Application of chloroflavone compound as anti-candida albicans drug

Abstract

The invention relates to an application of a chloroflavone derivative as an anti-candida albicans drug. The invention provides an anti-Candida albicans infection agent, which is characterized in that the anti-Candida albicans infection agent takes a compound represented by a formula I and / or a pharmaceutically acceptable salt thereof as an active ingredient and is used for treating infectious diseases caused by Candida albicans.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to the application of a class of chlorinated flavone compounds as anti-Candida albicans drugs. Background Art

[0002] Candida albicans exists as a commensal bacterium in the human oral cavity or gastrointestinal tract, but under certain specific conditions, it becomes an opportunistic pathogen under the action of a series of virulence factors. Clinically, Candida albicans infections account for 70% of all yeast infections. Despite the intervention of antifungal treatment, the crude mortality rate is still as high as 40%. Especially in severely immunocompromised patients, Candida albicans can spread through the blood to internal organs, leading to life-threatening invasive fungal infections and becoming the main cause of healthcare-associated bloodstream infections in the United States. In 2022, the World Health Organization issued the first Fungal Priority Pathogens List (FPPL), which included 19 human fungal pathogens associated with a high risk of severe death or morbidity, aiming to guide the research on invasive fungal diseases caused by them, and Candida albicans was listed as the highest level - critical priority.

[0003] As a eukaryote, fungi have a close evolutionary relationship with humans, which severely limits the number of fungal-specific targets available for drug development and further hinders the development of antifungal drugs. So far, the FDA has only approved polyenes, azoles, echinocandins, flucytosine, and allylamines for the treatment of fungal infections. However, all current antifungal drugs are broad-spectrum fungicides or antibacterial agents, and there is no single selective antibacterial agent available, resulting in frequent occurrence of multidrug resistance. Due to the high mortality rate of invasive fungal infections, the toxic side effects of existing antifungal drugs, and the increasing drug resistance, there is an urgent need to develop novel-structured antifungal drugs with a narrow antibacterial spectrum. Summary of the Invention

[0004] Only some aspects of the present invention are generally described below and are not limited thereto. These aspects and other parts are more fully described later. All references in this specification are incorporated herein by reference in their entirety. When there are differences between the disclosure of this specification and the cited literature, the disclosure of this specification shall prevail.

[0005] The present invention provides a class of chlorinated flavone compounds for use as anti-Candida albicans agents. Specifically, the present invention relates to compounds of formula I or pharmaceutically acceptable salts thereof or solvates of salts thereof. The present invention also discloses the application of such compounds as anti-Candida albicans agents in antifungal treatment. The compounds of the present invention have excellent inhibitory activity against Candida albicans and have good application prospects.

[0006] Specifically:

[0007] The present invention relates to a compound of formula I structure or a pharmaceutically acceptable salt thereof or a solvate of its salt, characterized in that the compound has the following structure:

[0008] wherein R1 and R2 are each independently optionally H,

[0009] and R1 and R2 cannot both be H. Specifically,

[0010]

[0011]

[0012] In another embodiment of the present invention, a class of compounds is provided as antifungal drugs, characterized in that it comprises compound 1–24 of formula I or a pharmaceutically acceptable salt thereof as an active ingredient.

[0013] The term "pharmaceutically acceptable salt" in the present invention refers to a non-toxic inorganic or organic acid and / or base addition salt; see "Salt selection for basic drugs", Int. J. Pharm. 1986, 33, 201–217.

[0014] In addition, in the embodiment of the present invention, a class of compounds is provided that does not have antifungal activity, characterized in that it comprises compound b-q of formula I or a pharmaceutically acceptable salt thereof as an active ingredient.

[0015]

[0016] and R1 and R2 cannot both be H. Specifically,

[0017] Detailed implementation mode

[0018] For the convenience of further understanding of the present invention, the following examples provide a more detailed description of it; however, these examples are only for better understanding the invention and are not used to limit the scope or implementation principle of the present invention, and the implementation mode of the present invention is not limited to the following content.

[0019] Example 1: Compound 1

[0020]

[0021] Weigh chlorflavonin (hereinafter referred to as "Compound a") (15 mg, 1 eq), 2-chlorobenzoic acid (8.3 mg, 1.5 eq), 4-dimethylaminopyridine (19.4 mg, 4 eq) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (30.4 mg, 4 eq) successively into a sealed tube, add dichloromethane and stir to completely dissolve. After the reaction mixture reacts at 45 °C for 1 h, monitor the reaction by TLC. After the reaction is complete, quench the reaction with water. Extract with dichloromethane solvent three times, combine the organic layers, concentrate under reduced pressure to obtain the product, and obtain a yellow solid after treatment with a normal-phase silica gel column, with a yield of 50%; 1 H NMR (400 MHz, CDCl3): δ 12.29 (1H, s), 8.03 (1H, d, J = 8.0 Hz), 7.69 (1H, dd, J = 8.1, 1.6 Hz), 7.63 (1H, dd, J = 8.1, 1.6 Hz), 7.49–7.38 (3H, overlapped), 7.33–7.29 (1H, m), 6.40 (1H, s), 3.91 (3H, s), 3.75 (3H, s), 3.69 (3H, s). 13 C NMR (100 MHz, CDCl3) δ 179.0, 162.0, 158.8, 157.5, 154.1, 149.1, 145.4, 140.3, 134.6, 133.6, 132.9, 132.1, 131.4, 129.9, 129.1, 128.9, 128.4, 127.2, 126.9, 126.4, 105.8, 95.9, 61.7, 61.2, 56.5. HRESIMS m / z 517.0458 [M+H] + (calcd for C 25 H 19 O8Cl2 + , 517.0451).

