2-azidoethyl mannoside derivatives in combination with fluconazole for the preparation of a medicament for the treatment of candida albicans resistant strains

Abstract

The application discloses application of 2-azidoethyl mannose derivative and fluconazole in preparation of a drug for resisting Candida albicans drug-resistant strains. The 2-azidoethyl mannose derivative and the fluconazole have no antibacterial effect on the Candida albicans drug-resistant strains when used alone, but have a synergistic antibacterial effect on the Candida albicans drug-resistant strains when used in combination. The 2-azidoethyl mannose derivative provided by the application has a simple preparation method, and has a remarkable effect on resisting the Candida albicans drug-resistant strains in combination with the fluconazole, and is expected to further solve the infection of the Candida albicans drug-resistant strains.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to the application of 2-azidoethylmannoside derivatives in combination with fluconazole in the preparation of drugs against drug-resistant Candida albicans strains. Background Technology

[0002] Candidiasis poses a significant threat to human health, especially to immunocompromised individuals. With the widespread clinical use of antibiotics (fluconazole, itraconazole, etc.), the resistance of Candida albicans is gradually increasing. Therefore, efforts are being made to develop new therapeutic drugs and diagnostic methods.

[0003] The cell wall of Candida albicans mediates the binding, initial adhesion, and invasion of Candida albicans to host cells. It is mainly composed of polysaccharides (mannan, etc.). β It is composed of glucan and chitin, forming a network that serves as a scaffold for highly glycosylated proteins. N- Mannan is the polysaccharide structure of the outermost layer of the Candida albicans cell wall and is closely related to pathogenicity. Its main chain is α-1,6-mannan with branches containing α-1,2-mannose residues, which terminate at α-1,2-, α-1,3-, or β-1,2-mannose residues. Studies have shown that α-1,2-mannan is related to… β -1,2-Mannan can act as an antigen to stimulate the body to produce protective antibodies. Therefore, it is essential to study and apply oligosaccharides with specific structures that correspond to polysaccharide fragments in the cell walls of pathogenic fungi using chemical methods.

[0004] The applicant conducted research on the synthesis of oligosaccharide fragments corresponding to the outer layer structure of the Candida albicans cell wall. During the research, the applicant experimentally determined that the combination of 2-azidoethylmannoside derivatives and fluconazole produced a synergistic effect against drug-resistant Candida albicans strains. Summary of the Invention

[0005] The purpose of this invention is to provide the application of 2-azidoethylmannoside derivatives in combination with fluconazole in the preparation of drugs against drug-resistant Candida albicans strains. This invention is achieved as follows:

[0006] Application of 2-azidoethylmannoside derivatives in combination with fluconazole in the preparation of drugs against drug-resistant Candida albicans strains.

[0007] Furthermore, the mass ratio of the 2-azidoethylmannoside derivative to fluconazole is (0.5~1.5):(0.5~1.5).

[0008] Furthermore, the mass ratio of the 2-azidoethylmannoside derivative to fluconazole is (0.5~1):(0.5~1).

[0009] Furthermore, the mass ratio of the 2-azidoethylmannoside derivative to fluconazole is 1:1.

[0010] Furthermore, the chemical structure of the 2-azidoethylmannoside derivative is as follows: Where R is an acetyl group or or One of them.

[0011] Furthermore, the chemical structure of the 2-azidoethylmannoside derivative is as follows:

[0012] .

[0013] Furthermore, the chemical structure of the 2-azidoethylmannoside derivative is as follows:

[0014] .

[0015] Furthermore, the chemical structure of the 2-azidoethylmannoside derivative is as follows:

[0016] .

[0017] Furthermore, the drug-resistant strain of Candida albicans is drug-resistant Candida albicans SC5314-FR.

