A natural product 3-methylcarbazole derivative, a preparation method and application thereof

Abstract

The application discloses a natural product 3-methylcarbazole derivative with a general formula B and a preparation method and application thereof in the technical field of organic chemistry. S. aureus S. epidermidis The derivative has good antibacterial activity, can significantly inhibit Staphylococcus aureus, Staphylococcus epidermidis and methicillin-resistant Staphylococcus aureus (MRSA), and can be used for preparing a drug for treating related bacterial infections.​

Description

Technical Field

[0001] This invention relates to the field of organic chemistry, specifically to a natural product 3-methylcarbazole derivative, its preparation method, and its applications. Background Technology

[0002] Currently, with the widespread use of antibiotics, various drug-resistant bacteria, multidrug-resistant bacteria, and superdrug-resistant bacteria have emerged, seriously threatening human health. This has led to many infectious diseases in clinical practice being incurable.

[0003] Since naturally derived substances have been used to treat human diseases, their diverse chemical structures and biological activities, as well as their degree of compliance with human body, have become excellent starting points for drug development.

[0004] Therefore, it is of great significance to start with natural products, modify and optimize their structures, and develop novel antibacterial drugs to address these worrying problems. Summary of the Invention

[0005] This invention utilizes knowledge of organic chemistry, medicinal chemistry, and natural product structure modification and optimization to design and synthesize a series of 3-methylcarbazole derivatives for antibacterial activity studies. Results show that some target compounds exhibit good antibacterial activity against Staphylococcus aureus (Staphylococcus aureus). S. aureus Staphylococcus epidermidis ( S. epidermidis It has a significant inhibitory effect on both methicillin-resistant Staphylococcus aureus (MRSA) and other pathogens.

[0006] Firstly, to achieve the above objectives, the present invention adopts the following technical solution: a natural product 3-methylcarbazole derivative having the following general chemical structural formula B: , Wherein, R1 is selected from hydrogen, fluorine or methoxy; R2 is selected from phenyl, methyl-substituted phenyl, fluorine-substituted phenyl, chlorine-substituted phenyl, bromo-substituted phenyl, nitro-substituted phenyl, methoxy-substituted phenyl, thiophene, methyl-substituted thiophene, furanyl or methyl-substituted furanyl.

[0007] Preferably, the 3-methylcarbazole derivative is selected from any one of the following: B3: R1 is H, R2 is 4-CH3Ph; B4: R1 is H, R2 is 2-FPh; B5: R1 is H, R2 is 3-FPh; B6: R1 is H, R2 is 4-FPh; B11: R1 is H, R2 is 4-NO2Ph; B12: R1 is H, R2 is 3,4,5-tri-OCH3Ph; B13: R1 is H, R2 is 3,4,5-tri-FPh; B17: R1 is 6-F, R2 is 3,4,5-tri-FPh; B18: R1 is 8-F, R2 is 3,4,5-tri-FPh; B19: R1 is 6-OCH3, and R2 is 3,4,5-tri-FPh.

[0008] In a second aspect, the present invention provides a drug comprising the 3-methylcarbazole derivative described above, wherein the derivative is used as the sole active ingredient or in combination with an antibacterial drug or other antibacterial active ingredients.

[0009] Thirdly, the present invention also provides that the above-mentioned 3-methylcarbazole derivatives, such as any one or more combinations of B3, B5, B6, B11, B12, B13, B17, B18, and B19, or drugs containing them, can be used in the preparation of medicaments for treating and / or preventing Staphylococcus aureus infections.

[0010] Fourthly, the present invention also provides the use of any one or more combinations of the above-mentioned 3-methylcarbazole derivatives, such as B3, B5, B6, B11, B12, B13, B17, B18, and B19, or pharmaceuticals containing them, in the preparation of medicaments for the treatment and / or prevention of Staphylococcus epidermidis infections.

[0011] Fifthly, the present invention also provides the use of the above-mentioned 3-methylcarbazole derivatives, such as any one or more combinations of B6, B11, B12, B13, B17, B18, and B19, or drugs containing them, in the preparation of medicaments for treating and / or preventing methicillin-resistant Staphylococcus aureus infections.

[0012] In a sixth aspect, the present invention also provides the above-mentioned 3-methylcarbazole derivative, preferably B4 or a drug containing said B4, for use in the preparation of a drug for treating and / or preventing Escherichia coli infectious diseases.

[0013] In a seventh aspect, the present invention provides a method for preparing the 3-methylcarbazole derivative, which is prepared according to the following synthetic route: .

[0014] The method specifically includes the following steps: Preparation of Compound 1: Phenylhydrazine hydrochloride or substituted phenylhydrazine, acetic acid and 4-methylcyclohexanone were mixed and reacted under heating conditions. After the reaction was completed, the mixture was cooled, quenched with distilled water, and cooled to crystallize, yielding an intermediate. The obtained intermediate was mixed with iodine and dimethyl sulfoxide and reacted under heating conditions. After the reaction was completed, the mixture was cooled, quenched with concentrated hydrochloric acid, stirred with an appropriate amount of saturated sodium thiosulfate solution, extracted with ethyl acetate, washed, dried, and purified to obtain Compound 1. Preparation of Compound 3: Hydroxylamine hydrochloride was reacted with benzaldehyde or substituted benzaldehyde in an alcohol-water mixed solvent, washed with an appropriate amount of saturated brine, extracted with dichloromethane, dried, and concentrated to obtain an intermediate; this intermediate was then reacted with... N -Chlorosuccinimide, N , N The reaction with dimethylformamide was quenched with saturated brine, extracted with ethyl acetate, washed, dried, and purified to obtain compound 2; compound 2 was reacted with 3-bromopropyne in dichloromethane and saturated NaHCO3 solution, and after washing, drying, and purification, compound 3 was obtained. Preparation of compound B: Compounds 1 and 3 were reacted with Cs₂CO₃, N , N The reaction with dimethylformamide was quenched with saturated brine, extracted with ethyl acetate, washed, dried, and purified to give compound B.