[0022] Example 2: Compound 2

[0023]

[0024] Refer to the preparation method of Example 1 to obtain a yellow solid, with a yield of 55%; 11H NMR (400 MHz, CDCl3): δ 12.24 (1H, s), 8.08–8.04 (2H, overlapped), 7.68 (1H, dd, J = 8.0, 1.6 Hz), 7.63 (1H, dd, J = 8.0, 1.6 Hz), 7.45–7.38 (3H, overlapped), 6.37 (1H, s), 3.89 (3H, s), 3.75 (3H, s), 3.74 (3H, s). 13 13C NMR (100 MHz, CDCl3): δ 179.1, 163.0, 159.0, 157.7, 154.2, 149.1, 145.8, 140.8, 140.4, 133.0, 132.0 (CH×2), 130.1, 129.3 (CH×2), 129.2, 129.2, 127.3, 127.3, 126.5, 105.9, 96.0, 61.9, 61.3, 56.7. HRESIMS m / z 517.0455 [M+H] + (calcd for C 25 H 19 O8Cl2 + , 517.0451).

[0025] Example 3: Compound 3

[0026]

[0027] A yellow solid was obtained by referring to the preparation method of Example 1, with a yield of 43%; 1 1H NMR (400 MHz, CDCl3): δ 12.25 (1H, s), 8.28–8.04 (2H, overlapped), 7.68 (1H, dd, J = 8.0, 1.6 Hz), 7.63 (1H, dd, J = 7.8, 1.6 Hz), 7.40 (1H, t, J = 8.0 Hz), 7.11 (2H, t, J = 8.6 Hz), 6.37 (1H, s), 3.89 (3H, s), 3.75 (3H, s), 3.75 (3H, s). 1313C NMR (100 MHz, CDCl3): δ 178.7, 164.9, 162.3 (d, J = 244.5 Hz), 162.3 (d, J = 244.5 Hz) 158.5, 157.2, 153.8, 148.7, 145.4, 139.9, 132.9 (d, J = 8.1 Hz) (CH×2), 132.8 (d, J = 244.5 Hz) (CH×2), 132.5, 129.6, 128.7, 128.7, 126.7, 126.0, 124.6 (d, J = 3.3 Hz), 124.5 (d, J = 3.3 Hz), 115.8 (d, J = 21.2 Hz) (CH×2), 115.6 (d, J = 21.2 Hz) (CH×2), 105.5, 95.5, 61.4, 60.9, 56.2. HRESIMS m / z 501.0752 [M+H] + (calcd for C 25 H 19 O8ClF + , 501.0747).

[0028] Example 4: Compound 4

[0029]

[0030] A yellow solid was obtained by referring to the preparation method of Example 1, with a yield of 23%; 1 1H NMR (400 MHz, CDCl3): δ 12.26 (1H, s), 8.84–8.66 (1H, m), 8.27 (1H, dt, J = 7.8, 1.2 Hz), 7.87 (1H, td, J = 7.8, 1.6 Hz), 7.69 (2H, dq, J = 8.0, 1.6 Hz), 7.50 (1H, ddd, J = 7.6, 4.7, 1.2 Hz), 7.41 (1H, t, J = 8.0 Hz), 6.36 (1H, s), 3.88 (3H, s), 3.75 (3H, s), 3.74 (3H, s). 13 13C NMR (100 MHz, CDCl3): δ 179.0, 162.3, 158.7, 157.5, 153.9, 150.2, 150.2, 146.8, 145.8, 140.3, 137.3, 132.9, 130.0, 129.1, 129.0, 127.7, 127.1, 126.2, 126.2, 105.8, 95.8, 61.7, 61.2, 56.5. HRESIMS m / z 484.0793 [M+H] + (calcd for C 24 H19 O8NCl + ,484.0794).

