Antifungal azole derivatives, methods for their synthesis and use

Abstract

The application discloses an antifungal azole derivative, a synthesis method and application thereof, and has a general formula shown in formula (I). The azole derivative is synthesized by recombination of fluconazole and ketoconazole structural units, and the application of the azole derivative provided by the application is the application in preparation of antifungal drugs. The azole derivative synthesized by the application is superior to fluconazole (FLC) in inhibiting effect on Candida albicans, and the MIC 50 value can be as low as 0.0218 μg / mL, thereby providing a new direction for research and preparation of an antifungal drug for Candida albicans.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of chemical synthesis, and particularly relates to an antifungal azole derivative and a synthesis method and application thereof. BACKGROUND

[0002] Candida albicans is a diploid polymorphic yeast human microbiome member commonly found in the gastrointestinal tract, respiratory tract and urogenital tract of humans, and is the main cause of invasive candidiasis and the main cause of hospital-acquired infections. Candida albicans is extremely harmful to the human body, and the mortality rate of adults infected with Candida albicans is as high as 40% to 70%. With the use of various medical devices, the risk of infection caused by Candida albicans is also gradually increasing. Currently, azole drugs are widely used in clinical practice, such as fluconazole and ketoconazole, which are both azole antifungal drugs, used for the treatment and prevention of superficial and systemic fungal infections, and can selectively interfere with the activity of cytochrome P-450, thereby inhibiting the biosynthesis of ergosterol on the fungal cell membrane. However, with the long-term and widespread use of antifungal drugs, drug resistance problems have become increasingly prominent, and therefore there is an urgent need to develop new highly effective antifungal drugs.

[0003] The application aims to provide a new class of antifungal azole derivatives. SUMMARY

[0004] A first object of the application is to provide an antifungal azole derivative, a second object of the application is to provide a synthesis method of the antifungal azole derivative, and a third object of the application is to provide an application of the antifungal azole derivative.

[0005] The first object of the application is achieved by an antifungal azole derivative having the general formula shown in formula (I):

[0006]

[0007] In formula (I), R represents a hydrocarbon group, an acyl group or a sulfonyl group;

[0008] The hydrocarbon group is

[0009] The acyl group is

[0010] The sulfonyl group is

[0011] The second object of the application is achieved by a synthesis method of the antifungal azole derivative, which is specifically implemented according to the following steps:

[0012] 1) stirring the mixture of N-acetyl-N'-(4-hydroxyphenyl)piperazine and 1,2-dibromoethane in acetonitrile and K2CO3 at 80-100 °C for 12-48 h, adding 10% aqueous base solution with the concentration of 10% and stirring for 10-30 min, extracting with dichloromethane for 3-4 times, combining the dichloromethane layers, drying over anhydrous sodium sulfate and concentrating under reduced pressure, and subjecting the crude product to column chromatography with dichloromethane:methanol (100:1-100:1.5 by volume) as the eluent to obtain compound 1; wherein the molar ratio of N-acetyl-N'-(4-hydroxyphenyl)piperazine, 1,2-dibromoethane and K2CO3 is 1:2-5:1-3, and the volume of acetonitrile added per mole of N-acetyl-N'-(4-hydroxyphenyl)piperazine is 2-5 L; and the volume ratio of acetonitrile and 10% aqueous base solution is 5:0.2-1;

[0013] 2) stirring phthalimide and K2CO3 in DMF at 50-80 °C for 1-2 h to obtain potassium phthalimide salt, adding compound 1 obtained in step 1) and stirring at 70-90 °C for 2-4 h; dissolving in dichloromethane and washing with water for 3 times, drying the dichloromethane layer over anhydrous sodium sulfate and concentrating under reduced pressure to obtain compound 2; wherein the molar ratio of phthalimide, K2CO3 and compound 1 is 1.2-3:1.5-4:1;

[0014] 3) adding anhydrous ethanol and 80% hydrazine hydrate to compound 2, stirring at 40-60 °C for 2-5 h, concentrating under reduced pressure, adding water, and extracting with dichloromethane for 3 times. Combining the dichloromethane layers, drying over anhydrous sodium sulfate and concentrating under reduced pressure, and subjecting to silica gel column chromatography with dichloromethane:methanol (100:1-100:1.5 by volume) as the eluent to obtain compound 3; wherein the molar ratio of compound 2 and hydrazine hydrate is 1:1.5-5, and the volume of anhydrous ethanol added per mole of compound 2 is 2-5 L; and the volume ratio of dichloromethane and water is 0.5-1:1;

[0015] 4) stirring 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone in 10-25% KOH or NaOH aqueous solution and toluene with trimethylsulfoxonium iodide at 40-70°C for 12-24h, adding dichloromethane, washing with water for 3 times, drying the dichloromethane layer with anhydrous sodium sulfate, and concentrating under reduced pressure, and then performing silica gel column chromatography with petroleum ether: ethyl acetate (1:1) as eluent to obtain compound 4; the molar ratio of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone to trimethylsulfoxonium iodide is 1:1-1.5, the volume of KOH or NaOH aqueous solution added per mole of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone is 0.4-1L; the volume ratio of KOH or NaOH aqueous solution to toluene is 1:2-5; the volume ratio of dichloromethane to toluene in extraction is 1-2:1.

[0016] 5) mixing compound 3 and compound 4, adding anhydrous ethanol and triethylamine, reacting at 50-85°C for 10-24h, adding water, stirring for 10-30min, extracting with dichloromethane for 3 times, combining the dichloromethane layers, drying with anhydrous sodium sulfate, concentrating under vacuum, and then performing silica gel column chromatography with dichloromethane:methanol (100:1-100:2) as eluent to obtain compound 5; wherein the molar ratio of compound 3, compound 4 and triethylamine is 1.2-2:1:0.2-1, and the volume of anhydrous ethanol added per mole of compound 4 is 4-5L; the volume ratio of anhydrous ethanol to water is 1:1-2.

[0017] 6) reacting the R-X compound with compound 5 obtained in step 5) to obtain target compounds 6a-6v;

[0018] The R-X compound is a halogenated hydrocarbon compound, an acyl halide compound or a sulfonyl chloride compound; R represents a hydrocarbon group, an acyl group or a sulfonyl group;

[0019] The hydrocarbon group is

[0020] The acyl group is

[0021] The sulfonyl group is

[0022] The third object of the present application is achieved in that the application of the azole derivative is the application in the preparation of an antifungal drug.

