acids according to the second step of Example 2.

[0045] Some compounds of the general formula (I) of the present invention can be prepared according to the method of synthetic route (2).

[0046] Synthesis route (2):

[0047]

[0048] Example 3: Preparation of (E)-3-(Benzo[d][1,3]dioxolan-5-yl)-N-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl))butan-2-yl)acrylamide (Compound 22)

[0049] Step 1: (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol [Intermediate (6)]

[0050] The raw material (5) 1-(((2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole (2.0 g, 8 mmol), sodium azide (776 mg, 12 mmol) and ammonium chloride (553 mg, 10.4 mmol) were weighed into a 100 mL round-bottom flask, and 20 mL of DMF was added. The reaction was stirred at 80 ° C for 10 h. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL*3). The organic layers were combined, washed three times with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oil. The obtained oil was added to a 50 mL round-bottom flask, 10 mL of methanol was added to dissolve, and 200 mg of 10% Pd / C was added. The gas was replaced with hydrogen three times. After reacting at room temperature for 5 h, the crude product was concentrated under reduced pressure and purified by silica gel column (eluent DCM: MeOH = 10: 1) to obtain 1.41 g of white solid (yield 66%). The structure of the compound was confirmed by H NMR ( 1 H NMR) and LC-MS identification, the data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.26(s,1H),7.64(s,1H),7.26(td,J=8.9,7.2Hz,1H),7.12(ddd,J=11.9,9.2,2.5Hz, 1H),6.87(td,J=8.5,2.5Hz,1H),4.66(q,J=14.4Hz,2H),1.90(s,2H),0.70(d,J=6.5Hz,3H).m / z:269.4[M+H] + ,267.1[MH] - .

[0051] Step 2: Preparation of (E)-3-(benzo[d][1,3]dioxolan-5-yl)-N-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl))butan-2-yl)acrylamide (Compound 22)

[0052] In a 25 mL round-bottom flask, (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol [intermediate (6)] (83 mg, 3.1 mmol), 3,4-(methylenedioxy)cinnamic acid (66 mg, 3.4 mmol) and 5 mL of DMF were added and stirred, and HATU (155 mg, 4.0 mmol) was added thereto, and N,N-diisopropylethylamine (DIEA, 150 μL, 9.3 mmol) was added dropwise. The mixture was stirred at room temperature for 4 h. After the reaction was completed, the mixture was extracted three times with ethyl acetate (10 mL*3), and the organic layer was washed three times with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column (eluent: EA:PE=2:1) ​​to obtain 87 mg of a white solid (yield: 65%). The compound had a hydrogen nuclear magnetic resonance spectrum ( 1 The characterization data of HNMR and LC-MS are shown in Table 1.

[0053] (I)c Compounds 23-30 can be prepared by amide condensation using the corresponding carboxylic acids according to the second step of Example 3.

[0054] The compound of the general formula (II) of the present invention can be prepared according to the method of synthetic route (3).

[0055] Synthesis route (3):

[0056]

[0057] Example 4: Preparation of 1-((3R,5R)-(5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)-N-(benzo[d][1,3]dioxolan-5-ylmethyl)methanamine (Compound 31)

[0058] Step 1: Preparation of methyl ((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)4-methylbenzenesulfonate [Intermediate (8)]

