Use of an indole-3-aryl ketone derivative for the preparation of a medicament for the treatment or prevention of an infectious disease caused by Staphylococcus aureus

Abstract

The present application belongs to the technical field of medicine, and relates to a use of an indole-3-aryl ketone derivative in preparation of a medicine for treating or preventing an infectious disease caused by Staphylococcus aureus, in particular, in preparation of a medicine for treating or preventing an infectious disease caused by drug-resistant Staphylococcus aureus. A chemical structural formula of the indole-3-aryl ketone derivative of the present application is shown as formula I. The results of the present application show that the compound I (i.e. the indole-3-aryl ketone derivative shown as formula I) exhibits strong inhibitory activity on methicillin-resistant Staphylococcus aureus ATCC43300, and the inhibitory effect is dependent on a concentration gradient, and the MIC 50 value is 27.45 ug / mL, while the MIC 50 value of the positive medicine, streptomycin sulfate, is greater than 200 ug / mL. Therefore, the indole-3-aryl ketone derivative can be used in treatment or prevention of an infectious disease caused by Staphylococcus aureus.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to the use of an indole-3-aryl ketone derivative in the preparation of medicaments for treating or preventing infectious diseases caused by Staphylococcus aureus, particularly in the preparation of medicaments for treating or preventing infectious diseases caused by drug-resistant Staphylococcus aureus. Background Technology

[0002] Staphylococci are a group of Gram-positive cocci, with *Staphylococcus aureus* being the most pathogenic species. They can cause everything from skin infections (such as abscesses and cellulitis) to life-threatening sepsis, pneumonia, and endocarditis. The widespread use of penicillin in the 1940s effectively controlled their spread, but subsequent evolution of resistance led to methicillin-resistant *Staphylococcus aureus* (MRSA), becoming a major pathogen in hospital and community infections. MRSA evades the effects of β-lactam antibiotics by altering the penicillin-binding protein (PBP2a). Furthermore, some strains exhibit reduced sensitivity to vancomycin (a last-line defense drug) (such as VISA / VRSA), and even multidrug-resistant (MDR) phenotypes. Global surveillance shows that the detection rate of MRSA in healthcare institutions is as high as 30%-50%, and the clonal spread of community-acquired MRSA (CA-MRSA) further complicates prevention and control. Drug-resistant Staphylococcus aureus (DRG) leads to longer hospital stays, higher treatment costs, and forces clinicians to rely on more potent alternative drugs. The World Health Organization (WHO) has listed it as a "high-priority drug-resistant pathogen," necessitating the development of novel antimicrobial agents.

[0003] Indole-3-aryl ketone derivatives are an important class of heterocyclic compounds. Due to their core structure combining an indole ring and an aryl ketone group, they show broad application prospects in various fields, such as anti-tumor drug development, nervous system drug development, and agricultural pesticides. Currently, no compounds of this type have been reported to combat pathogenic bacterial infections. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides the use of an indole-3-aryl ketone derivative in the preparation of a medicament for treating or preventing infectious diseases caused by Staphylococcus aureus.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0006] Use of an indole-3-aryl ketone derivative and / or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of infectious diseases caused by Staphylococcus aureus, wherein the chemical structure of the indole-3-aryl ketone derivative is shown in Formula I;

[0007] , Formula I.

[0008] Further, the *Staphylococcus aureus* is a drug-resistant *Staphylococcus aureus*. Preferably, the *Staphylococcus aureus* is at least one of methicillin-intermediate *Staphylococcus aureus* and methicillin-resistant *Staphylococcus aureus*. More preferably, the *Staphylococcus aureus* is methicillin-resistant *Staphylococcus aureus* ATCC43300.

[0009] Furthermore, the drug is used in combination with a compound of Formula I and a pharmaceutically acceptable carrier.

[0010] Furthermore, in the aforementioned drug, an indole-3-aryl ketone derivative of the structure shown in Formula I or a pharmaceutically acceptable salt thereof is used as the active pharmaceutical ingredient.

[0011] Furthermore, in the aforementioned drug, the mass fraction of the active pharmaceutical ingredient is 0.1% to 99%.

[0012] In this invention, the meaning of methicillin-resistant Staphylococcus aureus (MRSA) can be found in the description in Chinese patent application CN109498619A. The meaning of methicillin-resistant Staphylococcus aureus (MRSA) is common knowledge in this field.