[0031] Example 5: Compound 5

[0032]

[0033] A yellow solid was obtained according to the preparation method of Reference Example 1, with a yield of 18%; 1 H NMR(400MHz,CDCl3):δ12.29(1H,s),8.63(1H,ddd,J=4.8,1.8,0.9Hz),7.83(1H,d,J=15.7Hz),7.71(1H,td,J=7.7,1.8Hz),7.66(1H,dd,J=8.0,1.6Hz),7.60(1H,dd,J=7.8,1.6Hz),7.43(1H,dt,J=7.8,1.1Hz),7.37(1H,t,J=8.0Hz),7.31–7.26(1H,m),7.05(1H,d,J=15.7Hz),6.38(1H,s),3.89(3H,s),3.82(3H,s),3.77(3H,s). 13 C NMR(100MHz,CDCl3):δ179.1,163.3,158.8,157.6,154.3,152.5,150.4,149.1,146.2,145.7,140.3,136.9,132.8,129.8,129.1,129.0,126.9,126.3,125.0,124.8,120.3,105.9,95.8,61.8,61.2,56.5.HRESIMS m / z510.0952[M+H] + (calcd for C 26 H 21 O8NCl + ,510.0950).

[0034] Example 6: Compound 6

[0035]

[0036] A yellow solid was obtained according to the preparation method of Reference Example 1, with a yield of 21%; 11H NMR (400 MHz, CDCl3): δ 12.25 (1H, s), 7.93 (1H, dd, J = 10.4, 8.3 Hz), 7.70 (1H, dd, J = 8.0, 1.6 Hz), 7.67 (1H, dd, J = 8.0, 1.6 Hz), 7.42 (1H, t, J = 8.0 Hz), 7.30 (1H, dd, J = 9.8, 6.9 Hz), 6.41 (1H, s), 3.91 (3H, s), 3.74 (3H, s), 3.73 (3H, s). 13 13C NMR (100 MHz, CDCl3): δ 178.8, 166.9, 158.8, 157.5 (C×2), 156.8 (d, J = 245.2 Hz), 156.8 (d, J = 245.2 Hz), 153.6, 149.0, 147.5 (d, J = 245.2 Hz), 147.5 (d, J = 245.2 Hz), 145.1, 140.2, 132.8, 132.6, 129.8, 129.0, 128.8, 127.3, 126.0, 121.4, 120.8 (d, J = 21.0 Hz), 120.6 (d, J = 21.0 Hz), 105.6, 95.9, 61.6, 61.1, 56.4. HRESIMS m / z 553.0267 [M+H] + (calcd for C 25 H 17 O8Cl2F2 + , 553.0263).

[0037] Example 7: Compound 7

[0038]

[0039] A yellow solid was obtained by referring to the preparation method of Example 1, with a yield of 60%; 1 1H NMR (400 MHz, CDCl3): δ 12.31 (1H, s), 7.95–7.83 (2H, overlapped), 7.59 (1H, dd, J = 7.9, 1.6 Hz), 7.45 (1H, dd, J = 7.7, 1.6 Hz), 7.23 (1H, d, J = 7.9 Hz), 7.11–6.96 (2H, overlapped), 6.41 (1H, s), 5.37 (2H, s), 3.91 (3H, s), 3.76 (3H, s), 3.74 (3H, s). 1313C NMR (100 MHz, CDCl3): δ 192.1, 178.9, 164.7, 158.6, 157.6, 155.1, 153.4, 149.0, 140.0, 133.3, 131.0, 131.0 (d, J = 8.3 Hz) (CH×2), 130.9 (d, J = 8.3 Hz) (CH×2), 129.9, 128.8, 128.5, 126.7, 125.4, 116.0 (d, J = 21.8 Hz) (CH×2), 115.8 (d, J = 21.8 Hz) (CH×2), 105.9, 95.8, 76.0, 61.6, 61.0, 56.5. HRESIMS m / z 515.0911 [M+H] + (calcd for C 26 H 21 O8ClF + , 515.0903).

[0040] Example 8: Compound 8

[0041]

[0042] A yellow solid was obtained according to the preparation method of Reference Example 1, with a yield of 21%; HRESIMS m / z 484.0775 [M+H] + (calcd for C 24 H 19 O8NCl + , 484.0794).

[0043] Example 9: Compound 9

[0044]

[0045] A yellow solid was obtained according to the preparation method of Reference Example 1, with a yield of 56%; 1 1H NMR (400 MHz, CDCl3): δ 12.29 (1H, s), 8.05–7.99 (1H, m), 7.69 (1H, dd, J = 8.0, 1.6 Hz), 7.66–7.59 (2H, overlapped), 7.41 (1H, t, J = 7.9 Hz), 7.38–7.32 (2H, overlapped), 6.40 (1H, s), 3.90 (3H, s), 3.75 (3H, s), 3.67 (3H, s). 1313C NMR (100 MHz, CDCl3): δ 179.0, 162.1, 158.5, 157.6, 153.8, 148.8, 145.0, 140.0, 134.4, 133.3, 132.5, 131.8, 130.1, 129.6, 128.8, 128.5, 127.2, 126.9, 126.1, 122.2, 105.6, 95.6, 61.4, 60.9, 56.2. HRESIMS m / z 560.9964 [M+H] + (calcd for C 25 H 19 O8BrCl + , 560.9946).