[0023] The present application synthesizes and prepares a new azole derivative by recombination of the structural units of fluconazole and ketoconazole (the synthesis route is as shown in Figure 21), the inhibitory effect of the synthetic azole derivatives on Candida albicans is mostly better than FLC, and the MIC 50 The value can be as low as 0.0218 μg / mL, which provides a new direction for the research and preparation of anti-Candida albicans drugs. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 The H NMR spectrum of compound 6a is as follows: 1 The H NMR spectrum of compound 6a is as follows:

[0025] Figure 2 The H NMR spectrum of compound 6b is as follows: 1 The H NMR spectrum of compound 6b is as follows:

[0026] Figure 3 The H NMR spectrum of compound 6b is as follows: 13 The H NMR spectrum of compound 6b is as follows:

[0027] Figure 4 The H NMR spectrum of compound 6e is as follows: 1 The H NMR spectrum of compound 6e is as follows:

[0028] Figure 5 The H NMR spectrum of compound 6e is as follows: 13 The H NMR spectrum of compound 6e is as follows:

[0029] Figure 6 The H NMR spectrum of compound 6f is as follows: 1 The H NMR spectrum of compound 6f is as follows:

[0030] Figure 7 The H NMR spectrum of compound 6f is as follows: 13 The H NMR spectrum of compound 6f is as follows:

[0031] Figure 8 The H NMR spectrum of compound 6g is as follows: 1 The H NMR spectrum of compound 6g is as follows:

[0032] Figure 9 The H NMR spectrum of compound 6g is as follows: 13 The H NMR spectrum of compound 6g is as follows:

[0033] Figure 10 The H NMR spectrum of compound 6n is as follows: 1 The H NMR spectrum of compound 6n is as follows:

[0034] Figure 11 The H NMR spectrum of compound 6n is as follows: 13 The H NMR spectrum of compound 6n is as follows:

[0035] Figure 12 The H NMR spectrum of compound 6p is as follows: 1 The H NMR spectrum of compound 6p is as follows:

[0036] Figure 13 The H NMR spectrum of compound 6p is as follows: 13 The H NMR spectrum of compound 6p is as follows:

[0037] Figure 14 is compound 6r 1 H NMR spectrum;

[0038] Figure 15 is compound 6r 13 C NMR spectrum;

[0039] Figure 16 is compound 6s 1 H NMR spectrum;

[0040] Figure 17 is compound 6s 13 C NMR spectrum;

[0041] Figure 18 is compound 6t 1 H NMR spectrum;

[0042] Figure 19 is compound 6t 13C NMR spectrum;

[0043] Figure 20 is compound 6v 1H NMR spectrum;

[0044] Figure 21 is compound 6v 13C NMR spectrum. DETAILED DESCRIPTION

[0045] The present application will be further described in conjunction with the following examples, but not in any way limited thereto, any transformation or replacement based on the teaching of the present application shall fall within the protection scope of the present application.

[0046] The present application is an anti-fungal azole derivative, having the general formula shown in formula (I):

[0047]

[0048] In formula (I), R represents a hydrocarbon group, an acyl group or a sulfonyl group;

[0049] The hydrocarbon group is

[0050] The acyl group is

[0051] The sulfonyl group is

[0052] The present application also provides a synthesis method of the anti-fungal azole derivative, which is realized according to the following steps:

[0053] 1) stirring the mixture of N-acetyl-N'-(4-hydroxyphenyl)piperazine and 1,2-dibromoethane in acetonitrile and K2CO3 at 80-100 °C for 12-48 h, adding 10% aqueous base solution with a concentration of 10% stirring for 10-30 min, extracting with dichloromethane for 3-4 times, combining the dichloromethane layers, drying over anhydrous sodium sulfate and then concentrating under reduced pressure, and subjecting the crude product to column chromatography with dichloromethane:methanol (100:1-100:1.5 by volume) as the eluent to obtain compound 1; wherein the molar ratio of N-acetyl-N'-(4-hydroxyphenyl)piperazine, 1,2-dibromoethane and K2CO3 is 1:2-5:1-3, and the volume of acetonitrile added per mole of N-acetyl-N'-(4-hydroxyphenyl)piperazine is 2-5 L; the volume ratio of acetonitrile and 10% aqueous base solution is 5:0.2-1;

[0054] 2) stirring phthalimide and K2CO3 in DMF at 50-80 °C for 1-2 h to obtain potassium phthalimide salt, adding compound 1 obtained in step 1) and stirring at 70-90 °C for 2-4 h; dissolving in dichloromethane and washing with water for 3 times, drying the dichloromethane layer over anhydrous sodium sulfate and then concentrating under reduced pressure to obtain compound 2; wherein the molar ratio of phthalimide, K2CO3 and compound 1 is 1.2-3:1.5-4:1;

[0055] 3) adding anhydrous ethanol and 80% hydrazine hydrate to compound 2, stirring at 40-60 °C for 2-5 h, concentrating under reduced pressure, adding water, and extracting with dichloromethane for 3 times. Combining the dichloromethane layers, drying over anhydrous sodium sulfate and concentrating under reduced pressure, and then subjecting to silica gel column chromatography with dichloromethane:methanol (100:1-100:1.5 by volume) as the eluent to obtain compound 3; wherein the molar ratio of compound 2 and hydrazine hydrate is 1:1.5-5, and the volume of anhydrous ethanol added per mole of compound 2 is 2-5 L; the volume ratio of dichloromethane and water is 0.5-1:1;

[0056] 4) 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone is stirred with trimethylsulfoxonium iodide in 10-25% KOH or NaOH aqueous solution and toluene at 40-70°C for 12-24 h, after adding dichloromethane, washing with water for 3 times. The dichloromethane layer is dried with anhydrous sodium sulfate and concentrated under reduced pressure, and then subjected to silica gel column chromatography with petroleum ether: ethyl acetate (1:1, by volume) as eluent to obtain compound 4; the molar ratio of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone to trimethylsulfoxonium iodide is 1:1-1.5, the volume of KOH or NaOH aqueous solution added per mole of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone is 0.4-1 L; the volume ratio of KOH or NaOH aqueous solution to toluene is 1:2-5; the volume ratio of dichloromethane to toluene in extraction is 1-2:1.

[0057] 5) After mixing compound 3 and compound 4, adding anhydrous ethanol and triethylamine, stirring at 50-85°C for 10-24 h, adding water and stirring for 10-30 min, extracting with dichloromethane for 3 times, combining the dichloromethane layers, drying with anhydrous sodium sulfate, vacuum concentration, and then subjecting to silica gel column chromatography with dichloromethane:methanol (100:1-100:2, by volume) as eluent to obtain compound 5; wherein the molar ratio of compound 3, compound 4 and triethylamine is 1.2-2:1:0.2-1, the volume of anhydrous ethanol added per mole of compound 4 is 4-5 L; the volume ratio of anhydrous ethanol to water is 1:1-2.

[0058] 6) reacting the R-X compound with compound 5 obtained in step 5) to obtain target compounds 6a-6v;

[0059] The R-X compound is a halogenated hydrocarbon compound, an acyl halide compound or a sulfonyl chloride compound; R represents a hydrocarbon group, an acyl group or a sulfonyl group;

[0060] The hydrocarbon group is

[0061] The acyl group is

[0062] The sulfonyl group is

[0063] In step 2), the aqueous alkaline solution is sodium hydroxide aqueous solution, sodium carbonate aqueous solution, potassium carbonate aqueous solution or potassium hydroxide aqueous solution.

[0064] In step 2), the stirring speed is 300-600 rpm.