[0015] Preferably, as an improvement, in the preparation of compound 1, the reaction temperature under the heating conditions is 80~130℃. Detailed Implementation

[0016] The present invention will be further described below with reference to the embodiments. However, the present invention is not limited to the following embodiments. It is foreseeable that various changes may occur in the implementation when those skilled in the art combine it with the prior art.

[0017] The natural product 3-methylcarbazole derivative of this invention has the structure of general formula B, and its synthetic route is as follows: .

[0018] Example 1: Preparation of compound B12 Preparation of Compound 1: 20 mmol of phenylhydrazine hydrochloride, 10.00 mL of acetic acid, and 20 mmol of 4-methylcyclohexanone were weighed and reacted at 100 °C. After 30 min, the reaction was completed, cooled, and quenched with distilled water. After cooling, crystallization occurred, and a white solid was precipitated and set aside. 10 mmol of the above product, 4 mmol of iodine, and 5 mL of dimethyl sulfoxide were weighed and reacted at 80 °C for 11 h. After cooling, the reaction was quenched with concentrated hydrochloric acid, stirred with an appropriate amount of saturated sodium thiosulfate solution for 1 h, extracted with ethyl acetate, washed with saturated saline solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain Compound 1.

[0019] Preparation of compound 3: Weigh 10 mmol of hydroxylamine hydrochloride, 10 mmol of 3,4,5-trimethoxybenzaldehyde, 5 mL of ethanol, and 5 mL of water. React at room temperature for 30 min. Wash with an appropriate amount of saturated brine, extract with dichloromethane, dry under anhydrous sodium sulfate, and concentrate under reduced pressure for later use. Weigh 4 mmol and 6.22 mmol of the above-mentioned prepared compounds. N -Chlorosuccinimide and 5 mL N , N -Dimethylformamide was reacted at room temperature for 3 h, then quenched with saturated brine, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 2. 5 mmol of compound 2, 15 mmol of 3-bromopropyne, 10 mL of dichloromethane, and 5 mL of saturated NaHCO3 solution were weighed and reacted at room temperature for 12 h. After the reaction was complete, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 3.

[0020] Preparation of compound B12: Weigh 0.4 mmol of compound 1, 10.4 mmol of compound 3, 0.8 mmol of Cs2CO3 and 5 mL of... N , N -Dimethylformamide was reacted at room temperature for 8 h until the reaction ended. The reaction was quenched with saturated brine, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B12.

[0021] Example 2: Preparation of compound B13 Preparation of Compound 1: 20 mmol of phenylhydrazine hydrochloride, 10.00 mL of acetic acid, and 20 mmol of 4-methylcyclohexanone were weighed and reacted at 130 °C. After 20 min, the reaction was completed, cooled, and quenched with distilled water. After cooling, crystallization occurred, and a white solid was precipitated and set aside. 10 mmol of the above product, 4 mmol of iodine, and 5 mL of dimethyl sulfoxide were weighed and reacted at 100 °C for 11 h. After cooling, the reaction was quenched with concentrated hydrochloric acid, stirred with an appropriate amount of saturated sodium thiosulfate solution for 1 h, extracted with ethyl acetate, washed with saturated saline solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain Compound 1.

[0022] Preparation of compound 3: Weigh 10 mmol of hydroxylamine hydrochloride, 10 mmol of 3,4,5-trifluorobenzaldehyde, 5 mL of ethanol, and 5 mL of water. React at room temperature for 30 min. Wash with an appropriate amount of saturated brine, extract with dichloromethane, dry under anhydrous sodium sulfate, and concentrate under reduced pressure for later use. Weigh 4 mmol and 6.22 mmol of the above-mentioned prepared compounds. N -Chlorosuccinimide and 5 mL N , N -Dimethylformamide was reacted at room temperature for 3 h, then quenched with saturated brine, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 2. 5 mmol of compound 2, 15 mmol of 3-bromopropyne, 10 mL of dichloromethane, and 5 mL of saturated NaHCO3 solution were weighed and reacted at room temperature for 12 h. After the reaction was complete, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 3.

[0023] Preparation of compound B13: Weigh 0.4 mmol of compound 1, 10.4 mmol of compound 3, 0.8 mmol of Cs2CO3 and 5 mL of... N , N -Dimethylformamide was reacted at room temperature for 8 h until the reaction ended. The reaction was quenched with saturated brine, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B13.