[0018] The specific steps for preparing the 2-azidoethylmannoside derivative are as follows:

[0019] (1) Synthesis of mannose trichloroacetylimine ester donor 5: Starting from D-mannose, after full acetylation, it was reacted with 33% HBr-HOAc to synthesize bromosugar 2; bromosugar 2 was heated under reflux in acetonitrile, anhydrous ethanol, and TBAB, and after orthoesterification, compound 3 was synthesized. Compound 3, with selective acetyl protection, was reacted with BnBr and KOH to obtain compound 4, with selective benzyl protection; after ring-opening by acidification with cation exchange resin, compound 4 was reacted with Cl3CCN and DBU to obtain mannose trichloroacetylimine ester donor 5; the route is as follows:

[0020] .

[0021] (2) Synthesis of α-(1→2)-linked mannans 6-10: Mannose trichloroacetylimine ester donor 5 was glycosylated with 2-azidoethanol under the action of TMSOTf to obtain mannomonose 6; mannomonose 6 was hydrolyzed under alkaline conditions of sodium methoxide to obtain mannomonose acceptor 7 with hydroxyl at 2-position and benzyl at other positions; acceptor 7 and donor 5 were glycosylated under the action of TMSOTf to synthesize α-(1→2)-linked mannobiose 8; 8 was hydrolyzed with sodium methoxide to obtain mannobiose acceptor 9 with hydroxyl at 2-position and benzyl at other positions; 9 and 5 were combined under the action of TMSOTf to obtain α-(1→2)-linked mannotriose 10; the specific synthetic route is as follows:

[0022] .

[0023] Advantages of this invention:

[0024] This invention provides the application of a 2-azidoethylmannoside derivative combined with fluconazole in the preparation of a drug against drug-resistant Candida albicans strains. Neither the 2-azidoethylmannoside derivative nor fluconazole alone has antibacterial activity against drug-resistant Candida albicans strains, but their combined use exhibits a synergistic antibacterial effect. The preparation method of the 2-azidoethylmannoside derivative provided by this invention is simple, and its combination with fluconazole shows significant efficacy against drug-resistant Candida albicans strains, potentially further addressing the infection caused by drug-resistant Candida albicans. Attached Figure Description

[0025] Figure 1 The structural formulas of 2-azidoethylmannoside derivatives 6, 8, and 10 described in this invention are as follows;

[0026] Figure 2 Synthetic route for synthesizing mannose trichloroacetylimine ester donor 5;

[0027] Figure 3 Synthetic routes for synthesizing 2-azidoethylmannoside derivatives 6, 8, and 10;

[0028] Figure 4 The 1H NMR spectrum of 2-azidoethylmannoside derivative 6 ( 1 H NMR (H NMR) diagram;

[0029] Figure 5 Carbon NMR spectrum of 2-azidoethylmannoside derivative 6 13 C NMR (C NMR) plot;

[0030] Figure 6 The 1H NMR spectrum of 2-azidoethylmannoside derivative 8 ( 1 H NMR (H NMR) diagram;

[0031] Figure 7The carbon NMR spectrum of 2-azidoethylmannoside derivative 8 ( 13 C NMR (C NMR) plot;

[0032] Figure 8 The 1H NMR spectrum of 2-azidoethylmannoside derivative 10 ( 1 H NMR (H NMR) diagram;

[0033] Figure 9 Carbon NMR spectrum of 2-azidoethylmannoside derivative 10 ( 13 C NMR (C NMR) plot; Detailed Implementation

[0034] The present invention will be further described below, but this is not intended to limit the invention in any way. Any modifications made based on the present invention are within the scope of protection of the present invention.

[0035] The purpose of this invention is to provide the application of 2-azidoethylmannoside derivative in combination with fluconazole in the preparation of drugs against drug-resistant Candida albicans strains.

[0036] The mass ratio of 2-azidoethylmannoside derivative to fluconazole is (0.5~1.5):(0.5~1.5).

[0037] The mass ratio of 2-azidoethylmannoside derivative to fluconazole was (0.5~1):(0.5~1).

[0038] The mass ratio of 2-azidoethylmannoside derivative to fluconazole was 1:1.

[0039] The chemical structure of the 2-azidoethylmannoside derivative is as follows: Where R is an acetyl group or or One of them.