[0065] When the R-X compound is a halogenated hydrocarbon compound, the step 6) is specifically as follows: after mixing the compound 5 and the halogenated hydrocarbon compound, dichloromethane and a base are added, the reaction is stirred at room temperature for 2-12 h, water is added and stirred for 10-30 min, dichloromethane is extracted for 3-4 times, the dichloromethane layers are combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then column chromatography on silica gel is performed with dichloromethane:methanol (200:1-100:1, by volume) as the eluent to obtain the target compound 6a-6j;

[0066] The molar ratio of the compound 5, the halogenated hydrocarbon compound and the base is 1:1.2-2:1.5-3, and the volume of dichloromethane added per mole of the compound 5 is 3-5 L; the volume ratio of dichloromethane to water is 1:1-1.5.

[0067] When the R-X compound is an acyl halide compound, the step 6) is specifically as follows: dichloromethane is added to the compound 5, a base is added under stirring in an ice bath, and then the acyl halide compound is added, the reaction is performed for 0.5-5 h, water is added and stirred for 10-30 min, dichloromethane is extracted for 3-4 times, the dichloromethane layers are combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then column chromatography on silica gel is performed with dichloromethane:methanol (200:1, by volume) as the eluent to obtain the compound 6k-6o.

[0068] The molar ratio of the compound 5, the acyl halide compound and the base is 1:1.2-2:1.5-3, and the volume of dichloromethane added per mole of the compound 5 is 3-5 L; the volume ratio of dichloromethane to water is 1:1-1.5.

[0069] When the R-X compound is a sulfonyl chloride compound, the step 6) is specifically as follows: dichloromethane is added to the compound 5, a base is added under stirring in an ice bath, and then the sulfonyl chloride compound is added, the reaction is performed for 1-5 h, water is added and stirred for 10-30 min, dichloromethane is extracted for 3-4 times, the dichloromethane layers are combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then column chromatography on silica gel is performed with dichloromethane:methanol (200:1-100:1, by volume) as the eluent to obtain the compound 6p-6v.

[0070] The molar ratio of the compound 5, the sulfonyl chloride compound and the base is 1:1.2-2:1.5-3, and the volume of dichloromethane added per mole of the compound 5 is 3-5 L; the volume ratio of dichloromethane to water is 1:1-1.5.

[0071] The base is triethylamine, diisopropylethylamine, sodium carbonate or potassium carbonate.

[0072] The application further provides use of the azole derivative in the preparation of an antifungal drug.

[0073] The fungus is Candida albicans.

[0074] The instruments and reagents used in the examples and detection examples of the present application are as follows: 400MHz or 500MHz nuclear magnetic resonance spectrometer (Bruker Company, Germany), RCT basic type magnetic stirrer, SHZ-D III circulating water vacuum pump, N-1100 rotary evaporator, BSM-120.4 electronic balance, fluconazole sensitive Candida albicans SC5314 purchased from American Type Culture Collection (ATCC). SC5314 is induced into resistant Candida albicans SC5314FR by FLC long-term treatment. Raw materials and reagents are commercially available and are of analytical purity.

[0075] Synthesis of compound 1 in example 1

[0076] Weigh 4.4g (20mmol) N-acetyl-N'-(4-hydroxyphenyl)piperazine and 5.5g (60mmol) potassium carbonate into a 100mL round-bottom flask, add 50mL acetonitrile and 8.6mL (100mmol) dibromoethane in turn, and react at 90℃ for 48h. After detecting the completion of the reaction by TLC, add 25mL of 10% sodium hydroxide aqueous solution to the reaction mixture and stir for 10min, extract with dichloromethane (3×25mL) three times, combine the dichloromethane layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is subjected to silica gel column chromatography with dichloromethane:methanol (volume ratio of 100:1 to 100:1.5) as the eluent to obtain 3.7g of white solid, which is compound 1, with a yield of 57%.

[0077] Synthesis of compound 2 in example 2

[0078] Weigh 1.94g (13.2mmol) phthalimide and 2.28g potassium carbonate (16.5mmol) into a 100mL round-bottom flask, add 15mL DMF, stir at 60℃ for 1h to obtain phthalimide potassium salt, then add 3.7g (11mmol) compound 1 prepared in example 1, and stir at 80℃ for 3h. After detecting the completion of the reaction by TLC, add 100mL dichloromethane to the reaction mixture, wash with water (3×100mL) three times, dry the dichloromethane layer over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 4.2g of light yellow solid, which is compound 2, with a yield of 97%.

[0079] Synthesis of compound 3 in example 3

[0080] To 4.2 g (10.7 mmol) of compound 2 prepared in example 2 was added 50 mL of absolute ethanol and 80% hydrazine hydrate 1.38 g (16 mmol) and stirred at 50 °C for 3 h. After completion of the reaction as monitored by TLC, it was concentrated under reduced pressure, 100 mL of water was added and extracted with dichloromethane (3 x 100 mL), the combined dichloromethane layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was column chromatographed using silica gel with dichloromethane: methanol (100:1 by volume) as eluent to get 2.1 g of compound 3 as white solid in 83% yield.

[0081] Example 4: Synthesis of compound 4

[0082] To 1.12 g (5 mmol) of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol)ethanone and 1.10 g (5 mmol) of trimethylsulfoxonium iodide in 100 mL round bottom flask was added 5 mL of 20% aqueous KOH solution, 25 mL of toluene and stirred at 60 °C for 16 h. After completion of the reaction as monitored by TLC, 30 mL of dichloromethane was added, washed with water (3 x 100 mL), the dichloromethane layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was column chromatographed using silica gel with petroleum ether: ethyl acetate (1:1 by volume) as eluent to get 889 mg of compound 4 as white solid in 75% yield.

[0083] Example 5: Synthesis of compound 5

[0084] To 900 mg (3.75 mmol) of compound 3 and 593 mg (2.5 mmol) of compound 4 in 100 mL round bottom flask was added 10 mL of absolute ethanol and 50 mg (0.5 mmol) of triethylamine and stirred at 75 °C for 12 h. After completion of the reaction as monitored by TLC, 10 mL of water was added and stirred for 10 min, extracted with dichloromethane (3 x 20 mL), the combined dichloromethane layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was column chromatographed using silica gel with dichloromethane: methanol (100:1 by volume) as eluent to get 1037 mg of compound 5 as white solid in 83% yield.

[0085] Example 6: Synthesis of compounds 6a-6j

[0086] Take 100 mg (0.2 mmol) of compound 5 and 0.24 mmol of halogenated hydrocarbon compound into a 5 mL round-bottom flask, add 1 mL of dichloromethane and 52 mg (0.4 mmol) of N, N-diisopropyl ethylamine (DIPEA), stir at room temperature for 12 h. After TLC detection of the completion of the reaction, add 5 mL of water and stir for 10 min, extract with dichloromethane (3 x 5 mL) three times, combine the dichloromethane layers, dry over anhydrous sodium sulfate and concentrate under reduced pressure. The crude product is column chromatographed with dichloromethane: methanol (volume ratio 200: 1) as eluent to obtain compounds 6a-6j, and the structures and yields of compounds 6a-6j are shown in Table 1.