[0024] Example 3: Preparation of compound B17 Preparation of Compound 1: 20 mmol of p-fluorophenylhydrazine hydrochloride, 10.00 mL of acetic acid, and 20 mmol of 4-methylcyclohexanone were weighed and reacted at 110 °C. After 20 min, the reaction was completed, cooled, and quenched with distilled water. After cooling, crystallization occurred, and a white solid was precipitated and set aside. 10 mmol of the above product, 4 mmol of iodine, and 5 mL of dimethyl sulfoxide were weighed and reacted at 100 °C for 10 h. After cooling, the reaction was quenched with concentrated hydrochloric acid, stirred with an appropriate amount of saturated sodium thiosulfate solution for 1 h, extracted with ethyl acetate, washed with saturated saline solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain Compound 1.

[0025] Preparation of compound 3: Weigh 10 mmol of hydroxylamine hydrochloride, 10 mmol of 3,4,5-trifluorobenzaldehyde, 5 mL of ethanol, and 5 mL of water. React at room temperature for 30 min. Wash with an appropriate amount of saturated brine, extract with dichloromethane, dry under anhydrous sodium sulfate, and concentrate under reduced pressure for later use. Weigh 4 mmol and 6.22 mmol of the above-mentioned prepared compounds. N -Chlorosuccinimide and 5 mL N , N -Dimethylformamide was reacted at room temperature for 3 h, then quenched with saturated brine, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 2. 5 mmol of compound 2, 15 mmol of 3-bromopropyne, 10 mL of dichloromethane, and 5 mL of saturated NaHCO3 solution were weighed and reacted at room temperature for 12 h. After the reaction was complete, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 3.

[0026] Preparation of compound B17: Weigh 0.4 mmol of compound 1, 10.4 mmol of compound 3, 0.8 mmol of Cs2CO3 and 5 mL of... N , N -Dimethylformamide was reacted at room temperature for 8 h until the reaction ended. The reaction was quenched with saturated brine, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B17.

[0027] Example 4: Preparation of compound B19 Preparation of Compound 1: 20 mmol of p-methoxyphenylhydrazine hydrochloride, 10.00 mL of acetic acid, and 20 mmol of 4-methylcyclohexanone were weighed and reacted at 80–130 °C. After 20 min, the reaction was stopped, cooled, and quenched with distilled water. The mixture was then cooled to crystallize, and a white solid was precipitated. This solid was then set aside. 10 mmol of the above product, 4 mmol of iodine, and 5 mL of dimethyl sulfoxide were weighed and reacted at 80–120 °C for 10 h. After cooling, the reaction was quenched with concentrated hydrochloric acid, stirred with an appropriate amount of saturated sodium thiosulfate solution for 1 h, extracted with ethyl acetate, washed with saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The mixture was then purified by column chromatography on silica gel to obtain Compound 1.

[0028] Preparation of compound 3: Weigh 10 mmol of hydroxylamine hydrochloride, 10 mmol of 3,4,5-trifluorobenzaldehyde, 5 mL of ethanol, and 5 mL of water. React at room temperature for 30 min. Wash with an appropriate amount of saturated brine, extract with dichloromethane, dry under anhydrous sodium sulfate, and concentrate under reduced pressure for later use. Weigh 4 mmol and 6.22 mmol of the above-mentioned prepared compounds. N -Chlorosuccinimide and 5 mL N , N -Dimethylformamide was reacted at room temperature for 3 h, then quenched with saturated brine, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 2. 5 mmol of compound 2, 15 mmol of 3-bromopropyne, 10 mL of dichloromethane, and 5 mL of saturated NaHCO3 solution were weighed and reacted at room temperature for 12 h. After the reaction was complete, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 3.

[0029] Preparation of compound B19: Weigh 0.4 mmol of compound 1, 10.4 mmol of compound 3, 0.8 mmol of Cs2CO3 and 5 mL of... N , N -Dimethylformamide was reacted at room temperature for 8 h until the reaction was complete. The reaction was then quenched with saturated brine, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography to obtain compound B19.