[0040] The chemical structure of the 2-azidoethylmannoside derivative is as follows:

[0041] .

[0042] The chemical structure of the 2-azidoethylmannoside derivative is as follows:

[0043] .

[0044] The chemical structure of the 2-azidoethylmannoside derivative is as follows:

[0045] .

[0046] The drug-resistant strain of Candida albicans is drug-resistant Candida albicans SC5314-FR.

[0047] The structural formula of the 2-azidoethylmannoside derivative is shown in [reference needed]. Figure 1 .

[0048] The specific steps for preparing the 2-azidoethylmannoside derivative are as follows:

[0049] (1) Synthesis of mannose trichloroacetylimine ester donor 5: Starting from D-mannose, after full acetylation, it was reacted with 33% HBr-HOAc to synthesize bromosugar 2; bromosugar 2 was heated under reflux in acetonitrile, anhydrous ethanol, and TBAB, and after orthoesterification, compound 3 was synthesized. Compound 3, with selective acetyl protection, was reacted with BnBr and KOH to obtain compound 4, with selective benzyl protection; after ring-opening by acidification with cation exchange resin, compound 4 was reacted with Cl3CCN and DBU to obtain mannose trichloroacetylimine ester donor 5; the synthetic route of donor 5 is shown in the figure. Figure 2 .

[0050] (2) Synthesis of α-(1→2)-linked mannans 6-10: Mannose trichloroacetylimine ester donor 5 was glycosylated with 2-azidoethanol under the action of TMSOTf to obtain mannomonose 6; mannomonose 6 was hydrolyzed under alkaline conditions of sodium methoxide to obtain mannomonose acceptor 7 with hydroxyl group at 2 position and benzyl group at other positions; acceptor 7 and donor 5 were glycosylated under the action of TMSOTf to synthesize α-(1→2)-linked mannobiose 8; 8 was hydrolyzed with sodium methoxide to obtain mannobiose acceptor 9 with hydroxyl group at 2 position and benzyl group at other positions; 9 and 5 were combined under the action of TMSOTf to obtain α-(1→2)-linked mannotriose 10; see the detailed synthetic route below. Figure 3 .

[0051] Example 1

[0052] Synthetic methods for 2-azidoethylmannoside derivatives

[0053] Synthesis of bromoglycosides (2)

[0054]

[0055] Add α-D-mannose (4 g, 22.2 mmol) to a dry round-bottom flask, dissolve in Ac2O (20 mL), add I2 (183.4 mg, 0.7 mmol), and stir at room temperature until the reaction system turns brown and transparent. Take a small amount of the reaction solution as the raw material for thin-layer chromatography (TLC), add dry CH2Cl2 (100 mL) to dilute the reaction solution, then cool to 0 °C, add 33% HBr-HOAc (42 mL) dropwise under N2 protection, stir at 0 °C for 30 min, and then react at room temperature for 4 h. Monitor the reaction for completeness by TLC. After the reaction is complete, dilute the reaction solution with dichloromethane (100 mL), wash with ice water (75 mL × 2), adjust the pH of the organic layer to neutral with saturated NaHCO3 solution, wash with dilute sodium thiosulfate solution (75 mL × 2), dry with anhydrous sodium sulfate for 4 h, filter, and concentrate to obtain crude product 10.1 g, Rf = 0.66 (PE:EA = 2:1). V / V ).

[0056] Synthesis of orthoester (3)

[0057]

[0058] Compound 2 (10.1 g, 24.6 mmol) was dissolved in MeCN (80 mL) in a round-bottom flask, and anhydrous CH3CH2OH (5 mL) was added. TBAB (4 g, 12.3 mmol) and TEA (7 mL) were then added. The mixture was heated under reflux at 60 °C for 1 h, and the reaction was monitored by TLC until complete. After the reaction was complete, the reaction solution was diluted with ethyl acetate (150 mL), washed successively with water (100 mL) and saturated brine (100 mL), dried over anhydrous NaSO4 for 4 h, filtered, concentrated, dissolved in anhydrous ethanol (20 mL), and then dissolved in petroleum ether (60 mL). Recrystallization yielded 8.2 g of compound 3 as a white solid, with a yield of 89%.