[0087] Compound 6a: 1 H NMR (400 MHz, CDCl3) δ: 8.04 (s, 1H), 7.77 (s, 1H), 7.54-7.58 (m, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H), 6.73-6.79 (m, 4H), 5.20 (s, 1H), 4.44 (d, J = 14.4 Hz, 1H), 3.61-3.79 (m, 4H), 3.06-3.37 (m, 1H), 3.05 (d, J = 5.1 Hz, 1H), 2.82-2.97 (m, 4H), 2.81 (d, J = 5.6 Hz, 1H), 2.71-2.77 (m, 2H), 2.14 (s, 3H).

[0088] Compound 6b: 1 H NMR (400 MHz, CDCl3) δ: 8.05 (s, 1H), 7.76 (s, 1H), 7.52-7.58 (m, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H), 6.71-6.78 (m, 4H), 5.29 (s, 1H), 4.57 (d, J = 14.2 Hz, 1H), 4.41 (d, J = 14.3 Hz, 1H), 3.73-3.79 (m, 4H), 3.64 (t, J = 5.0 Hz, 2H), 3.54 (q, J = 13.8 Hz, 2H), 3.35 (d, J = 14.2 Hz, 1H), 3.03-3.09 (m, 4H), 2.95 (d, J = 14.2 Hz, 1H), 2.69-2.85 (m, 2H), 2.14 (s, 3H); 13C NMR (101 MHz, CDC13) δ: 169.13, 153.01, 151.22, 145.91, 144.91, 136.57, 133.34, 130.17, 128.70, 118.98, 115.38, 73.41, 73.35, 66.22, 59.94, 59.49, 59.45, 56.06, 56.01, 54.64, 51.23, 50.84, 46.55, 41.65, 21.50.

[0089] Compound 6c: 1 H NMR (400 MHz, CDC13) δ: 8.04 (s, 1H), 7.77 (s, 1H), 7.53-7.59 (m, 1H), 6.93-7.02 (m, 1H), 6.90 (d, J = 9.0 Hz, 3H), 6.71-6.80 (m, 5H), 5.21 (s, 1H), 4.58 (d, J = 14.2 Hz, 1H), 4.42 (d, J = 14.3 Hz, 1H), 3.73-3.78 (m, 4H), 3.63 (t, J = 4.9 Hz, 2H), 3.48 (d, J = 2.6 Hz, 2H), 3.34 (d, J = 14.2 Hz, 1H), 3.02-3.30 (m, 5H), 2.93 (d, J = 14.2 Hz, 1H), 2.79-2.84 (m, 1H), 2.68-2.74 (m, 1H), 2.14 (s, 3H); 13 C NMR (101 MHz, CDC13) δ: 169.13, 153.01, 151.22, 145.91, 144.91, 136.57, 133.34, 130.17, 128.70, 118.98, 115.38, 73.41, 73.35, 66.22, 59.94, 59.49, 59.45, 56.06, 56.01, 54.64, 51.23, 50.84, 46.55, 41.65, 21.50.

[0090] Compound 6d: 1H NMR (400 MHz, CDC13) δ: 8.11 (s, 1H), 7.75 (s, 1H), 7.50-7.56 (m, 1H), 6.90 (d, J = 9.1 Hz, 2H), 6.74-6.80 (m, 4H), 5.54-5.64 (m, 1H), 5.37 (s, 1H), 4.98-5.07 (m, 2H), 4.58 (d, J = 14.2 Hz, 1H), 4.47 (d, J = 14.4 Hz, 1H), 3.75 (d, J = 3.5 Hz, 4H), 3.62 (t, J = 4.9 Hz, 2H), 3.27 (d, J = 14.1 Hz, 1H), 3.01-3.06 (m, 1H), 2.99 (d, J = 5.6 Hz, 1H), 2.93 (d, J = 7.4 Hz, 1H), 2.86 (d, J = 14.1 Hz, 1H), 2.72-2.81 (m, 2H), 2.12 (s, 3H); 13 C NMR (101 MHz, CDC13) δ: 169.07, 164.08, 163.96, 161.60, 161.48, 160.29, 160.17, 157.84, 157.72, 153.14, 145.79, 144.85, 133.80, 129.98, 129.89, 129.83, 118.94, 115.36, 111.60, 111.57, 111.39, 111.36, 104.46, 104.20, 103.93, 72.81, 72.75, 66.26, 58.95, 58.92, 58.69, 56.17, 56.12, 54.71, 51.19, 50.80, 46.50, 41.59, 21.44.

[0091] Compound 6e: 1 H NMR (400 MHz, CDC13) δ: 8.03-8.06 (m, 3H), 7.76 (s, 1H), 7.52-7.59 (m, 1H), 7.25-7.27 (m, 2H), 6.89 (d, J = 9.0 Hz, 2H), 6.69-6.77 (m, 4H), 5.20 (s, 1H), 4.61 (d, J = 14.2 Hz, 1H), 4.45 (d, J = 14.4 Hz, 1H), 3.77 (t, J = 5.1 Hz, 4H), 3.60-3.65 (m, 4H), 2.85 (d, J = 8.8 Hz, 1H), 2.73-2.82 (m, 2H), 2.13 (s, 3H); 13C NMR (101 MHz, CDC13) δ: 169.11, 164.22, 164.10, 161.73, 161.61, 160.07, 159.96, 157.62, 157.51, 152.73, 151.33, 147.32, 146.12, 145.99, 130.00, 129.97, 123.67, 118.91, 115.29, 111.82, 111.79, 111.62, 111.59, 104.61, 104.36, 104.09, 74.04, 73.98, 66.01, 60.21, 54.81, 51.11, 50.71, 46.50, 41.60, 21.46.

[0092] Compound 6f: 1 H NMR (400 MHz, CDC13) δ: 8.04 (s, 1H), 7.73 (s, 1H), 7.50-7.56 (m, 1H), 7.33 (d, J = 8.3 Hz, 2H), 6.95 (d, J = 8.3 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 6.69-6.76 (m, 4H), 5.27 (s, 1H), 4.55 (d, J = 14.2 Hz, 1H), 4.40 (d, J = 14.3 Hz, 1H), 3.71-3.76 (m, 4H), 3.61 (t, J = 4.8 Hz, 2H), 3.50 (q, J = 13.8 Hz, 2H), 3.33 (d, J = 14.2 Hz, 1H), 3.01-3.07 (m, 4H), 2.94 (d, J = 14.2 Hz, 1H), 2.68-2.83 (m, 2H), 2.12 (s, 3H); 13 C NMR (101 MHz, CDC13) δ: 169.03, 164.08, 163.96, 161.59, 161.47, 160.08, 159.96, 157.63, 157.51, 152.89, 151.11, 145.81, 144.81, 137.05, 131.54, 130.42, 129.92, 129.86, 129.83, 129.77, 126.03, 125.99, 125.90, 125.86, 121.30, 118.87, 115.29, 111.65, 111.61, 111.44, 111.41, 104.50, 104.25, 103.98, 73.37, 73.31, 66.12, 59.90.59.44, 59.41, 55.96, 55.91, 54.55, 51.11, 50.72, 46.45, 41.55, 21.41.