[0030] The relevant data for each 3-methylcarbazole derivative are as follows: 5-[(3-methyl-9-] H [-Carbazole-9-yl)methyl]-3-phenylisoxazole (B1): White solid, mp 162.2~163.1 ℃. 1 H NMR (400 MHz, CDCl3) d8.10 (d, J = 7.8 Hz, 1H, ArH), 7.93 (s, 1H,ArH), 7.66-7.61 (m, 2H, ArH), 7.49-7.44 (m, 1H, ArH), 7.42-7.24 (m, 7H, ArH), 6.09 (s, 1H, isoxazoleH), 5.56 (s, 2H, CH2), 2.56 (s, 3H, CH3). 13 C NMR (101MHz, CDCl3) d : 168.62, 162.61, 140.21, 138.27, 130.10, 129.34, 128.83, 128.50,127.49, 126.78, 126.04, 123.42, 123.16, 120.56 (d, J = 7.5 Hz), 119.71, 108.49,108.26, 100.23, 39.16, 21.43. 5-[(3-methyl-9-] H [-carbazole-9-yl)methyl]-3-o-tolylisoxaazole (B2): white solid, mp 148.0~149.21 ℃. 1 H NMR (400 MHz, CDCl3) d 8.13 (d, J = 7.8 Hz, 1H, ArH), 7.96 (s,1H, ArH), 7.52-7.49 (m, 1H, ArH), 7.44 (d, J = 8.2 Hz, 1H, ArH), 7.38-7.23 (m,6H, ArH), 7.22-7.18 (m, 1H, ArH), 6.06 (s, 1H, isoxazoleH), 5.54 (s, 2H,CH2), 2.60 (s, 3H, carbazole-CH3), 2.44 (s, 3H, CH3). 13 C NMR (101 MHz, CDCl3) d :167.64, 163.27, 140.29, 138.35, 136.91, 131.11, 129.50 (d, J = 11.9 Hz),129.29, 128.25, 127.50, 125.99 (d, J= 9.8 Hz), 123.45, 123.19, 120.57 (d, J =7.4 Hz), 119.71, 108.58, 108.34, 102.92, 39.02, 21.48, 21.26. 5-[(3-methyl-9-] H [-carbazole-9-yl)methyl]-3-p-tolylisoxaazole (B3): white solid, mp 149.7~150.1 ℃. 1 H NMR (400 MHz, CDCl3) d 8.10 (d, J = 7.8 Hz, 1H, ArH), 7.93 (s,1H, ArH), 7.53 (d, J = 8.0 Hz, 2H, ArH), 7.48-7.44 (m, 1H, ArH), 7.40 (d, J = 8.2Hz, 1H, ArH), 7.34-7.24 (m, 3H, ArH), 7.16 (d, J = 7.9 Hz, 2H, ArH), 6.06 (s,1H, isoxazoleH), 5.54 (s, 2H, CH2), 2.56 (s, 3H, carbazole-CH3), 2.34 (s, 3H,CH3). 13 C NMR (101 MHz, CDCl3) d : 168.43, 162.56, 140.24 (d, J = 2.7 Hz), 138.28,129.52, 129.30, 127.48, 126.65, 126.02, 125.64, 123.41, 123.14, 120.53 (d, J =7.5 Hz), 119.68, 108.51, 108.27, 100.14, 39.15, 21.40. 5-[(3-methyl-9-] H [-carbazole-9-yl)methyl]-3-o-fluorophenylisoxazole (B4): white solid, mp 124.6~125.4 ℃. 1 H NMR (400 MHz, CDCl3) d 8.10 (d, J= 7.8 Hz, 1H, ArH), 7.93 (s,1H, ArH), 7.89-7.85 (m, 1H, ArH), 7.50-7.42 (m, 2H, ArH), 7.39-7.25 (m, 4H,ArH), 7.18-7.15 (m, 1H, ArH), 7.11-7.06 (m, 1H, ArH), 6.37 (d, J = 3.3 Hz, 1H, isoxazoleH), 5.54 (s, 2H, CH2), 2.56 (s, 3H, CH3). 13 C NMR (101 MHz, CDCl3) d :168.36 (d, J = 1.8 Hz), 161.36, 158.86, 158.07 (d, J = 1.6 Hz), 140.26, 138.31,131.76 (d, J = 8.6 Hz), 129.28, 129.08 (d, J = 2.9 Hz), 127.47, 126.01, 124.55(d, J = 3.5 Hz), 123.43, 123.17, 120.54 (d, J = 7.8 Hz), 119.68, 116.42, 116.20,108.53, 108.28, 102.83 (d, J = 8.6 Hz), 38.92, 21.43. 5-[(3-methyl-9-] H [-Carbazole-9-yl)methyl]-3-m-fluorophenylisoxazole (B5): White solid, mp 137.5~138.2 ℃. 1 H NMR (400 MHz, CDCl3) d 8.10 (d, J = 7.7 Hz, 1H, ArH), 7.93 (s,1H, ArH), 7.49-7.45 (m, 1H, ArH), 7.40-7.35 (m, 3H, ArH), 7.34-7.24 (m, 4H,ArH), 7.09-7.04 (m, 1H, ArH), 6.06 (s, 1H, isoxazoleH), 5.53 (s, 2H, CH2), 2.56 (s, 3H, CH3).13 C NMR (101 MHz, CDCl3) d : 169.04, 164.08, 162.02 - 161.43(m), 140.17, 138.22, 130.52 (t, J = 8.5 Hz), 129.41, 127.53, 126.07, 123.44,123.18, 122.54 (d, J = 3.1 Hz), 120.60 (d, J = 7.2 Hz), 119.78, 117.14, 116.93,113.85, 113.62, 108.45, 108.21, 100.21, 39.06, 21.43. 