[0059] (4) Synthesis

[0060]

[0061] Compound 3 (2.5 g, 6.64 mmol) was placed in a round-bottom flask, and KOH (4.5 g, 80 mmol) and BnBr (4.7 mL, 39 mmol) were added. The mixture was dissolved in THF (30 mL), and heated under reflux at 70 °C for 5 h. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was diluted with dichloromethane (60 mL), washed successively with water (60 mL) and saturated brine (60 mL), dried over anhydrous Na₂SO₄, filtered, concentrated, and recrystallized from anhydrous ethanol (10 mL) to give 2.7 g of compound 4 as a white solid, with a yield of 80%.

[0062] (5) Synthesis

[0063]

[0064] Compound 4 (2.7 g, 5.5 mmol) was placed in a round-bottom flask, and cation exchange resin was added and stirred until the reaction system became colorless and transparent. After TLC monitoring showed that all the starting materials had reacted, the cation exchange resin was removed by filtration, and the mixture was dried three times with toluene to obtain the reaction intermediate. The reaction intermediate was dissolved in dichloromethane (30 mL), then cooled to 0 °C, and CCl3CN (2.8 mL, 27.5 mmol) was added. Then, DBU (0.42 mL, 2.75 mmol) was slowly added dropwise, and the mixture was allowed to react at room temperature for 4 h. After the reaction was completed according to TLC monitoring, the reaction solution was evaporated to dryness and subjected to silica gel column chromatography [eluent: petroleum ether / ethyl acetate = 8 / 1]. V / V [(Containing 1% TEA)] The purified compound 5 was 3 g of a pale yellow oily liquid with a yield of 86%. Due to its unstable properties at room temperature, it was stored at -20°C and used directly in the next step.

[0065] (6) Synthesis

[0066]

[0067] Take 5 g (0.7 g, 1.1 mmol) of trichloroacetylimine ester donor into a round-bottom flask, add 2-azidoethanol (67 g / mL) µ L (0.85 mmol) and 4 μS MS (100 mg), stirred at room temperature for 30 min under N2 protection, then cooled to -42 °C, and TMSOTf (75 mg) was added dropwise. µ L, 0.43 mmol), and continued the reaction at -42 ℃ for 20 min, with TLC monitoring for complete reaction. After the reaction was complete, TEA (0.1 mL) was added to quench the reaction, the reaction solution was filtered through diatomaceous earth, washed with saturated sodium bicarbonate solution (60 mL), extracted with DCM (3 × 20 mL), the organic layers were combined, washed with saturated brine (60 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (eluent: PE / EA = 6 / 1, V / V After purification, 60.52 g of the compound was obtained.

[0068] (6): Colorless oily liquid, yield 84%. 1H NMR(600 MHz, CDCl3) δ:7.37 -7.26 (m,13H), 7.19-7.13 (m, 2H), 5.39 (dd, J = 3.4, 1.9 Hz, 1H), 4.90 (d, J = 1.8 Hz,1H), 4.86(d, J = 10.8 Hz, 1H), 4.68 (dd, J = 15.4, 11.6 Hz, 2H), 4.56-4.45(m, 3H), 4.01 (dd, J = 9.2, 3.4 Hz,1H), 3.91-3.77 (m, 4H), 3.71 (dd, J =10.7, 1.8 Hz, 1H), 3.61 (ddd, J = 10.4, 6.1, 4.2 Hz, 1H), 3.38 (dt, J = 5.8, 3.7 Hz, 2H), 2.15 (s, 3H); 13 C NMR(125 MHz, CDCl3) δ:170.61, 163.57, 138.43,138.25, 137.99, 128.54, 128.48, 128.28, 128.03, 127.92, 127.79, 98.10,78.11,75.30, 74.28, 73.58, 72.03, 71.85, 68.96, 68.75, 66.90, 50.57, 21.24.