[0093] Compound 6g: 1 H NMR (400 MHz, CDC13) δ: 8.05 (s, 1H), 7.75 (s, 1H), 7.52-7.58 (m, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 9.0 Hz, 2H), 6.68-6.78 (m, 4H), 5.27 (s, 1H), 4.59 (d, J = 14.2 Hz, 1H), 4.43 (d, J = 14.3 Hz, 1H), 3.74-3.78 (m, 4H), 3.59-3.63 (m, 4H), 3.37 (d, J = 14.2 Hz, 1H), 3.03-3.09 (m, 4H), 2.98 (d, J = 14.2 Hz, 1H), 2.71-2.87 (m, 2H), 2.14 (s, 3H); 13 C NMR (101 MHz, CDC13) δ: 169.11, 164.18, 161.70, 157.67, 152.94, 151.26, 145.93, 144.92, 142.37, 130.02, 129.92, 192.57, 128.94, 125.98, 125.85, 125.55, 125.45, 125.42, 125.38, 122.84, 118.96, 115.35, 111.77, 111.74, 111.57, 111.53, 104.59, 104.33, 104.07, 73.68, 73.63, 66.19, 60.27, 59.69, 59.66, 55.95, 55.90, 54.84, 51.18, 50.79, 46.52, 41.62, 21.47.

[0094] Compound 6h: 1 H NMR (400 MHz, CDC13) δ: 8.07 (s, 1H), 7.75 (s, 1H), 7.46-7.52 (m, 1H), 6.89 (d, J = 9.1 Hz, 2H), 6.73-6.80 (m, 4H), 5.11 (s, 1H), 4.60 (q, J = 14.2 Hz, 2H), 3.73-3.80 (m, 4H), 3.60 (t, J = 10.0 Hz, 2H), 3.40 (d, J = 14.4 Hz, 1H), 3.24 (d, J = 17.6 Hz, 1H), 3.00-3.10 (m, 4H), 2.82-2.89 (m, 3H), 2.15 (s, 1H), 2.11 (s, 3H).

[0095] Compound 6i:1 H NMR (400 MHz, CDC13) δ: 8.19 (s, 1H), 7.72 (s, 1H), 7.57-7.63 (m, 1H), 7.35-7.38 (m, 2H), 6.85 (q, J = 5.7 Hz, 3H), 6.74-6.78 (m, 2H), 6.67 (d, J = 9.0 Hz, 2H), 4.60 (q, J = 14.2 Hz, 2H), 4.05 (d, J = 12.2 Hz, 1H), 3.94 (d, J = 18.8 Hz, 3H), 3.77 (s, 1H), 3.72-3.76 (m, 1H), 3.59-3.70 (m, 3H), 3.01-3.05 (m, 6H), 2.93-3.00 (m, 1H), 2.79-2.85 (m, 1H), 2.13 (s, 3H); 13 C NMR (101 MHz, CDC13) δ: 169.16, 151.03, 149.31, 144.87, 128.55, 122.27, 118.92, 115.23, 110.12, 110.01, 74.03, 73.98, 61.91, 56.27, 56.22, 56.12, 54.13, 51.22, 50.86, 46.52, 41.62, 21.51.

[0096] Compound 6j: 1 H NMR (500 MHz, CDC13) δ: 8.17 (s, 1H), 7.80 (s, 1H), 7.64 (q, J = 8.9 Hz, 1H), 6.80-6.88 (m, 4H), 6.73-6.78 (m, 2H), 6.68 (s, 1H), 6.63 (q, J = 10.4 Hz, 1H), 6.37 (d, J = 1.8 Hz, 1H), 6.34 (d, J = 1.8 Hz, 1H), 5.75 (q, J = 1.8 Hz, 2H), 4.60-4.68 (m, 1H), 4.18 (d, J = 14.6 Hz, 1H), 3.91-3.96 (m, 2H), 3.71-3.77 (m, 4H), 3.60-3.69 (m, 2H), 3.46-3.51 (m, 1H), 3.01-3.07 (m, 4H), 2.13 (s, 3H).

[0097] Synthesis of compounds 6k-6o of Example 7

[0098] Take 100 mg (0.2 mmol) of compound 5 into a 5 mL round-bottom flask, add 1 mL of dichloromethane, add 40 mg (0.5 mmol) of triethylamine under stirring in an ice bath, then add 0.24 mmol of acyl halide compound, and react for 1 h. After the reaction is completed as detected by TLC, add 5 mL of water and stir for 10 min, extract with dichloromethane three times (5 mL x 3), combine the dichloromethane layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is subjected to column chromatography with dichloromethane:methanol (volume ratio 200:1) as the eluent to obtain compounds 6k-6o, the structures and yields of which are shown in Table 1.

[0099] Compound 6k: 1 H NMR (500 MHz, CDC13) δ: 8.19 (s, 1H), 7.85 (s, 1H), 7.70 (q, J = 8.7 Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 6.83-6.90 (m, 4H), 6.69 (d, J = 8.9 Hz, 2H), 6.32 (s, 1H), 4.70 (s, 2H), 4.16 (d, J = 14.6 Hz, 1H), 4.01 (d, J = 14.7 Hz, 1H), 3.93 (s, 1H), 3.75-3.91 (m, 3H), 3.60-3.69 (m, 3H), 3.44 (d, J = 15.0 Hz, 1H), 3.01-3.06 (m, 4H), 2.13 (s, 3H); 13 C NMR (101 MHz, CDC13) δ: 174.21, 169.14, 151.66, 146.22, 145.03, 139.19, 130.61, 127.21, 125.77, 118.92, 115.26, 112.08, 111.93, 104.29, 65.25, 56.69, 53.90, 51.14.50.81, 50.73, 46.52, 41.62, 21.46.

[0100] Compound 6k: 1H NMR (500 MHz, CDC13) δ: 8.18 (s, 1H), 7.84 (s, 1H), 7.66-7.73 (m, 1H), 7.30-7.32 (m, 2H), 6.84-6.90 (m, 4H), 6.70 (d, J = 8.9 Hz, 2H), 6.39 (s, 1H), 4.72-4.77 (m, 2H), 4.31 (d, J = 14.7 Hz, 1H), 4.23 (q, J = 14.9 Hz, 1H), 3.95 (d, J = 15.3 Hz, 2H), 3.77 (t, J = 5.0 Hz, 3H), 3.62 (t, J = 5.0 Hz, 2H), 3.47-3.50 (m, 2H), 3.01-3.06 (m, 5H), 2.13 (s, 3H); 13 CNMR (101 MHz, CDC13) δ: 169.13, 152.84, 151.58, 146.09, 144.96, 130.73, 129.68, 128.74, 127.24, 118.97, 115.27, 65.55, 56.78, 53.78, 51.23, 50.82, 49.84, 46.54, 41.64, 21.47.

[0101] Compound 6m: 1 H NMR (500 MHz, CDC13) δ: 8.20 (s, 1H), 7.84 (s, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.31 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 6.84-6.90 (m, 4H), 6.68 (d, J = 8.5 Hz, 2H), 6.39 (s, 1H), 4.68 (s, 2H), 4.14 (d, J = 14.6 Hz, 1H), 3.98 (d, J = 14.5 Hz, 1H), 3.89 (s, 3H), 3.69-3.77 (m, 4H), 3.62 (t, J = 5.0 Hz, 2H), 3.42 (d, J = 14.1 Hz, 1H), 3.01-3.07 (m, 2H), 2.12 (s, 3H); 13 CNMR (101 MHz, CDC13) δ: 169.14, 151.59, 146.16, 145.03, 136.14, 129.02, 128.25, 118.95, 115.28, 112.05, 111.90, 65.43.54.20, 51.19, 50.78, 46.53, 41.63, 21.46.