5-[(3-methyl-9-] H [-carbazole-9-yl)methyl]-3-p-fluorophenylisoxazole (B6): white solid, mp 172.5~173.1 ℃. 1 H NMR (400 MHz, CDCl3) d 8.10 (d, J = 7.1 Hz, 1H, ArH), 7.93 (s,1H, ArH), 7.63-7.59 (m, 2H, ArH), 7.48-7.44 (m, 1H, ArH), 7.39 (d, J = 8.1 Hz,1H, ArH), 7.32-7.24 (m, 3H, ArH), 7.06-7.00 (m, 2H, ArH), 6.03 (s, 1H, isoxazoleH), 5.54 (s, 2H, CH2), 2.55 (s, 3H, CH3). 13 C NMR (101 MHz, CDCl3) d :168.83, 165.02, 162.54, 161.68, 140.17, 138.23, 129.39, 128.72 (d, J = 8.6 Hz),127.50, 126.05, 124.72 (d, J = 3.4 Hz), 123.43, 123.16, 120.57 (d, J= 7.3 Hz),119.75, 116.05, 115.83, 108.45, 108.21, 100.07, 39.12, 21.41. 5-[(3-methyl-9-] H [-carbazole-9-yl)methyl]-3-o-chlorophenylisoxazole (B7): white solid, mp 196.2~197.2 ℃. 1 H NMR (400 MHz, CDCl3) d 8.11 (d, J = 7.8 Hz, 1H, ArH), 7.94 (s,1H, ArH), 7.61 (dd, J = 7.5, 2.0 Hz, 1H, ArH), 7.53-7.22 (m, 8H, ArH), 6.40 (s,1H, isoxazoleH), 5.53 (s, 2H, CH2), 2.58 (s, 3H, CH3). 13 C NMR (101 MHz, CDCl3) d :167.79, 161.27, 140.28, 138.35, 132.81, 130.97, 130.37, 129.28, 127.93,127.50, 127.08, 126.04, 123.44, 123.19, 120.57 (d, J = 7.8 Hz), 119.71, 108.61,108.36, 103.75, 38.94, 21.49. 5-[(3-methyl-9-] H [-carbazole-9-yl)methyl]-3-m-chlorophenylisoxazole (B8): white solid, mp 106.2~106.8 ℃. 1 H NMR (400 MHz, CDCl3) d 8.11 (d, J = 7.8 Hz, 1H, ArH), 7.94 (s,1H, ArH), 7.65 (s, 1H), 7.50-7.46 (m, 2H, ArH), 7.39-7.22 (m, 6H, ArH), 6.05(s, 1H, isoxazoleH), 5.49 (s, 2H, CH2), 2.58 (s, 3H, CH3). 13 C NMR (101 MHz, CDCl3) d: 169.08, 161.49, 140.17, 138.22, 134.82, 130.25, 130.13 (d, J = 2.7Hz), 129.42, 127.56, 126.82 (d, J = 2.5 Hz), 126.10, 124.88, 123.45, 123.20,120.63 (d, J = 6.9 Hz), 119.81, 108.47, 108.24, 100.15 (d, J = 9.1 Hz), 38.99, 21.43. 5-[(3-methyl-9-] H [-carbazole-9-yl)methyl]-3-o-bromophenylisoxazole (B9): white solid, mp 121.4~122.5 ℃. 1 H NMR (400 MHz, CDCl3) d 8.10 (d, J = 7.8 Hz, 1H, ArH), 7.93 (s,1H, ArH), 7.60 (dd, J = 8.0, 1.3 Hz, 1H, ArH), 7.53-7.42 (m, 3H, ArH), 7.38-7.27 (m, 4H, ArH), 7.26-7.20 (m, 1H, ArH), 6.35 (s, 1H, isoxazoleH), 5.54 (s,2H, CH2), 2.58 (s, 3H, CH3). 13 C NMR (101 MHz, CDCl3) d : 167.64, 162.60, 140.28,138.34, 133.56, 130.04, 129.27, 127.54 (d, J = 9.3 Hz), 126.03, 123.44, 123.18,122.17, 120.56 (d, J = 7.8 Hz), 119.71, 108.63, 108.38, 103.88, 38.97, 21.49. 5-[(3-methyl-9-] H [-carbazole-9-yl)methyl]-3-m-bromophenylisoxazole (B10): white solid, mp 117.8~118.5 ℃. 1H NMR (400 MHz, CDCl3) d 8.11 (d, J = 1.1 Hz, 1H, ArH), 7.93 (s,1H, ArH), 7.79 (s, 1H, ArH), 7.55-7.53 (m, 1H, ArH), 7.50-7.44 (m, 2H, ArH), 7.38 (d, J = 8.2 Hz, 1H, ArH), 7.33-7.25 (m, 3H, ArH), 7.19 (t, J = 7.9 Hz, 1H, ArH), 6.05 (s, 1H, isoxazoleH), 5.52 (s, 2H, CH2), 2.56 (s, 3H, CH3). 13 C NMR (101 MHz, CDCl3) d : 169.08, 161.38, 140.16, 138.21, 133.02, 130.48, 130.35 (d, J = 4.2 Hz), 129.71, 129.42, 127.54, 126.08, 125.32, 123.45, 123.19, 122.89,120.61 (d, J = 8.5 Hz), 119.79, 108.43, 108.20, 100.12 (d, J = 11.3 Hz), 39.07, 21.44. 