[0046] Example 10: Compound 10

[0047]

[0048] A yellow solid was obtained according to the preparation method of Example 1 with a yield of 40%; 1 1H NMR (400 MHz, CDCl3): δ 12.25 (1H, s), 8.65 (2H, d, J = 4.7 Hz), 7.74 (1H, d, J = 16.1 Hz), 7.66 (2H, td, J = 8.1, 1.6 Hz), 7.44–7.34 (3H, overlapped), 6.69 (1H, d, J = 16.1 Hz), 6.37 (1H, s), 3.88 (3H, s), 3.80 (3H, s), 3.75 (3H, s). 13 13C NMR (100 MHz, CDCl3): δ 179.0, 162.7, 158.9, 157.6, 154.0, 150.7 (CH×2), 149.0, 145.5, 144.5, 141.3, 140.3, 132.9, 129.9, 129.0, 129.0, 127.1, 126.0, 122.2, 122.2, 120.9, 105.8, 95.9, 61.7, 61.2, 56.5. HRESIMS m / z 510.0952 [M+H] + (calcd for C 26 H 21 O8NCl + , 510.0950).

[0049] Example 11: Compound 11

[0050]

[0051] A yellow solid was obtained according to the preparation method of Example 1, with a yield of 52%; 1 1H NMR (400 MHz, CDCl3): δ 12.28 (s, 1H), 7.77 (1H, d, J = 16.0 Hz,), 7.66 (1H, dd, J = 7.8, 1.6 Hz), 7.62 (1H, dd, J = 7.8, 1.6 Hz), 7.47–7.42 (2H, overlapped), 7.40–7.31 (3H, overlapped), 6.50 (1H, d, J = 16.0 Hz), 6.37 (1H, s), 3.88 (3H, s), 3.81 (3H, s), 3.76 (3H, s). 13 13C NMR (100 MHz, CDCl3): δ 178.7, 163.0, 158.5, 157.3, 153.9, 148.7, 145.9, 145.4, 139.9, 136.6, 132.5, 132.3, 129.5, 129.4 (CH×2), 129.0 (CH×2), 128.7, 128.7, 126.6, 125.9, 116.4, 105.5, 95.5, 61.4, 60.8, 56.2. HRESIMS m / z 543.0613 [M+H] + (calcd for C 27 H 21 O8Cl2 + , 543.0608).

[0052] Example 12: Compound 12

[0053]

[0054] A yellow solid was obtained according to the preparation method of Example 1, with a yield of 44%; 1 1H NMR (400 MHz, CDCl3): δ 12.35 (1H, s), 7.61 (1H, dd, J = 8.1, 1.6 Hz), 7.56 (1H, dd, J = 7.8, 1.6 Hz), 7.33 (1H, t, J = 7.9 Hz), 7.31–7.22 (4H, overlapped), 6.46 (1H, s), 4.00 (2H, s), 3.97 (3H, s), 3.76 (3H, s), 3.66 (3H, s). 1313C NMR (100 MHz, CDCl3): δ 178.9, 167.1, 158.8, 157.5, 153.9, 149.2, 145.4, 140.1, 134.5, 132.7, 131.6, 131.2, 129.7, 129.4, 129.0, 128.9, 126.9, 126.9, 125.8, 120.5, 105.8, 95.7, 61.7, 61.0, 56.5, 38.6. HRESIMS m / z 531.0627 [M+H] + (calcd for C 26 H 21 O8Cl2 + , 531.0608).

[0055] Example 13: Compound 13

[0056]

[0057] A yellow solid was obtained according to the preparation method of Example 1 with a yield of 47%; 1 1H NMR (400 MHz, CDCl3): δ 12.30 (1H, s), 7.61 (1H, dd, J = 7.9, 1.6 Hz), 7.57 (1H, dd, J = 7.9, 1.6 Hz), 7.34 (1H, t, J = 7.9 Hz), 7.24–7.15 (2H, overlapped), 6.86 (2H, overlapped), 6.46 (1H, s), 3.96 (3H, s), 3.81 (2H, s), 3.72 (3H, s), 3.69 (3H, s). 13 13C NMR (100 MHz, CDCl3): δ 178.6, 167.8, 163.1, 158.6, 157.34, 153.5, 148.6, 145.2, 139.8, 132.5, 130.8 (d, J = 8.6 Hz), 130.7 (d, J = 8.6 Hz) (CH×2), 129.5, 128.6, 128.5, 128.4 (d, J = 3.3 Hz), 128.3 (d, J = 3.3 Hz), 126.7, 125.5, 115.2 (d, J = 21.2 Hz), 115.0 (d, J = 21.2 Hz) (CH×2), 105.5, 95.5, 61.4, 60.8, 56.3, 39.9. HRESIMS m / z 515.0892 [M+H] + (calcd for C 26 H 21 O8ClF + , 515.0903).