[0102] Compound 6n: 1H NMR (500 MHz, CDC13) δ: 8.16 (s, 1H), 7.84 (s, 1H), 7.63 (q, J = 9.0 Hz, 1H), 6.81-6.89 (m, 5H), 6.67-6.69 (m, 2H), 5.90 (s, 1H), 4.82 (d, J = 14.1 Hz, 1H), 4.64 (d, J = 14.1 Hz, 1H), 4.27 (d, J = 14.3 Hz, 1H), 3.96-3.99 (m, 1H), 3.85-3.87 (m, 2H), 3.77 (t, J = 5.0 Hz, 2H), 3.60-3.66 (m, 4H), 3.00-3.06 (m, 4H), 2.12 (s, 3H); 13 C NMR (101 MHz, CDC13) δ: 169.13, 168.93, 152.84, 151.62, 146.05, 144.90, 134.53, 131.68, 131.05, 128.72, 128.28, 118.93, 115.34, 65.92, 51.24, 50.83, 50.20, 46.55, 41.65, 21.47.

[0103] Compound 6o: 1 H NMR (500 MHz, CDC13) δ: 8.16 (s, 1H), 7.83 (s, 1H), 7.70 (q, J = 6.5 Hz, 1H), 7.32-7.34 (m, 1H), 7.28 (d, J = 1.5 Hz, 1H), 6.82-6.89 (m, 4H), 6.72-6.80 (m, 2H), 6.28 (s, 1H), 4.81 (q, J = 14.2 Hz, 2H), 4.38 (d, J = 14.7 Hz, 1H), 4.05 (d, J = 15.3 Hz, 1H), 3.90-3.93 (m, 2H), 3.77 (t, J = 5.1 Hz, 2H), 3.56-3.62 (m, 3H), 3.40-3.45 (m, 1H), 3.00-3.06 (m, 4H), 2.13 (s, 3H); 13 C NMR (101 MHz, CDC13) δ: 169.13, 168.93, 152.84, 151.62, 146.05, 144.90, 134.53, 131.68, 131.05, 128.72, 128.28, 118.93, 115.34, 65.92, 51.24, 50.83, 50.20, 46.55, 41.65, 21.47.

[0104] Synthesis of compounds 6p-6v of Example 8

[0105] Take 100 mg (0.2 mmol) of compound 5 into a 5 mL round-bottom flask, add 1 mL of dichloromethane, add 40 mg (0.5 mmol) of triethylamine under stirring in an ice bath, then add 0.24 mmol of sulfonyl chloride compound, and react for 3-5 h. After the reaction is completed as detected by TLC, add 5 mL of water and stir for 10 min, extract with dichloromethane three times (5 mL x 3), combine the dichloromethane layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is subjected to column chromatography with dichloromethane:methanol (volume ratio 200:1) as the eluent to obtain compounds 6p-6v, the structures and yields of which are shown in Table 1.

[0106] Compound 6p: 1 H NMR (400 MHz, CDCl3) δ: 7.95 (s, 1H), 7.79 (s, 1H), 7.66 (q, J = 8.8 Hz, 4H), 7.44-7.51 (m, 1H), 6.87 (d, J = 9.1 Hz, 2H), 6.75-6.80 (m, 2H), 6.72 (d, J = 9.0 Hz, 2H), 5.42 (s, 1H), 5.05 (d, J = 14.6 Hz, 1H), 4.78 (d, J = 14.5 Hz, 1H), 4.16-4.22 (m, 1H), 4.01-4.10 (m, 2H), 3.78 (t, J = 5.0 Hz, 2H), 3.68-3.71 (m, 1H), 3.60-3.64 (m, 3H), 3.36 (d, J = 15.2 Hz, 1H), 3.02-3.08 (m, 4H), 3.13 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ: 169.12, 152.51, 151.91, 146.06, 144.57, 137.70, 132.67, 129.02, 128.32, 118.90, 115.35, 111.93, 104.45, 66.55, 56.00, 55.21, 55.15, 51.14, 50.77, 50.59, 46.51, 41.61, 21.49.

[0107] Compound 6q: 1H NMR (400 MHz, CDC13) δ: 7.96 (s, 1H), 7.78 (s, 1H), 7.74 (d, J = 8.9 Hz, 2H), 7.46-7.52 (m, 1H), 6.97 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 6.75-6.78 (m, 4H), 5.43 (s, 1H), 5.00 (d, J = 14.6 Hz, 1H), 4.80 (d, J = 14.6 Hz, 1H), 4.08-4.21 (m, 2H), 4.03 (d, J = 15.0 Hz, 1H), 3.85 (s, 3H), 3.78 (t, J = 4.8 Hz, 2H), 3.61-3.68 (m, 3H), 3.44-3.51 (m, 1H), 3.29 (d, J = 15.2 Hz, 1H), 3.02-3.08 (m, 4H), 2.14 (s, 3H); 13 C NMR (101 MHz, CDC13) δ: 169.14, 163.49, 151.77, 144.58, 130.39, 129.75, 118.94, 115.52, 114.64, 112.02, 104.65, 67.40, 55.81, 51.24, 50.82, 46.51, 41.61, 21.50.

[0108] Compound 6r: 1 H NMR (400 MHz, CDC13) δ: 7.96 (s, 1H), 7.78 (s, 1H), 7.74 (d, J = 8.9 Hz, 2H), 7.46-7.52 (m, 1H), 6.97 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 6.75-6.78 (m, 4H), 5.43 (s, 1H), 5.00 (d, J = 14.6 Hz, 1H), 4.80 (d, J = 14.6 Hz, 1H), 4.08-4.21 (m, 2H), 4.03 (d, J = 15.0 Hz, 1H), 3.85 (s, 3H), 3.78 (t, J = 4.8 Hz, 2H), 3.61-3.68 (m, 3H), 3.44-3.51 (m, 1H), 3.29 (d, J = 15.2 Hz, 1H), 3.02-3.08 (m, 4H), 2.14 (s, 3H); 13C NMR (101 MHz, CDC13) δ: 169.10, 164.47, 161.97, 161.85, 159.78, 157.45, 157.33, 152.53, 152.06, 145.90, 144.46, 139.78, 136.02, 133.32, 133.23, 131.89, 130.42, 130.36, 130.32, 130.27, 127.41, 123.43, 123.39, 123.30, 123.26, 118.80, 115.10, 112.09, 112.06, 111.88, 111.85, 104.68, 104.42, 65.22, 55.04, 54.97, 54.93, 51.13, 50.76, 48.80, 46.50, 41.60, 21.47.