5-[(3-methyl-9-] H [-carbazole-9-yl)methyl]-3-p-nitrophenylisoxazole (B11): yellow solid, mp 201.9~202.3 ℃. 1 H NMR (400 MHz, DMSO-) d 6) d 8.23 (d, J = 8.8 Hz, 2H, ArH), 8.08(d, J = 7.7 Hz, 1H, ArH), 8.00 (d, J = 8.9 Hz, 2H, ArH), 7.92 (s, 1H, ArH), 7.70(d, J = 8.3 Hz, 1H, ArH), 7.61 (d, J= 8.4 Hz, 1H, ArH), 7.42 (t, J = 7.7 Hz, 1H,ArH), 7.27 (d, J = 7.8 Hz, 1H, ArH), 7.18 (t, J = 7.5 Hz, 1H, ArH), 7.04 (s, 1H, isoxazoleH), 5.88 (s, 2H, CH2), 2.43 (s, 3H, CH3). 13 C NMR (101 MHz, DMSO-) d 6) d :170.57, 160.94, 148.77, 140.46, 138.57, 134.65, 128.87, 128.36, 127.73,126.31, 124.68, 123.05, 122.77, 120.72 (d, J = 8.0 Hz), 119.81, 109.87, 109.69,101.87, 38.40, 21.45. 5-[(3-methyl-9-] H [-carbazole-9-yl)methyl]-3-(3,4,5-trimethoxyphenyl)isoxazole (B12): white solid, mp 153.0~153.7 ℃. 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.8 Hz, 1H, ArH),7.81 (s, 1H, ArH), 7.35 (t, J = 7.7 Hz, 1H, ArH), 7.27 (d, J = 8.1 Hz, 1H, ArH),7.22-7.10 (m, 3H, ArH), 6.75 (s, 2H, ArH), 5.95 (s, 1H, isoxazoleH), 5.42 (s,2H, CH2), 3.74 (s, 3H, Ar- p -OCH3), 3.71 (s, 6H, Ar- m -2OCH3), 2.43 (s, 3H,CH3). 13 C NMR (101 MHz, CDCl3) d: 167.70, 161.44, 152.43, 139.14, 138.55, 137.19,128.29, 126.42, 124.98, 122.87, 122.34, 122.07, 119.46 (d, J = 6.9 Hz), 118.65,107.41, 107.16, 102.92, 99.05, 59.84, 55.18, 38.15, 20.32. 5-[(3-methyl-9-] H [-carbazole-9-yl)methyl]-3-(3,4,5-trifluorophenyl)isoxazole (B13): white solid, mp 141.1~141.9 ℃. 1 H NMR (400 MHz, CDCl3) d : 8.10 (d, 1H, ArH), 7.93 (s, 1H, ArH), 7.47 (t, J = 8.4 Hz, 1H, ArH), 7.38 (d, J = 8.1 Hz, 1H, ArH), 7.35-7.24 (m,4H, ArH), 7.21 (d, J = 3.7 Hz, 1H, ArH), 6.98 (t, J = 5.0 Hz, 1H, ArH), 6.00 (s,1H, isoxazoleH), 5.52 (s, 2H, CH2), 2.56 (s, 3H, CH3). 13 C NMR (101 MHz, CDCl3) d :168.64, 157.85, 140.19, 138.24, 130.17, 129.39, 127.88, 127.66, 127.52,127.44, 126.35-125.84 (m), 123.44, 123.17, 120.75-120.36 (m), 119.76 (d, J =17.7 Hz), 108.88-107.92 (m), 100.35, 100.11, 39.09, 21.43 (d, J = 12.9 Hz). 5-[(3-methyl-9-] H[-carbazole-9-yl)methyl]-3-(thiophen-2-yl)isoxazole (B14): white solid, mp 115.5~116.7 ℃. 1 H NMR (400 MHz, CDCl3) d 8.10 (d, J = 7.7 Hz, 1H, ArH), 7.93 (s,1H, ArH), 7.47 (t, J = 8.4 Hz, 1H, ArH), 7.38 (d, J = 8.1 Hz, 1H, ArH), 7.35-7.24(m, 4H, ArH), 7.21 (d, J = 3.7 Hz, 1H, ArH), 6.98 (t, J = 5.0 Hz, 1H, ArH), 6.00(s, 1H, isoxazoleH), 5.52 (s, 2H, CH2), 2.56 (s, 3H, CH3). 13 C NMR (101 MHz, CDCl3) d : 168.64, 157.85, 140.19, 138.24, 130.17, 129.39, 127.88, 127.66,127.52, 127.44, 126.35-125.84 (m), 123.44, 123.17, 120.75-120.36 (m), 119.76(d, J = 17.7 Hz), 108.88-107.92 (m), 100.35, 100.11, 39.09, 21.43 (d, J = 12.9Hz). 5-[(3-methyl-9-] H [-carbazole-9-yl)methyl]-3-(5-methylthiophen-2-yl)isoxazole (B15): white solid, mp 151.7~152.8 ℃. 1 H NMR (400 MHz, CDCl3) d 8.00 (d, J = 7.8 Hz, 1H, ArH),7.83 (s, 1H, ArH), 7.37 (t, J = 8.3 Hz, 1H, ArH), 7.29 (d, J= 8.2 Hz, 1H, ArH),7.22-7.15 (m, 3H, ArH), 6.91 (d, J = 3.5 Hz, 1H, ArH), 6.55 (d, J = 3.8 Hz, 1H,ArH), 5.86 (s, 1H, isoxazoleH), 5.43 (s, 2H, CH2), 2.46 (s, 3H, CH3), 2.36 (s,3H, thiophene-CH3). 