[0069] 1H NMR spectrum of 2-azidoethylmannoside derivative 6 1 (H NMR) image Figure 4 ; Carbon NMR spectrum of 2-azidoethylmannoside derivative 6 ( 13 (C NMR) image see Figure 5 .

[0070] (7) Synthesis

[0071]

[0072] Compound 6 (1.3 g, 2.7 mmol) was placed in a round-bottom flask, and sodium methoxide (144 mg, 2.8 mmol) was added. The solution was dissolved in methanol (13 mL), and the mixture was stirred at room temperature for 2 h to carry out hydrolysis. After the reaction was completed, cation exchange resin was added to the reaction solution to adjust the pH to neutral. The solution was filtered to remove the cation exchange resin, and the filtrate was concentrated. The solution was dried three times with toluene to obtain a colorless oily liquid 7, which was used as the acceptor for subsequent glycosylation reaction with trichloroacetylimine ester donor 5.

[0073] (8) Synthesis

[0074]

[0075] Trichloroacetylimine ester donor 5 (1.4 g, 2.2 mmol) was placed in a round-bottom flask, and acceptor 7 (0.9 g, 1.7 mmol) and 4 μL MS (100 mg) were added. The mixture was stirred at room temperature for 30 min, then cooled to -42 °C, and TMSOTf (150 µL, 0.85 mmol) was added dropwise. The reaction was then continued at -42 °C for another 30 min, and the reaction was monitored by TLC to ensure complete reaction. After the reaction was complete, TEA was added to quench the reaction. The reaction solution was filtered through diatomaceous earth, washed with saturated sodium bicarbonate solution (60 mL), extracted with dichloromethane (3 × 100 mL), and the organic layers were combined. The mixture was washed with saturated brine (60 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (eluent: PE / EA = 5 / 1). V / V After purification, 81.4 g of the compound was obtained.

[0076] (8): Colorless oily liquid, yield 82%. 1 H NMR (600 MHz, CDCl3) δ 7.37 – 7.27 (m,23H), 7.26 – 7.15 (m, 7H), 5.55 (s, 1H), 5.04 (s, 1H), 4.96 (s, 1H), 4.87(dd, J = 10.8, 4.8 Hz, 2H), 4.72 – 4.62 (m, 5H), 4.56 (t, J = 12.3 Hz, 2H), 4.52– 4.46 (m, 2H), 4.42 (d, J = 10.8 Hz, 1H), 4.02 – 3.92 (m, 4H), 3.84 (ddd, J =16.3, 9.6, 5.6 Hz, 2H), 3.75 (ddt, J = 19.4, 12.7, 9.4 Hz, 6H), 3.39 (ddd, J =10.5, 6.8, 3.6 Hz, 1H), 3.24 (qdd, J = 13.2, 6.4, 3.6 Hz, 2H), 2.14 (s, 3H). 13CNMR(125 MHz, CDCl3) δ: 170.23, 138.56, 138.52, 138.48, 138.45, 138.30,138.09, 128.51, 128.45, 128.42, 128.41, 128.28, 128.14, 128.00, 127.94,127.79, 127.74,127.70, 127.62, 127.55, 99.83, 98.92, 79.60, 78.21, 75.22,75.20, 75.11, 74.54, 74.52, 73.57, 73.40, 72.25, 72.21, 72.02, 71.95, 69.39, 69.34, 68.80, 66.56, 50.49, 21.24.

[0077] 1H NMR spectrum of 2-azidoethylmannoside derivative 8 1 (H NMR) image Figure 6 ; Carbon NMR spectrum of 2-azidoethylmannoside derivative 6 ( 13 (C NMR) image see Figure 7 .

[0078] (9) Synthesis

[0079]

[0080] Compound 8 (0.34 g, 0.34 mmol) was placed in a round-bottom flask, and CH3ONa (22 mg, 0.4 mmol) and MeOH (5 mL) were added. The mixture was stirred at room temperature for 4 h. After hydrolysis, cation exchange resin was added to adjust the pH to neutral. The cation exchange resin was removed by filtration, and the mixture was dried three times with toluene to obtain disaccharide acceptor 9.