[0109] Compound 6s: 1 H NMR (400 MHz, CDC13) δ: 7.95 (s, 1H), 7.79-7.83 (m, 3H), 7.45-7.52 (m, 1H), 7.18 (t, J = 17.1 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.74-6.81 (m, 4H), 5.43 (s, 1H), 5.05 (d, J = 14.6 Hz, 1H), 4.79 (d, J = 14.6 Hz, 1H), 4.19-4.23 (m, 1H), 4.06-4.18 (m, 2H), 3.77-4.02 (m, 1H), 3.67-3.76 (m, 1H), 3.58-3.63 (m, 3H), 3.35 (d, J = 15.1 Hz, 1H), 3.02-3.08 (m, 4H), 2.14 (s, 3H); 13 C NMR (101 MHz, CDC13) δ: 169.10, 164.47, 161.97, 161.85, 159.78, 157.45, 157.33, 152.53, 152.06, 145.90, 144.46, 139.78, 136.02, 133.32, 133.23, 131.89, 130.42, 130.36, 130.32, 130.27, 127.41, 123.43, 123.39, 123.30, 123.26, 118.80, 115.10, 112.09, 112.06, 111.88, 111.85, 104.68, 104.42, 65.22, 55.04, 54.97, 54.93, 51.13, 50.76, 48.80, 46.50, 41.60, 21.47.

[0110] Compound 6s: 1H NMR (400 MHz, CDC13) δ: 7.95 (s, 1H), 7.79 (s, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.43-7.51 (m, 3H), 6.87 (d, J = 9.0 Hz, 2H), 6.75-6.79 (m, 2H), 6.72 (d, J = 9.1 Hz, 2H), 5.42 (s, 1H), 5.05 (d, J = 14.6 Hz, 1H), 4.78 (d, J = 14.5 Hz, 1H), 4.16-4.22 (m, 1H), 4.01-4.10 (m, 2H), 3.75-3.77 (m, 2H), 3.68-3.70 (m, 1H), 3.60-3.63 (m, 3H), 3.36 (d, J = 15.1 Hz, 1H), 3.02-3.07 (m, 4H), 3.13 (s, 3H); 13 C NMR (101 MHz, CDC13) δ: 169.12, 164.47, 164.36, 161.98, 161.86, 159.93, 157.59, 157.48, 152.52, 151.90, 146.08, 144.57, 139.84, 137.15, 130.46, 130.41, 130.37, 130.32, 129.68, 128.95, 128.41, 128.32, 123.33, 118.89, 115.35, 112.14, 111.90, 104.45, 104.18, 66.61, 56.02, 55.22, 55.15, 51.13, 50.76, 50.63, 46.51, 41.61, 21.48.

[0111] Compound 6u: 1 H NMR (400 MHz, CDC13) δ: 7.94 (s, 1H), 7.80 (s, 1H), 7.54 (q, J = 9.5 Hz, 1H), 6.75-6.90 (m, 6H), 5.35 (s, 1H), 5.01 (d, J = 14.5 Hz, 1H), 4.68 (d, J = 14.5 Hz, 1H), 4.22-4.28 (m, 1H), 4.05-4.10 (m, 1H), 3.87-3.98 (m, 2H), 3.71-3.77 (m, 3H), 3.56-3.66 (m, 5H), 3.30-3.38 (m, 1H), 3.03-3.18 (m, 5H), 2.27-2.32 (m, 2H), 2.13 (s, 3H).

[0112] Compound 6v: 1H NMR (400 MHz, CDC13) δ: 7.95 (s, 1H), 7.87 (d, J = 9.0 Hz, 2H), 7.80 (s, 1H), 7.47-7.51 (m, 1H), 7.31-7.46 (m, 2H), 6.86 (d, J = 9.1 Hz, 2H), 6.76-6.82 (m, 2H), 6.71 (d, J = 9.0 Hz, 2H), 5.43 (s, 1H), 5.07 (d, J = 14.6 Hz, 1H), 4.78 (d, J = 15.6 Hz, 1H), 4.18-4.24 (m, 1H), 4.04-4.11 (m, 2H), 3.66-3.78 (m, 4H), 3.60-3.62 (m, 2H), 3.37 (d, J = 15.1 Hz, 1H), 3.01-3.07 (m, 4H), 2.14 (s, 3H); 13 C NMR (101 MHz, CDC13) δ: 169.13, 152.54, 151.96, 146.11, 144.58, 137.11, 129.74, 121.18, 118.91, 115.33, 111.94, 66.44, 55.13, 51.15, 50.77, 50.55, 46.52, 41.62, 21.49.

[0113] Table 1. R group structures and yields of compounds 6a-6v

[0114]

[0115]

[0116] In vitro anti-C. albicans activity detection of compounds 6a-6v in Example 1

[0117] I. Experimental method

[0118] The minimum inhibitory concentration (MIC) of compounds 6a-6v against C. albicans was determined by microdilution method. The strains SC5314 and SC5314FR frozen at -80°C were inoculated on Sabouraud's Dextrose Agar (SDA) as 0 generation, and after 24h interval, an appropriate amount of strain was scraped from the 0 generation plate and spread on SDB as 1 generation, and then successively subcultured to stabilize, and the incubated C. albicans was scraped into SDB medium to adjust the final concentration to 1 x 105CFU / mL. 5CFU / mL, according to the control group, FLC group, compound group, compound + FLC group, gradient dilution was carried out by adding corresponding drugs by microdilution method, fungal suspension was added respectively, SC4314 was incubated in a constant temperature and humidity incubator at 30 DEG C for 24h, SC4314FR was incubated in a constant temperature and humidity incubator at 37 DEG C for 24h, the absorbance (OD value 630nm) of each group was determined by using an enzyme label instrument, and the MIC and combined bacteriostatic index (FICI) of each group were calculated. When FICI is less than or equal to 0.5, the two drugs are synergistic. When 0.5 < FICI < 4, the mode of action of the two drugs is irrelevant. When FICI is greater than 4, the mode of action of the two drugs is antagonistic.

[0119] II. Results

[0120] The MIC value and FICI value are shown in Table 2.

[0121] Table 2 Inhibition of Candida albicans by compounds 6a-6v

[0122]

[0123]

[0124] As can be seen from Table 2, the azole derivatives of the present application can inhibit the activity of sensitive strain SC5314 of Candida albicans alone, but the effect of inhibiting fungi is not significantly increased when combined with fluconazole. Among them, compound 6r has the best inhibitory effect on sensitive strains (MIC 50 0.0218 μg / mL), which is significantly better than fluconazole (MIC 50 1.8 μg / mL), but neither of them can inhibit SC5314FR, a drug-resistant strain of Candida albicans, indicating that they are cross-resistant, and their target points for Candida albicans should be consistent. However, the effect of compound 6r is better than that of fluconazole, which is expected to replace FLC as the main drug for anti-fungal infection and become an effective strategy for optimizing the treatment of clinical fungal infection.

[0125] The present application designs and prepares a series of new azole derivatives by recombination of fluconazole and ketoconazole structural units. Almost all the compounds have good inhibitory effect on Candida albicans SC5314. Among them, 8 azole compounds 6a, 6e, 6n, 6p, 6r, 6s, 6t and 6v have better bacteriostatic activity than FLC, and the bacteriostatic activity of compound 6r is the strongest (MIC 50 0.02 μg / mL). In view of its good biological activity, the azole derivatives synthesized by the present application can be further studied as candidate new drugs.