[0058] Example 14: Compound 14

[0059]

[0060] A yellow solid was obtained according to the preparation method of Example 1, with a yield of 47%; HRESIMS m / z 573.1921 [M+H] + (calcd for C 29 H 33 O8N2Cl + , 573.1918).

[0061] Example 15: Compound 15

[0062]

[0063] A yellow solid was obtained according to the preparation method of Example 1, with a yield of 52%; 1 H NMR (400 MHz, DMSO-d6): δ 12.23 (1H, s), 7.98–7.83 (1H, m), 7.77 (1H, d, J = 8.7 Hz), 7.75–7.70 (1H, m), 7.54 (1H, t, J = 7.9 Hz), 6.60 (2H, d, J = 2.4 Hz), 6.46 (1H, s), 6.44 (2H, d, J = 3.9 Hz), 3.88 (3H, s), 3.67 (3H, s), 3.60 (3H, s). 13 C NMR (100 MHz, DMSO-d6): δ 178.3, 160.6, 158.6, 156.5, 154.6, 154.1, 148.4, 145.1, 139.4, 136.0, 134.3, 132.6, 130.0, 128.4, 127.7, 127.4, 126.3, 114.7, 111.5, 110.9, 104.9, 96.2, 60.9, 60.5, 56.6. HRESIMS m / z 531.0562 [M+H] + (calcd for C 25 H 20 O8NCl2 + , 532.0560).

[0064] Example 16: Compound 16

[0065]

[0066] A yellow solid was obtained according to the preparation method of Example 1, with a yield of 48%; 11H NMR (400 MHz, CDCl3): δ 12.25 (1H, s), 7.99 (1H, d, J = 1.9 Hz), 7.97 (1H, d, J = 1.9 Hz), 7.68 (1H, dd, J = 8.1, 1.6 Hz, 1H), 7.63 (1H, dd, J = 8.1, 1.6 Hz), 7.59 (1H, d, J = 1.9 Hz), 7.57 (1H, d, J = 1.9 Hz), 7.40 (1H, t, J = 7.9 Hz,), 6.38 (1H, s), 3.90 (3H, s), 3.75 (3H, s), 3.75 (3H, s). 13 13C NMR (100 MHz, CDCl3): δ 178.7, 163.0, 158.8, 157.5, 154.1, 149.0, 145.6, 140.2, 132.9, 132.2 (CH×2), 131.9 (CH×2), 129.9, 129.4, 129.0, 129.0, 127.5, 127.1, 126.3, 105.8, 95.9, 61.7, 61.2, 56.5. HRESIMS m / z 560.9940 [M+H] + (calcd for C 25 H 19 O8BrCl + , 560.9946).

[0067] Example 17: Compound 17

[0068]

[0069] A yellow solid was obtained according to the preparation method of Example 1, with a yield of 50%; 1 1H NMR (400 MHz, CDCl3): δ 12.30 (1H, s), 8.07 (1H, d, J = 8.9 Hz), 7.67 (1H, dd, J = 8.1, 1.6 Hz), 7.61 (1H, dd, J = 7.9, 1.6 Hz), 7.38 (1H, t, J = 7.9 Hz), 6.94 (1H, d, J = 2.5 Hz), 6.80 (1H, dd, J = 8.9, 2.5 Hz), 6.39 (1H, s), 3.90 (3H, s), 3.83 (3H, s), 3.74 (3H, s), 3.73 (3H, s). 1313C NMR (100 MHz, CDCl3): δ 179.0, 163.4, 161.4, 158.7, 157.5, 154.3, 149.1, 145.7, 140.2, 137.0, 134.2, 132.8, 129.8, 129.1, 129.0, 127.0, 126.4, 119.8, 116.9, 112.9, 105.8, 95.8, 61.8, 61.2, 56.5, 55.9. HRESIMS m / z 547.0560 [M+H] + (calcd for C 26 H 21 O9Cl2 + , 547.0557). 50% yield.

[0070] Example 18: Compound 18

[0071]

[0072] A yellow solid was obtained by referring to the preparation method of Example 1, with a yield of 43%; 1 1H NMR (400 MHz, CDCl3): δ 12.34 (1H, s), 7.70 (1H, dd, J = 8.1, 1.6 Hz), 7.57 (1H, dd, J = 7.8, 1.6 Hz), 7.42 (1H, t, J = 7.9 Hz), 7.35 (1H, td, J = 8.3, 5.8 Hz), 7.19 (1H, dt, J = 8.1, 1.0 Hz), 7.07–6.94 (1H, m), 6.44 (1H, s), 3.92 (3H, s), 3.74 (3H, s), 3.65 (3H, s). 1313C NMR (100 MHz, CDCl3): δ 179.1, 161.7, 160.0 (d, J = 245.5 Hz), 159.1 (d, J = 245.5 Hz), 158.7, 157.6, 153.9, 149.4, 145.0, 140.5, 133.3 (d, J = 8.6 Hz), 133.2 (d, J = 8.6 Hz), 133.0, 132.8 (d, J = 8.6 Hz), 132.7 (d, J = 8.6 Hz), 130.0, 129.1, 128.7, 127.7, 126.5, 126.1 (d, J = 3.1 Hz), 126.1 (d, J = 3.1 Hz), 120.5 (d, J = 21.5 Hz), 120.3 (d, J = 21.5 Hz), 115.0 (d, J = 21.5 Hz), 114.8 (d, J = 21.5 Hz), 105.9, 95.8, 61.6, 61.1, 56.5. HRESIMS m / z 535.0362 [M+H]+ + (calcd for C 25 H 18 O8Cl2F + , 535.0357).