[0059] 5.9 g of starting material (7) ((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methanol (20 mmol) was added to 50 mL of DCM, followed by pyridine (7.9 g, 100 mmol) and 4-dimethylaminopyridine (DMAP, 0.73 g, 6 mmol). Under nitrogen protection, the temperature was lowered to 0°C, 4-methylbenzenesulfonyl chloride (TsC1, 13.3 g, 70 mmol) was added at once, and the temperature was raised to room temperature for overnight reaction. The reaction solution was quenched with 20 mL of saturated ammonium chloride solution, and then washed once with 10 mL of saturated sodium bicarbonate and 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude yellow oil. 10 mL of isopropanol was added, and the mixture was stirred at 50-60°C to dissolve. 10 mL of n-hexane was added dropwise, and the mixture was cooled to room temperature for crystallization and stirred for 1.5 h. The mixture was filtered and washed with 10 mL of n-hexane to obtain a white solid compound. The structure of the compound was determined by hydrogen nuclear magnetic resonance spectroscopy ( 1 H NMR) and LC-MS identification, the data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.28(s,1H),7.79(d,J=8.3Hz,2H),7.75(s,1H),7.49(d,J= 8.1Hz,2H),7.23(dtd,J=15.8,9.1,4.7Hz,2H),6.95(td,J=8.5,2.4Hz,1H),4.50(s, 2H),3.96–3.82(m,3H),3.55(dd,J=8.8,7.0Hz,1H),2.43(s,3H),2.42–2.35(m,1H) ,2.29(ddd,J=10.5,8.0,2.1Hz,1H),1.98(dd,J=13.1,8.1Hz,1H).m / z:450.30[M+H] + ,448.10[MH] - .

[0060] Step 2: Preparation of 1-((3R,5R)-(5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)-N-(benzo[d][1,3]dioxolan-5-ylmethyl)methanamine (Compound 31)

[0061] In a 50 mL round-bottom flask, ((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)4-methylbenzenesulfonic acid methyl ester [intermediate (8)] (70 mg, 2.95 mmol), K2CO3 (53 mg, 3.8 mmol) and 10 mL of N-methylpyrrolidone (NMP) were added, stirred and mixed, and 3,4-methylenediamine was added dropwise. Oxybenzylamine solution (49 mg, 3.54 mmol) was stirred in an oil bath at 80°C for 5 h. The reaction was monitored by TLC. After cooling, the mixture was extracted three times with ethyl acetate (10 mL*3), and the organic layer was washed three times with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (eluent: DCM:MeOH=15:1) to obtain 71 mg of a white solid (yield: 60%). The compound was analyzed by hydrogen nuclear magnetic resonance (H NMR) spectrum ( 1 H NMR) and LC-MS characterization data are shown in Table 1.

[0062] Example 5: Preparation of 1-((2R,4R)-4-((Benzo[d][1,3]dioxolan-5-yloxy)methyl)-2-(2,4-difluorophenyl)tetrahydrofuran-2-yl)methyl)-1H-1,2,4-triazole (Compound 32)

[0063] Sesamol (30 mg, 1.97 mmol) was added to a round-bottom flask containing 8 mL of DMF. Under an ice bath, NaH (14 mg, 0.58 mmol) was slowly added, stirred for 0.5 h, and then ((3S, 5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)4-methylbenzenesulfonic acid methyl ester [Intermediate (8)] (80 mg, 0.17 mmol) was added. The mixture was subjected to microwave reaction for 3 h. The microwave reactor was set to a temperature of 90° C. and a maximum output power of 100 W. After the reaction was completed, the mixture was extracted three times with ethyl acetate (10 mL*3), and the organic layer was washed three times with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column (eluent: EA:PE=2:1) ​​to obtain 60 mg of a colorless oil (yield: 85%). The H NMR spectrum of this compound ( 1 H NMR) and LC-MS characterization data are shown in Table 1.

[0064] Example 6: The azole compounds synthesized by the present invention have antifungal effects, and the pharmacological test results are as follows:

[0065] (I) Experimental method: conventional in vitro antibacterial experimental method

[0066] 1. Preparation of bacterial suspension: Candida albicans was activated by culturing in YEPD liquid medium at 35°C for 16 hours to make the fungus in the late logarithmic growth phase. The fungi were counted using a hemocytometer and the bacterial concentration was adjusted to 10 with RPMI 1640 liquid medium. 3 Pieces / mL.

[0067] 2. Preparation of the test solution: The test compound of the present invention was dissolved in dimethyl sulfoxide to prepare a 6.4 mg / mL drug storage solution, which was diluted to 320 μg / mL with RPMI1640 before the experiment, and then diluted 10 times to a multiple of 10 concentrations.

[0068] 3. Plate laying and drug addition: 200μL of RPM1640 was added to well 1 of the 96-well plate as a blank control; 100μL of bacterial suspension was added to wells 3 to 12, and 180μL of bacterial suspension and 20μL of drug solution were added to well 2. The drug concentrations of wells 2 to 11 were diluted in 10 steps, and the final drug concentrations of each well were 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, and 0.0625μg / mL, respectively. No drug solution was added to well 12 as a positive control, and fluconazole was used as the control drug.