Claims

1. An antifungal azole derivative having the general formula shown in formula (I): （I）； In formula (I), R is selected from the following groups: , , , , , , , , or ; , , , or ; , , , , , or .

2. The method for synthesizing the antifungal azole derivative according to claim 1, characterized in that, To achieve this, follow these steps: 1) A mixture of N-acetyl-N'-(4-hydroxyphenyl)piperazine and 1,2-dibromoethane was stirred at 80-100 °C for 12-48 h in the presence of acetonitrile and K2CO3. Then, a 10% alkaline aqueous solution was added and stirred for 10-30 min. The mixture was extracted 3-4 times with dichloromethane. The dichloromethane layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was subjected to column chromatography with a volume ratio of dichloromethane:methanol of 100:1-100:1.5 as the eluent to obtain compound 1. The molar ratio of N-acetyl-N'-(4-hydroxyphenyl)piperazine, 1,2-dibromoethane, and K2CO3 was 1:2-5:1-3. The volume of acetonitrile added to each mole of N-acetyl-N'-(4-hydroxyphenyl)piperazine was 2-5 L. The volume ratio of acetonitrile to the 10% alkaline aqueous solution was 5:0.2-1. 2) Phthalimide and K2CO3 were reacted in DMF at 50-80 °C for 1-2 h to obtain potassium phthalimide. Compound 1 obtained in step 1) was added and reacted at 70-90 °C for 2-4 h. Dichloromethane was added to dissolve the compound, and the mixture was washed three times with water. The dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 2. The molar ratio of phthalimide, K2CO3 and compound 1 was 1.2-3:1.5-4:

1. 3) Anhydrous ethanol and 80% hydrazine hydrate were added to compound 2, and the mixture was stirred at 40-60 °C for 2-5 h. The mixture was then concentrated under reduced pressure, water was added, and the mixture was extracted three times with dichloromethane. The dichloromethane layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was then subjected to silica gel column chromatography with a dichloromethane:methanol ratio of 100:1 to 100:1.5 (v / v) to obtain compound 3. The molar ratio of compound 2 to hydrazine hydrate was 1:1.5-5. The volume of anhydrous ethanol added per mole of compound 2 was 2-5 L. The volume ratio of dichloromethane to water was 0.5-1:

1. 4) 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl) ethyl ketone was reacted with trimethyl sulfoxide in 10-25% KOH or NaOH aqueous solution and toluene at 40-70 °C for 12-24 h with stirring. After adding dichloromethane, the mixture was washed three times with water. The dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Silica gel column chromatography was performed using petroleum ether:ethyl acetate (v / v) as eluent to give compound 4. The molar ratio of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl) ethyl ketone to trimethyl sulfoxide was 1:1-1.5, and the molar ratio of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl) ethyl ketone to trimethyl sulfoxide was 1:1-1.

5. The volume of KOH or NaOH aqueous solution added to (-1,2,4-triazolyl) ethyl ketone is 0.4~1L; the volume ratio of KOH or NaOH aqueous solution to toluene is 1:2~5; the volume ratio of dichloromethane to toluene during extraction is 1~2:

1. 5) Compounds 3 and 4 were mixed and then anhydrous ethanol and triethylamine were added. The mixture was reacted at 50–85 °C for 10–24 h. Water was then added and the mixture was stirred for 10–30 min. The mixture was extracted three times with dichloromethane. The dichloromethane layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The mixture was then subjected to silica gel column chromatography with a dichloromethane:methanol ratio of 100:1–100:2 (v / v) to obtain compound 5. The molar ratio of compound 3, compound 4, and triethylamine was 1.2–2:1:0.2–1. The volume of anhydrous ethanol added to each mole of compound 4 was 4–5 L. The volume ratio of anhydrous ethanol to water was 1:1–2. 6) React the RX compound with the compound obtained in step 5) to obtain the target compounds 6a~6v; The RX compound is a halocarbon compound, an acyl halide compound, or a sulfonyl chloride compound; R is selected from the following groups: , , , , , , , , or , , , , or ; , , , , , or .

3. The synthesis method according to claim 2, characterized in that, In step 2), the alkaline aqueous solution is an aqueous solution of sodium hydroxide, sodium carbonate, potassium carbonate, or potassium hydroxide.

4. The synthesis method according to claim 2, characterized in that, In step 2), the stirring speed is 300-600 rpm.

5. The synthesis method according to claim 2, characterized in that, When the RX compound is a haloalkane compound, the specific steps of step 6) are as follows: After mixing compound 5 and the haloalkane compound, dichloromethane and alkali are added, and the mixture is stirred at room temperature for 2-12 h. Water is added and stirred for 10-30 min. The mixture is extracted with dichloromethane 3-4 times, the dichloromethane layers are combined, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to silica gel column chromatography with a volume ratio of dichloromethane:methanol of 200:1-100:1 as the eluent to obtain target compounds 6a-6j. The molar ratio of compound 5, haloalkanes and base is 1:1.2~2:1.5~3, and the volume of dichloromethane added to each mole of compound 5 is 3~5 L; the volume ratio of dichloromethane to water is 1:1~1.

5.

6. The synthesis method according to claim 2, characterized in that, When the RX compound is an acyl halide compound, the specific steps of step 6) are as follows: add dichloromethane to compound 5, add alkali under stirring in an ice bath, then add the acyl halide compound, react for 0.5-5 h, add water and stir for 10-30 min, extract with dichloromethane 3-4 times, combine the dichloromethane layers, dry with anhydrous sodium sulfate and concentrate under reduced pressure, and finally perform silica gel column chromatography with dichloromethane:methanol at a volume ratio of 200:1 as the eluent to obtain compound 6k-6o; The molar ratio of compound 5, acyl halide, and base is 1:1.2~2:1.5~3, and the volume of dichloromethane added to each mole of compound 5 is 3~5 L; the volume ratio of dichloromethane to water is 1:1~1.

5.

7. The synthesis method according to claim 2, characterized in that, When the RX compound is a sulfonyl chloride compound, the specific steps of step 6) are as follows: add dichloromethane to compound 5, add alkali while stirring under ice bath conditions, then add sulfonyl chloride compound, react for 1-5 h, add water and stir for 10-30 min, extract with dichloromethane 3-4 times, combine the dichloromethane layers, dry with anhydrous sodium sulfate and concentrate under reduced pressure, and then perform silica gel column chromatography with dichloromethane:methanol at a volume ratio of 200:1-100:1 as eluent to obtain compounds 6p-6v; The molar ratio of compound 5, sulfonyl chloride compound and base is 1:1.2~2:1.5~3, and the volume of dichloromethane added to each mole of compound 5 is 3~5 L; the volume ratio of dichloromethane to water is 1:1~1.

5.

8. The synthesis method according to any one of claims 5 to 7, characterized in that, The alkali is triethylamine, diisopropylethylamine, sodium carbonate, or potassium carbonate.

9. The use of the azole derivative of claim 1 in the preparation of antifungal drugs, characterized in that, The fungus in question is Candida albicans.

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