[0073] Example 19: Compound 19

[0074]

[0075] A yellow solid was obtained according to the preparation method of Example 1, with a yield of 43%; HRESIMS m / z 551.0009 [M+H]+ + (calcd for C 25 H 18 O8Cl3 + , 551.0012).

[0076] Example 20: Compound 20

[0077]

[0078] A yellow solid was obtained according to the preparation method of Example 1, with a yield of 44%; 11H NMR(400 MHz, CDCl3): δ 12.25 (1H, s), 8.13 (1H, dd, J = 8.2, 1.0 Hz), 7.74–7.69 (2H, overlapped), 7.67 (1H, dd, J = 7.9, 1.6 Hz), 7.60–7.52 (1H, m), 7.44 (1H, t, J = 7.9 Hz), 6.41 (1H, s), 3.91 (3H, s), 3.74 (3H, s), 3.71 (3H, s). 13 13C NMR(100 MHz, CDCl3): δ 178.4, 160.6, 158.4, 157.1, 153.2, 148.6, 144.7, 139.8, 134.8 (d, J = 3.4 Hz), 134.8 (d, J = 3.4 Hz), 132.5, 132.2, 131.3, 129.5, 128.5, 128.4, 128.0 (q, J = 36.6 Hz), 128.0 (q, J = 36.6 Hz), 127.9 (q, J = 36.6 Hz), 127.9 (q, J = 36.6 Hz), 127.0, 125.7, 123.7, 123.6, 123.4 (q, J = 267.0 Hz), 123.4 (q, J = 267.0 Hz), 123.3 (q, J = 267.0 Hz), 123.3 (q, J = 267.0 Hz), 105.3, 95.5, 61.2, 60.8, 56.1. HRESIMS m / z 585.0332 [M + H] + (calcd for C 26 H 18 O8Cl2F3 + , 585.0325).

[0079] Example 21: Compound 21

[0080]

[0081] A yellow solid was obtained according to the preparation method of Reference Example 1, with a yield of 56%; HRESIMS m / z 533.0329 [M + H] + (calcd for C 25 H 19 O9Cl2 + , 533.0331).

[0082] Example 22: Compound 22

[0083]

[0084] A yellow solid was obtained according to the preparation method of Reference Example 1, with a yield of 37%;1 1H NMR (400 MHz, CDCl3): δ 12.28 (1H, s), 7.67 (1H, dd, J = 7.9, 1.6 Hz), 7.64 (1H, dd, J = 7.9, 1.6 Hz), 7.40 (1H, t, J = 7.9 Hz), 7.35 (1H, d, J = 3.6 Hz), 6.40 (1H, s), 6.34 (1H, d, J = 3.6 Hz), 3.92 (3H, s), 3.80 (3H, s), 3.75 (3H, s). 13 13C NMR (100 MHz, CDCl3): δ 178.9, 158.7, 157.5, 153.9, 153.7, 148.9, 144.7, 142.7, 142.2, 140.2, 132.8, 129.9, 129.0, 128.9, 127.2, 126.2, 122.4, 109.5, 105.7, 95.8, 61.7, 61.1, 56.4. HRESIMS m / z 507.0251 [M + H] + (calcd for C 23 H 17 O9Cl2 + , 507.0244).

[0085] Example 23: Compound 23

[0086]

[0087] A yellow solid was obtained according to the preparation method of Reference Example 1, with a yield of 40%; 1 1H NMR (400 MHz, CDCl3): δ 12.27 (1H, s), 7.73 (1H, d, J = 4.1 Hz), 7.66 (1H, dd, J = 8.1, 1.6 Hz), 7.61 (1H, dd, J = 8.1, 1.6 Hz), 7.39 (1H, t, J = 7.9 Hz), 6.94 (1H, d, J = 4.1 Hz), 6.40 (1H, s), 3.91 (3H, s), 3.78 (3H, s), 3.76 (3H, s). 13 13C NMR (100 MHz, CDCl3): δ 179.0, 158.8, 157.8, 157.6 (C×2), 153.9, 149.0, 145.1, 140.2, 139.4, 135.2, 132.9, 129.9, 129.6, 129.1, 127.8, 127.3, 126.4, 105.8, 95.9, 61.8, 61.2, 56.5. HRESIMS m / z 523.0022 [M + H] +(calcd for C 23 H 17 O8Cl2S + ,523.0016). 40% yield.