[0081] Synthesis of (10)

[0082]

[0083] Trichloroacetylimine ester donor 5 (555 mg, 0.87 mmol) was added to a round-bottom flask containing disaccharide acceptor 9 (630 mg, 0.67 mmol), and 4 μL MS (100 mg) was added. The mixture was stirred at room temperature for 30 min under N2 protection, then cooled to -42 °C, and TMSOTf (60 mg) was added dropwise to the reaction solution. µL, 0.34 mmol), and continued the reaction at -42 ℃ for 30 min, with TLC monitoring for complete reaction. After the reaction, the reaction was quenched with TEA (0.1 mL), the reaction solution was filtered through diatomaceous earth, washed with saturated sodium bicarbonate solution (60 mL), extracted with dichloromethane (3 × 100 mL), the organic layers were combined, washed with saturated brine (60 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (eluent: PE / EA = 5 / 1, V / V After purification, 10400 mg of the compound was obtained.

[0084] (10): Colorless oily liquid, yield 42%. 1 H NMR(600 MHz, CDCl3) δ 7.41 – 7.26 (m,22H), 7.26 – 7.09 (m, 23H), 5.54 (s, 1H), 5.17 (s,1H), 5.06 (s, 1H), 4.98 (s,1H), 4.87 – 4.80 (m, 3H), 4.67 (dd, J = 11.6, 8.7 Hz, 2H), 4.63– 4.48 (m,10H), 4.44 (dd, J = 10.9, 4.3 Hz, 2H), 4.33 (d, J = 12.1 Hz, 1H), 4.10 (t, J= 2.6 Hz, 1H),4.02 – 3.86 (m, 7H), 3.79 – 3.65 (m, 9H), 3.53 (d, J = 10.6 Hz, 1H), 3.36 – 3.30 (m, 1H), 3.20 (q, J = 5.1 Hz, 2H), 2.13 (s, 3H). 13C NMR(125MHz, CDCl3) δ 170.30, 138.67, 138.65, 138.54, 138.50, 138.46, 138.41, 138.31,138.16, 128.55, 128.46,128.41, 128.36, 128.30, 128.13, 128.06, 127.96,127.88, 127.82, 127.78, 127.74, 127.67, 127.64, 127.61, 127.55, 100.93,99.53, 98.98, 79.34, 78.22, 75.29, 75.24, 75.21, 75.13, 75.08, 74.91, 74.76, 74.35, 73.47, 73.43, 72.30, 72.25, 72.21, 72.06, 72.01, 69.89, 69.42, 68.86, 68.83, 66.55, 50.52, 29.83, 21.31.

[0085] The 1H NMR spectrum of 2-azidoethylmannoside derivative 10 is shown in the figure. Figure 8 The carbon nuclear magnetic resonance (13C NMR) spectrum of 2-azidoethylmannoside derivative 10 is shown in the figure. Figure 9 .

[0086] Example 2

[0087] Antifungal activity test

[0088] I. Materials and Methods

[0089] 1. Drugs and samples

[0090] 2-Azide ethyl mannoside derivatives 6, 8, and 10 were prepared in Example 1.

[0091] The positive control drug fluconazole (FLC) was dissolved in DMSO, sonicated for 10 min, centrifuged, and the supernatant was collected. The storage concentration was 50 mg / mL, and the solution was sealed and stored at 4°C. Samples 6, 8, and 10 were all dissolved in DMSO to a concentration of 50 mg / mL and stored sealed at 4°C.

[0092] 2. Culture medium and bacterial strain

[0093] (1) Culture medium

[0094] Sabouraud broth liquid culture medium and Sabouraud broth solid culture medium.

[0095] (2) Strains

[0096] Candida albicans fluconazole-sensitive strain SC5314 and Candida albicans fluconazole-resistant strain SC5314-FR.