[0069] 4. Culture and detection: Incubate at 35°C for 24 hours and measure OD with an enzyme-labeled instrument 630 , the optical density value (OD value) of the positive control well is set as 100%, and the lowest drug concentration with an optical density value lower than 50% of the positive control well is the minimum inhibitory concentration (MIC). When the MIC is higher than the highest concentration of 32μg / mL, it is counted as ">32μg / mL". If the MIC is the lowest concentration or below the lowest concentration, it is counted as "MIC≤0.0625μg / mL". If the MIC of the test compound is ≤0.0625μg / mL, the final drug concentrations of each well are 4, 2, 1, 0.5, 0.25, 0.125, 0.0625, 0.0312, 0.0156, and 0.008μg / mL for further testing. If the MIC is the lowest concentration or below the lowest concentration, no distinction is made and it is counted as "MIC≤0.008μg / mL".

[0070] (II) Experimental results

[0071] The results of the in vitro antifungal test of the compounds are shown in Table 2.

[0072] Table 2 Minimum inhibitory concentration (MIC, μg / mL) of the compounds against fungi in vitro

[0073]

[0074]

[0075] The above experimental results show that most of the compounds of the present invention have good antifungal activity characteristics, and some compounds have better inhibition on Candida albicans than the positive drug fluconazole, and have excellent antifungal activity.

[0076] The above is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several changes and improvements without departing from the inventive concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. An azole antifungal compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: The compound comprises a general formula (I) or (II), wherein the compound of the general formula (I) or (II) contains a structure of triazole or tetrazole and a difluorophenyl group. wherein X is selected from a C atom or a N atom; Y is selected from a methyl group or a H atom; Z is selected from -NH- or an O atom; When the compound is of general formula (I), R is selected from 3-[3,4-(methylenedioxy)phenyl]acryloyl, 3-[3,4-(methylenedioxy)phenyl]propionyl, 3-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)acryloyl, 1,4-benzodioxane-6-acryloyl, 3-(2,3-dihydrobenzofuran-5-yl)acryloyl, 3-hydroxy-4-methoxycinnamoyl, 4-hydroxy-3-methoxycinnamoyl, 3,4-dimethoxycinnamoyl; the carbon atom marked with * is a chiral carbon atom or an achiral carbon atom; When the compound is of the general formula (II), R is selected from 3,4-(methylenedioxy)phenethyl, 3,4-(methylenedioxy)benzyl, and 3,4-(methylenedioxy)phenyl; the carbon atom marked with * is a chiral carbon atom or an achiral carbon atom.

2. The azole antifungal compound, its optical isomer or its pharmaceutically acceptable salt according to claim 1, characterized in that: The compound (I) or (II) includes any one or a mixture of optical isomers.

3. The azole antifungal compound, its optical isomer or its pharmaceutically acceptable salt according to any one of claims 1 to 2, characterized in that: When the compound is of general formula (I), R is selected from 3-[3,4-(methylenedioxy)phenyl]acryloyl, 3-[3,4-(methylenedioxy)phenyl]propionyl, 3-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)acryloyl, 1,4-benzodioxane-6-acryloyl, 3-(2,3-dihydrobenzofuran-5-yl)acryloyl, 3-hydroxy-4-methoxycinnamoyl, 4-hydroxy-3-methoxycinnamoyl, and 3,4-dimethoxycinnamoyl.

4. The azole antifungal compound, its optical isomer or its pharmaceutically acceptable salt according to any one of claims 1 to 2, characterized in that: The compound structure is one of the following:

5. The azole antifungal compound, its optical isomer or its pharmaceutically acceptable salt according to claim 4, characterized in that: The pharmaceutically acceptable salt is hydrochloride, acetate, oxalate, sulfate, bisulfate, hydrobromide, methanesulfonate or citrate.

6. Use of an azole antifungal compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the preparation of an antifungal drug.

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