[0088] Example 24: Compound 24

[0089]

[0090] A yellow solid was obtained according to the preparation method of Reference Example 1, with a yield of 27%; 1 H NMR(400MHz, CDCl3): δ12.16(1H, s), 9.60(1H, s), 7.73(1H, dd, J=7.8, 1.6Hz), 7.70(1H, dd, J=8.1, 1.6Hz), 7.62(1H, d, J=1.9Hz), 7.45–7.37(2H, overlapped), 7.30–7.27(2H, overlapped), 6.33(1H, s), 3.91(3H, s), 3.89(3H, s), 3.74(3H, s). 13 C NMR(100MHz, CDCl3): δ178.6, 158.6, 157.5, 157.3, 153.6, 148.5, 144.8, 140.1, 135.6, 132.7, 129.9, 129.0, 128.0, 127.9, 126.9, 126.5, 126.3, 126.2, 125.6, 121.6, 113.3, 110.4, 105.4, 95.6, 61.8, 61.0, 56.2. HRESIMS m / z556.0566[M + H] + (calcd for C 27 H 20 O8NCl2 + ,556.0560).

[0091] Example 25: Compound d

[0092]

[0093] Weigh compound a(15mg, 1eq), 2-chlorobenzyl bromide(20.3mg, 2.5eq) and K2CO3(16.4mg, 3eq) into a sealed tube in sequence, add 3mL of anhydrous acetone, stir until completely dissolved, react at 60℃ for 4–5h, monitor the reaction by TLC, after the reaction is complete, quench the reaction with water. Extract the reaction solution three times with ethyl acetate solvent, combine the organic layers, concentrate under reduced pressure to obtain the product, and treat it by normal-phase silica gel column chromatography to obtain a yellow solid, with a yield of 80%; 11H NMR (400 MHz, CDCl3): δ 12.38 (1H, s), 7.60 (1H, dd, J = 8.0, 1.8 Hz), 7.40 (2H, ddd, J = 9.3, 7.5, 1.8 Hz), 7.26–7.18 (2H, m), 7.10 (2H, pd, J = 7.5, 1.8 Hz,), 6.42 (1H, s), 5.17 (2H, s), 3.93 (3H, s), 3.79 (3H, s), 3.73 (3H, s). 13 13C NMR (100 MHz, CDCl3): δ 179.0, 158.5, 157.5, 155.3, 153.5, 149.1, 140.0, 134.3, 133.2, 133.1, 129.8, 129.6, 129.5, 129.3, 129.1, 129.0, 127.1, 126.9, 125.2, 105.9, 95.7, 73.2, 61.7, 60.9, 56.5. HRESIMS m / z 503.0664 [M+H] + (calcd for C 25 H 21 O7Cl2 + , 503.0659).

[0094] Example 26: Compound m

[0095]

[0096] A white solid was obtained by referring to the preparation method of Example 1, with a yield of 40%; 1 1H NMR (400 MHz, CDCl3): δ 8.27–8.10 (2H, m), 8.10–7.99 (2H, m), 7.66 (1H, dd, J = 8.0, 1.6 Hz), 7.62 (1H, dd, J = 8.0, 1.6 Hz), 7.49 (1H, d, J = 2.0 Hz), 7.47 (1H, d, J = 2.0 Hz), 7.42 (1H, d, J = 2.0 Hz), 7.41–7.36 (2H, m), 6.74 (1H, s), 3.93 (3H, s), 3.85 (3H, s), 3.61 (3H, s). 1313C NMR (100 MHz, CDCl3): δ 173.1, 164.8, 162.8, 156.1, 152.5, 150.7, 145.7, 145.1, 142.0, 140.5, 140.2, 135.2, 132.7, 132.1 (CH×2), 131.9 (CH×2), 129.9, 129.1 (CH×2), 129.1 (CH×2), 129.0, 128.2, 127.2, 127.1, 126.4, 112.1, 105.1, 61.7, 61.0, 56.7. HRESIMS m / z 655.0325 [M+H] + (calcd for C 32 H 22 O9Cl3 + , 655.0324). 40% yield.

[0097] Example 27: Activity Tests against Candida spp. and Cryptococcus neoformans

[0098] (1) Test Strains: Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, Candida auris, and Cryptococcus neoformans; The determination was carried out according to the microbroth dilution method CLSI-M27-A3 formulated by the Clinical and Laboratory Standards Institute (CLSI) of the United States.

[0099] (2) Strain Recovery: The fungal strains stored in the ultra-low temperature refrigerator were recovered at room temperature for 30 min, then activated on the YPD medium plate by streaking in a laminar flow hood. After incubating in a biochemical incubator at 30 °C for 48 h, subculture activation was carried out again. After subculturing 2 times, a single colony was picked with an inoculation loop and inoculated into the YPD medium, and cultured in a shaker at 160 rpm and 30 °C until the logarithmic growth phase.