[0097] 3. Experimental Methods

[0098] A 96-well plate was prepared, and both the sample and fluconazole were diluted to an initial concentration of 200 μg / mL, with 100 μL per well. This was repeated 5-fold serially to create 6 concentration gradients, with 3 replicates per gradient. After activating the bacterial strain twice, a bacterial suspension was prepared. 100 μL of the fungal suspension was added to each well of the 96-well plate to achieve a final concentration of 1 × 10⁵ CFU / mL. The plate was incubated at 37°C for 24 h. The OD value at 625 nm was measured using a microplate reader. A blank control of the culture medium, a bacterial suspension control, and a fluconazole positive control were also included in the experiment.

[0099] 4. Calculation formula

[0100] Fungal activity inhibition rate (%) = (1 – Sample OD value / Experimental control well OD value) × 100%

[0101] The Joint Indicator Index (FICI) is calculated as follows: FICI = MICA / A + MICB / B (where A and B are the MIC values ​​of the two drugs used alone, and MICA and MICB are the MIC values ​​of the two drugs used in combination). When the MIC value is higher than the limit of detection, twice the limit of detection concentration is used to calculate the FICI. In this experiment, the MIC50 value is calculated as the percentage of inhibition of fluconazole at 50% fungal growth. When FICI ≤ 0.5, the two drugs act synergistically; when 0.5 < FICI ≤ 4, the two drugs act independently; and when FICI > 4, the two drugs act antagonistically.

[0102] II. Results

[0103] Table 1 Summary of the antibacterial activity experiments of the tested samples and fluconazole against Candida albicans.

[0104]

[0105] III. Conclusion

[0106] 1. Samples in which a single drug was effective against both susceptible and resistant strains of Candida albicans: None;

[0107] 2. Samples in which a single drug is effective only against susceptible strains of Candida albicans: None;

[0108] 3. Samples in which a single drug is effective only against drug-resistant Candida albicans: None;

[0109] 4. Samples that showed synergistic antibacterial activity against both susceptible and resistant Candida albicans strains when combined with fluconazole: None;

[0110] 5. Samples that showed synergistic antibacterial activity against only susceptible strains of Candida albicans when combined with fluconazole: None;

[0111] 6. Samples that showed synergistic antibacterial activity against drug-resistant Candida albicans when combined with fluconazole include: 6, 8, and 10.

[0112] When 2-azidoethylmannoside derivatives 6, 8, and 10 were used in combination with fluconazole, their inhibition rates against drug-resistant Candida albicans strains reached 99.5%, 99.4%, and 99.0%, respectively.

[0113] In summary, neither 2-azidoethylmannoside derivative nor fluconazole alone has any antibacterial effect against drug-resistant Candida albicans, but their combined use has a synergistic antibacterial effect against drug-resistant Candida albicans, with an inhibition rate of over 90%.

Claims

The application of 1,2-azidoethylmannoside derivatives in combination with fluconazole in the preparation of drugs against drug-resistant Candida albicans strains, characterized in that... The chemical structure of the 2-azidoethylmannoside derivative is as follows: Where R is an acetyl group or or One of them.

2. The application according to claim 1, characterized in that... The mass ratio of the 2-azidoethylmannoside derivative to fluconazole is (0.5~1.5):(0.5~1.5).

3. The application according to claim 2, characterized in that... The mass ratio of the 2-azidoethylmannoside derivative to fluconazole is (0.5~1):(0.5~1).

4. The application according to claim 3, characterized in that... The mass ratio of the 2-azidoethylmannoside derivative to fluconazole is 1:

1.

5. The application according to claim 1, characterized in that... The chemical structure of the 2-azidoethylmannoside derivative is as follows: 。 6. The application according to claim 1, characterized in that... The chemical structure of the 2-azidoethylmannoside derivative is as follows: 。 7. The application according to claim 1, characterized in that... The chemical structure of the 2-azidoethylmannoside derivative is as follows: 。 8. The application according to claim 1, characterized in that... The drug-resistant Candida albicans strain mentioned is drug-resistant Candida albicans SC5314-FR.

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