13 C NMR (101 MHz, CDCl3) d : 168.35, 157.99, 142.89, 140.22,138.28, 129.38, 127.97, 127.73, 127.51, 126.06, 125.82, 123.45, 123.18,120.56 (d, J = 7.7 Hz), 119.74, 108.51, 108.27, 99.98, 39.16, 21.43, 15.46. 5-[(3-methyl-9-] H [-carbazole-9-yl)methyl]-3-(5-methylfuran-2-yl)isoxazole (B16): white solid, mp 124.2~125.0 ℃. 1 H NMR (400 MHz, CDCl3) d 8.13 (d, J = 7.8 Hz, 1H, ArH),7.96 (s, 1H, ArH), 7.50 (t, J = 7.6 Hz, 1H, ArH), 7.40 (d, J = 8.2 Hz, 1H, ArH),7.36-7.28 (m, 3H, ArH), 6.65 (d, J = 3.3 Hz, 1H, ArH), 6.05 (dd, J = 3.4, 1.4 Hz,1H, ArH), 6.00 (s, 1H, isoxazoleH), 5.54 (s, 2H, CH2), 2.59 (s, 3H, CH3), 2.32(s, 3H, furan-CH3). 13 C NMR (101 MHz, CDCl3) d: 168.13, 154.99, 154.36, 142.01,140.22, 138.28, 129.35, 127.52, 126.07, 123.45, 123.18, 120.57 (d, J = 7.5 Hz),119.74, 111.88, 108.52, 108.28, 107.92, 99.59, 39.07, 21.45, 13.68. 5-[(3-methyl-6-fluoro-9-] H [-carbazole-9-yl)methyl]-3-(3,4,5-trifluorophenyl)isoxazole (B17): white solid, mp 164.6~165.6 ℃. 1 H NMR (400 MHz, CDCl3) d : 7.75 (s, 1H, ArH), 7.66-7.59(m, 1H, ArH), 7.26-7.13 (m, 5H, ArH), 7.13-7.05 (m, 1H, ArH), 5.91 (s, 1H, isoxazoleH), 5.44 (s, 2H, CH2), 2.44 (s, 3H, CH3). 13 C NMR (101 MHz, CDCl3) d :168.37, 159.15, 157.82, 155.47, 137.90, 135.33, 128.51, 127.16, 122.64 (d, J =9.4 Hz), 121.94 (d, J = 3.8 Hz), 119.76, 112.83, 112.57, 110.38-109.91 (m), 107.85 (d, J = 9.1 Hz), 107.30, 105.47, 105.23, 98.88, 38.09, 20.28. 5-[(3-methyl-8-fluoro-9-] H [-carbazole-9-yl)methyl]-3-(3,4,5-trifluorophenyl)isoxazole (B18): white solid, mp 151.8~152.4 ℃. 1 H NMR (400 MHz, CDCl3) d : 7.78-7.67 (m, 2H, ArH), 7.23(s, 2H, ArH), 7.17 (d, J= 6.3 Hz, 2H, ArH), 7.04 (q, J = 5.3 Hz, 2H, ArH), 6.02(s, 1H, isoxazoleH), 5.62 (s, 2H, CH2), 2.43 (s, 3H, CH3). 13 C NMR (101 MHz, CDCl3) d : 169.06, 159.06 (d, J = 2.6 Hz), 149.53, 147.13, 137.61, 129.01,127.22, 126.33 (d, J = 8.8 Hz), 125.91 (d, J = 4.9 Hz), 122.35 (d, J = 2.1 Hz), 119.60, 118.98 (d, J = 6.5 Hz), 115.20 (d, J = 3.5 Hz), 111.12, 110.94, 110.16(d, J = 6.5 Hz), 110.00 (d, J = 6.5 Hz), 107.49, 98.95, 39.69 (d, J = 6.8 Hz), 20.27. 5-[(3-methyl-6-methoxy-9-] H [-carbazole-9-yl)methyl]-3-(3,4,5-trifluorophenyl)isoxazole (B19): white solid, mp 148.5~148.9 ℃. 1 H NMR (400 MHz, CDCl3) d : 7.76 (s, 1H, ArH), 7.45(s, 1H, ArH), 7.14 (p, J = 6.2 Hz, 5H, ArH), 6.97 (dd, J = 8.9, 4.0 Hz, 1H, ArH), 5.84 (s, 1H, isoxazoleH), 5.36 (s, 2H, CH2), 3.82 (s, 3H, carbazole-OCH3), 2.43 (s, 3H, CH3). 13 C NMR (101 MHz, CDCl3) d: 168.74, 159.08, 153.10, 137.62,133.91, 127.99, 126.49, 122.53, 122.23, 119.50, 113.88, 110.14 (d, J = 6.5 Hz), 109.97 (d, J = 6.5 Hz), 107.99, 107.13, 102.48, 98.76, 54.95, 38.00, 20.29. The antibacterial activity test of this invention: using oxacillin and norfloxacin as control drugs, the antibacterial activity of each of the above natural product 3-methylcarbazole derivatives against Staphylococcus aureus was determined by microdilution method. S. aureus ), Escherichia coli ( E. coli Staphylococcus epidermidis ( S. epidermidis The minimum inhibitory concentrations (MICs) of methicillin-resistant Staphylococcus aureus (MRSA) are shown in Table 1 below.