[0100] (3) Sample Preparation: All compounds of the present invention were prepared into a stock solution of 3.2 mg / mL, and completely dissolved and mixed using a vortex oscillator and ultrasound, and set aside.

[0101] (4) Activity Screening: The fungal broth in the logarithmic growth phase was collected by centrifugation at 3000 rpm for 3 min, resuspended with PBS, compared with the standard No. 1 McFarland turbidity tube, and the concentration of the bacterial suspension was adjusted to 3×10 8 CFU / mL, and then diluted to 1×10 with YPD medium5 Reserve at CFU / mL. Add 198 μL of the bacterial solution and 2 μL of the medicinal solution into a 96-well plate, so that the final concentrations in the wells are 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, and 0.0625 μg / mL in sequence. Set positive control amphotericin B (AmB) and negative control in the experiment. Each group is in parallel for 3 times. Observe the results after incubating in a biochemical incubator at 30 °C for 24 h.

[0102] (5) Result observation: After culturing the 96-well plate at 30 °C for 24 h, visually observe the inhibitory effects of all compounds of the present invention, and take the minimum concentration corresponding to the clear solution well as the MIC value.

[0103] Example 28: Activity test of Aspergillus fumigatus

[0104] (1) Test strain: Aspergillus fumigatus, determined according to the microbroth dilution method CLSI-M27-A3 formulated by CLSI.

[0105] (2) Preparation of spore suspension: Spread Aspergillus fumigatus on PDA medium in a laminar flow hood, activate it at 28 °C, and after culturing for one week, conidia will be produced on the surface of the pathogenic fungus. Add 3 mL of sterile water, gently wash and scrape the spores on the surface of the fungus, then transfer them to a 250 mL conical flask pre-placed with several sterile glass beads and sterilized. After shaking well, filter with sterilized absorbent cotton, and then rinse the filter residue with sterile water 2 - 3 times. Prepare the mother liquor concentration to be 1×10 7 CFU / mL for reserve.

[0106] (3) Activity screening: Dilute the spore suspension to 1×10 5 CFU / mL. Add 198 μL of the bacterial solution and 2 μL of the medicinal solution into a 96-well plate, so that the final concentrations in the wells are 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, and 0.0625 μg / mL in sequence. Set positive control amphotericin B (AmB) and negative control in the experiment. Each group is in parallel for 3 times. Culture at 28 °C in a biochemical incubator for 48 h, observe the results, and take the sample concentration of the last well without precipitation (no hyphal growth) as the MIC value.

[0107] Test results:

[0108] Table 1 Inhibitory activities of some compounds of the present invention against different fungi

[0109]

[0110] Note: In the table, "++++" means MIC ≤ 0.125 μg / mL; "+++" means 0.125 μg / mL < MIC ≤ 0.5 μg / mL; "++" means 0.5 μg / mL < MIC ≤ 2 μg / mL; "+" means 2 μg / mL < MIC ≤ 8 μg / mL; "o" means 8 μg / mL < MIC ≤ 32 μg / mL; "-" means MIC > 32 μg / mL.

[0111] Note: In this invention, compound a was tested in parallel and compounds b - q were used as controls.

[0112] Conclusion:

[0113] (1) Through the activity screening of 6 pathogenic fungi, it was found that the compounds 1 - 24 of this invention showed significant inhibitory activity against Candida albicans, and the activity was generally higher than that of compound a. However, the same - type compounds b - q did not show inhibitory activity at the maximum screening concentration (32 μg / mL), indicating the structural particularity of the compounds 1 - 24 of this invention.

[0114] (2) At the maximum screening concentration, the compounds 1 - 24 of this invention did not show inhibitory activity against Candida glabrata, Candida parapsilosis, Candida auris and Cryptococcus neoformans. At the same time, the inhibitory activities of the compounds 1 - 24 against Candida tropicalis and Aspergillus fumigatus were lower than those of compound a, but the inhibitory activity against Candida albicans was generally enhanced compared with compound a, indicating that the compounds 1 - 24 of this invention selectively inhibit the growth of Candida albicans.

[0115] (3) The compounds of this invention have strong inhibitory activity against Candida albicans and can be made into drugs for treating Candida albicans infections, with broad application prospects.

[0116] Finally, it should be noted that there are other ways to implement this invention; accordingly, the embodiments of this invention are illustrative, but not limited to the content described in this invention, and may also be modifications within the scope of this invention or equivalent content added in the claims; all publications or patents cited in this invention will be used as references for this invention.

Claims

1. A chlorinated compound of formula I, or a pharmaceutically acceptable salt thereof, or a solvate of said salt, characterized in that The compound has the following structure: wherein R1 and R2 are each independently optionally H and R1 and R2 cannot both be H at the same time. Specifically, 2. An anti-Candida albicans agent, characterized in that It contains the compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

3. Use of the compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an agent against Candida albicans.

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