[0013] This invention has the following technical advantages: It provides the use of an indole-3-aryl ketone derivative in the preparation of a medicament for treating or preventing infectious diseases caused by Staphylococcus aureus. The results of this invention show that compound I (i.e., the indole-3-aryl ketone derivative as shown in Formula I) exhibits strong inhibitory activity against methicillin-resistant Staphylococcus aureus ATCC43300, with the inhibitory effect being concentration-gradient dependent, and the MIC... 50 The value was 27.45 μg / mL, while the MIC of the positive control drug streptomycin sulfate was... 50 The value is greater than 200 μg / mL. Therefore, the aforementioned indole-3-aryl ketone derivative has great potential for the treatment or prevention of infectious diseases caused by Staphylococcus aureus, especially in the treatment or prevention of infectious diseases caused by drug-resistant Staphylococcus aureus. Attached Figure Description

[0014] Figure 1 The graph shows the inhibition of the growth of methicillin-resistant Staphylococcus aureus ATCC43300 by compound I.

[0015] Figure 2A graph showing the inhibition of the growth of methicillin-resistant Staphylococcus aureus ATCC43300 by streptomycin sulfate.

[0016] Figure 3 For compound I 1 H-NMR (400MHz, DMSO- d 6) Spectrum.

[0017] Figure 4 For compound I 13 C-NMR (100MHz, DMSO- d 6) Spectrum.

[0018] Figure 5 For compound I 19 F-NMR (376MHz, DMSO- d 6) Spectrum. Detailed Implementation

[0019] The technical solutions of the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, but the present invention is not limited to the following technical solutions.

[0020] Unless otherwise specified, all materials used in the following examples are commercially available or conventionally obtainable.

[0021] Streptomycin sulfate and DMSO were purchased from Sigma.

[0022] Tryptone soybean broth (TSB) was purchased from Guangdong Huankai Microbial Technology Co., Ltd.

[0023] Agar powder was purchased from Scientific Research Special.

[0024] Methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300 was purchased from ATCC (American Center for Type Culture Collection, Manassas, Virginia).

[0025] Example 1 Synthesis of Compound I

[0026] Synthesize indole-3-aryl ketone derivatives as shown in Formula I (hereinafter collectively referred to as Compound I):

[0027] , Formula I.

[0028] The specific method for synthesizing compound I has been disclosed in the specification of Chinese patent application 202511104457.1.

[0029] The synthetic route for compound I is as follows:

[0030]

[0031] Synthetic steps of formula (I): Under air atmosphere, acenaphthene quinone (M1) (0.3 mmol), compound M2 (0.2 mmol), cesium carbonate (0.4 mmol), and TFE (M3) (2 mL) were added to a 10 mL transparent open reaction tube. The mixture was stirred for 12 hours at room temperature under light at a wavelength of 460 nm and a power of 24 W. The reaction was quenched with saturated NaCl aqueous solution and extracted with 30 mL EtOAc. The organic layers were then combined, dried over anhydrous Na2SO4, filtered, and the ethyl acetate in the system was evaporated under reduced pressure. The residue was purified by silica gel rapid column chromatography ((dichloromethane:petroleum ether = 1: 10)) to give compound I. The product was further identified by NMR and HRMS.

[0032] The structural characterization results of compound I are as follows:

[0033] Yellow solid; Mp: 147.9 ℃; 89 mg, yield: 91%; IR (KBr): 3447, 2877, 2801, 1697, 1559, 1488, 1475, 1468, 858, 809, 669 cm⁻¹ -1 ; 1 HNMR (400 MHz, DMSO- d 6) δ 8.41 (d, J = 8.4 Hz, 1H, ArH), 8.31 (dd, J = 8.3,1.4 Hz, 1H, ArH), 8.27 – 8.21 (m, 2H, ArH), 7.98 (dd, J = 7.1, 1.3 Hz, 1H,ArH), 7.93 – 7.86 (m, 2H, ArH), 7.72 (q, J = 7.6 Hz, 2H, ArH), 7.58 (dd, J =8.4, 1.7 Hz, 1H, ArH), 4.39 (q, J = 8.9 Hz, 2H, CH2). 13 C NMR (100 MHz, DMSO- d6) δ 191.5, 166.9, 139.0, 137.6, 136.4, 134.7, 133.7, 132.0, 130.4, 130.2,129.4, 128.7, 127.1, 126.3, 126.0, 125.5 (q, J = 272.7 Hz), 124.0 (q, J =33.3 Hz), 123.6 (q, J = 278.8 Hz), 122.5, 118.8 (q, J = 3.0 Hz), 116.4, 110.3(q, J = 5.0 Hz), 60.4 (q, J = 35.4 Hz). 19 F NMR (376 MHz, DMSO- d 6) δ -59.33, -72.35 (t, J = 9.0 Hz). HRMS (ESI-TOF) m / z: [M +Na] + calcd for C 23 H 13 F6NNaO3: 488.0692, Found: 488.0697; Related spectra are as follows Figures 3-5 As shown.