[0031] Table 1

[0032] The experimental results above clearly demonstrate that the compounds of general formula B protected by this invention possess potential antibacterial activity. These compounds are effective against... S. aureus and S. epidermidis It has a significant inhibitory effect, among which compounds B6, B11, B12, B13, B17, B18 and B19 have a significant inhibitory effect. S. aureus The MIC was ≤16 μg / mL, and the antibacterial activity of some compounds was comparable to or better than that of the control drug; compounds B11, B12, B13, B17, B18 and B19 showed antibacterial activity against the control drug. S. epidermidis The MIC of these compounds is ≤16 μg / mL; some compounds exhibit antibacterial activity comparable to or superior to the control drug; simultaneously, most compounds also show significant efficacy against drug-resistant MRSA, such as compounds B6, B11, B12, B13, B17, B18, and B19, which have MICs ≤32 μg / mL against MRSA, demonstrating antibacterial activity far superior to the control drug. These compounds exhibit significant antibacterial activity against Gram-positive bacteria and can be used for... S. aureus , S. epidermidis And the application of MRSA. At the same time, these derivatives can also be used in combination with other antibacterial active substances.

[0033] The above descriptions are merely embodiments of the present invention, and common knowledge such as specific technical solutions and / or characteristics are not described in detail here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the technical solutions of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. A natural product 3-methylcarbazole derivative, characterized in that, Its general chemical formula B is shown below: ， Wherein, R1 is selected from hydrogen, fluorine or methoxy; R2 is selected from phenyl, methyl-substituted phenyl, fluorine-substituted phenyl, chlorine-substituted phenyl, bromo-substituted phenyl, nitro-substituted phenyl, methoxy-substituted phenyl, thiophene, methyl-substituted thiophene, furanyl or methyl-substituted furanyl.

2. The 3-methylcarbazole derivative according to claim 1, characterized in that, Choose from any of the following: B3: R1 is H, R2 is 4-CH3Ph; B4: R1 is H, R2 is 2-FPh; B5: R1 is H, R2 is 3-FPh; B6: R1 is H, R2 is 4-FPh; B11: R1 is H, R2 is 4-NO2Ph; B12: R1 is H, R2 is 3,4,5-tri-OCH3Ph; B13: R1 is H, R2 is 3,4,5-tri-FPh; B17: R1 is 6-F, R2 is 3,4,5-tri-FPh; B18: R1 is 8-F, R2 is 3,4,5-tri-FPh; B19: R1 is 6-OCH3, and R2 is 3,4,5-tri-FPh.

3. A drug, characterized in that, It includes the 3-methylcarbazole derivative of claim 1, wherein the derivative is used as the sole active ingredient or in combination with an antibacterial drug or other antibacterial active ingredients.

4. The use of the 3-methylcarbazole derivative according to claim 2 or the drug according to claim 3 in the preparation of a medicament for treating and / or preventing Staphylococcus aureus infections, characterized in that, The derivative is selected from any one or more combinations of B3, B5, B6, B11, B12, B13, B17, B18, and B19.

5. The use of the 3-methylcarbazole derivative according to claim 2 or the drug according to claim 3 in the preparation of a medicament for treating and / or preventing Staphylococcus epidermidis infections, characterized in that, The derivative is selected from any one or more combinations of B3, B5, B6, B11, B12, B13, B17, B18, and B19.

6. The use of the 3-methylcarbazole derivative according to claim 2 or the drug according to claim 3 in the preparation of a medicament for treating and / or preventing methicillin-resistant Staphylococcus aureus infections, characterized in that... The derivative is selected from any one or more combinations of B6, B11, B12, B13, B17, B18, and B19.

7. The use of the 3-methylcarbazole derivative according to claim 2 or the drug according to claim 3 in the preparation of a medicament for treating and / or preventing Escherichia coli infections, characterized in that, The derivative is preferably B4.

8. The method for preparing the 3-methylcarbazole derivative according to claim 1, characterized in that: Prepared according to the following synthetic route: 。 9. The preparation method according to claim 8, characterized in that, Includes the following steps: Preparation of Compound 1: Phenylhydrazine hydrochloride or substituted phenylhydrazine, acetic acid and 4-methylcyclohexanone were mixed and reacted under heating conditions. After the reaction was completed, the mixture was cooled, quenched with distilled water, and cooled to crystallize, yielding an intermediate. The obtained intermediate was mixed with iodine and dimethyl sulfoxide and reacted under heating conditions. After the reaction was completed, the mixture was cooled, quenched with concentrated hydrochloric acid, stirred with an appropriate amount of saturated sodium thiosulfate solution, extracted with ethyl acetate, washed, dried, and purified to obtain Compound 1. Preparation of Compound 3: Hydroxylamine hydrochloride was reacted with benzaldehyde or substituted benzaldehyde in an alcohol-water mixed solvent, washed with an appropriate amount of saturated brine, extracted with dichloromethane, dried, and concentrated to obtain an intermediate; this intermediate was then reacted with... N -Chlorosuccinimide, N , N The reaction with dimethylformamide was quenched with saturated brine, extracted with ethyl acetate, washed, dried, and purified to obtain compound 2; compound 2 was reacted with 3-bromopropyne in dichloromethane and saturated NaHCO3 solution, and after washing, drying, and purification, compound 3 was obtained. Preparation of compound B: Compounds 1 and 3 were reacted with Cs₂CO₃, N , N The reaction with dimethylformamide was quenched with saturated brine, extracted with ethyl acetate, washed, dried, and purified to give compound B.

10. The preparation method according to claim 9, characterized in that: In the preparation of compound 1, the reaction temperature under the heating conditions is 80~130℃.

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