[0034] Example 2: Antibacterial activity test of the indole-3-aryl ketone derivative described in Example 1

[0035] Culture of methicillin-resistant Staphylococcus aureus ATCC43300: Methicillin-resistant Staphylococcus aureus ATCC43300 was streaked onto TSB solid medium and incubated at 37°C for 24 hours. Then, single colonies were picked and inoculated onto TSB liquid medium and incubated at 37°C for 24 hours before use.

[0036] Compound (I) and streptomycin sulfate were dissolved separately in DMSO (dimethyl sulfoxide). Solutions with concentrations of 200 μg / mL, 100 μg / mL, 40 μg / mL, 20 μg / mL, 10 μg / mL, 5 μg / mL, 2.5 μg / mL, and 1 μg / mL were then prepared using DMSO and Staphylococcus aureus liquid medium (TSB). The concentration of DMSO was 1%. Methicillin-resistant Staphylococcus aureus (MRSA) ATCC43300 was added to each well of a 96-well plate to achieve a final concentration of 5 × 10⁻⁶. 5CFU / mL, add 100 μL of prepared culture medium containing compound I to each well, and incubate in a constant temperature incubator at 37℃ for 24 h. Then, use an ELISA reader to measure the absorbance of each well at a wavelength of 625 nm and calculate the average OD value of each well. Analyze the changes in bacterial growth by comparing with the control group (DMSO-treated cells). Each concentration should be replicated at least 3 times. The experiment also included a culture medium blank control and a methicillin-resistant Staphylococcus aureus ATCC43300 control group with the same bacterial concentration as the treatment group. The percentage of the absorbance value of the experimental group (minus the blank control) relative to the absorbance value of the control group (minus the blank control) represents the survival rate or growth level of Staphylococcus aureus, i.e., the control group is assumed to be 100%. MIC50 (50% minimum inhibitory concentration) was calculated according to the Reed & Muench method. The calculation method is referenced in the literature (Bioorganic & Medicinal Chemistry Letters, 1991, 1(11), 611-614).

[0037] Figure 1 The results showed that compound I exhibited strong inhibitory activity against methicillin-resistant Staphylococcus aureus (ATCC43300), with the inhibitory effect being concentration-dependent. (MIC) 50 The value was 27.45 μg / mL. Meanwhile, the MIC of the positive control drug streptomycin sulfate was... 50 Value greater than 200 μg / mL ( Figure 2 ).

[0038] The above description is a preferred embodiment of the present invention and is not intended to limit the present invention. Any simple modifications, alterations, and equivalent structural transformations made to the above embodiments based on the technical essence of the present invention shall still fall within the protection scope of the present invention.

Claims

1. Use of an indol-3-aryl ketone derivative and / or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of an infectious disease caused by Staphylococcus aureus, characterized in that, The chemical structural formula of the indole-3-aryl ketone derivative is shown as formula I. Formula I.

2. Use according to claim 1, characterized in that, The Staphylococcus aureus is drug-resistant Staphylococcus aureus.

3. Use according to claim 1, characterized in that, The Staphylococcus aureus is at least one of methicillin intermediate Staphylococcus aureus and methicillin-resistant Staphylococcus aureus.

4. Use according to claim 1, characterized in that, The Staphylococcus aureus is methicillin-resistant Staphylococcus aureus ATCC43300.

5. Use according to claim 1, characterized in that, The medicine is combined with a pharmaceutically acceptable carrier.

6. Use according to claim 1, characterized in that, The medicine uses the indole-3-aryl ketone derivative or its pharmaceutically acceptable salt as the active pharmaceutical ingredient.

7. Use according to claim 6, characterized in that, The mass fraction of the active pharmaceutical ingredient in the medicine is 0.1%-99%.

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