5-quinoline pent-2, 4-diene amide derivative as well as preparation method and application thereof

Abstract

The invention discloses a 5-quinoline pent-2, 4-diene amide derivative as well as a preparation method and application thereof, and the structure of the compound is as shown in a formula (I). According to the preparation method of the 5-quinoline-pent-2, 4-dienamide derivative, quinoline-6-formaldehyde and crotonic acid are used as initial raw materials, the series of compounds can be synthesized through two-step condensation reaction, and the preparation method is simple and efficient; the invention also discloses an application of the 5-quinoline-pent-2, 4-dienamide derivative in preparation of drugs for treating bacterial infection, and the 5-quinoline-pent-2, 4-dienamide derivative has excellent bacteriostatic activity on escherichia coli and staphylococcus aureus. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a 5-quinolinepenta-2,4-dienamide derivative and a preparation method and application thereof. Background Art

[0002] At present, antimicrobial drugs worldwide have caused drug resistance in bacteria or fungi to a certain extent, making it difficult to effectively treat microbial infections. There are many reasons for drug resistance, including the production of inactivating enzymes in pathogens; changes in membrane permeability; changes in target structure in bacteria, etc. Natural products have become an important source of new antimicrobial drugs because of their unique chemical structure and rich material sources. Research on the antimicrobial mechanism of natural products is conducive to discovering some potential targets and mechanisms, and providing new ideas and directions for the research of new drugs; at the same time, some natural products have rich active sites and are good lead compounds. Different pharmacophores and substituents can be introduced to enhance their antibacterial effects or improve the physical and chemical properties of their drugs.

[0003] As an efflux pump inhibitor, piperine can inhibit bacterial resistance to a certain extent, fully demonstrating its advantages as a lead compound for new antibacterial drugs. Current related studies also show that improving the antibacterial activity of piperine through structural modification is an effective means. Considering that quinoline structural fragments are widely present in various drug molecules, 5-quinolinepenta-2,4-dienamide derivatives were designed and synthesized based on the chemical structure of piperine, thereby obtaining a new antibacterial agent with a novel chemical structure. Summary of the invention

[0004] Purpose of the invention: The purpose of the present invention is to provide a 5-quinolinepenta-2,4-dienamide derivative having antibacterial activity. Another purpose of the present invention is to provide a method for preparing the 5-quinolinepenta-2,4-dienamide derivative. The third purpose of the present invention is to provide the use of the 5-quinolinepenta-2,4-dienamide derivative in a drug for treating bacterial infection.

[0005] Technical solution: A 5-quinolinepenta-2,4-dienamide derivative of the present invention, the general structural formula of the derivative is as follows (I):

[0006]

[0007] Among them, R 1 and R 2 The groups are each independently selected from -CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH2 CH 2 CH 2 -, hydrogen, a linear or branched C1-C5 alkyl group, or a substituted or unsubstituted benzyl group.

[0008] Furthermore, the R 1 and R 2 -CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 CH 2 - a; when the R 1 With R 2 When all R 1 and R 2 is one of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, n-pentyl and isopentyl; when R 1 When R is hydrogen, 2 It is one of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, and substituted or unsubstituted benzyl.

[0009] Furthermore, the substituent group of the substituted benzyl group is selected from at least one of an alkyl group, a halogen group, an alkoxy group, a nitro group, a carboxyl group, and a cyano group.

[0010] Furthermore, the substitution site of each substituent group of the substituted benzyl group includes at least one of the 2nd, 3rd or 4th positions on the benzene ring, and the substituent group of the benzyl group is selected from the methyl or ethyl group in the alkyl group; the halogen includes fluorine, chlorine, and bromine; and the alkoxy includes methoxy and ethoxy.

[0011] Furthermore, the 5-quinolinepenta-2,4-dienamide derivative is selected from the following compounds:

[0012] (2E,4E)-1-(hexahydropyridin-1-yl)-5-(quinolin-6-yl)penta-2,4-dien-1-one (I-1);

[0013] (2E,4E)-N-ethyl-N-methyl-5-(quinolin-6-yl)penta-2,4-dienamide (I-2);

[0014] (2E,4E)-N,N-diethyl-5-(quinolin-6-yl)penta-2,4-dienamide (I-3);

[0015] (2E,4E)-N-Benzyl-5-(quinolin-6-yl)penta-2,4-dienamide (I-4);

[0016] The structural formula is as follows:

[0017]

[0018] Furthermore, a method for preparing the above-mentioned 5-quinolinepenta-2,4-dienamide derivative is provided, which uses quinoline-6-carboxaldehyde and crotonic acid as initial raw materials and is synthesized through a two-step condensation reaction. The synthetic route is as follows:

[0019]

[0020] Among them, R 1 and R 2 The groups are each independently selected from -CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 CH 2 -, hydrogen, a linear or branched C1-C5 alkyl group, or a substituted or unsubstituted benzyl group.

[0021] Furthermore, the method specifically includes the following steps:

[0022] Step 1: Add crotonic acid to a solvent to dissolve, then add reagents EDCI, DMAP and compound III in sequence, stir sufficiently to complete the reaction, add water to the reaction system, extract with dichloromethane several times, combine the organic phases, wash and dry, and rotary evaporate the organic solvent to obtain a crude product, which is separated and purified by column chromatography to obtain (2E)-but-2-enamide;

[0023] Step 2: Add quinoline-6-carboxaldehyde to a solvent to dissolve it, add 50% KOH solution, add the compound (2E)-but-2-enamide obtained in step 1, stir to complete the reaction, add water to the reaction system, extract with dichloromethane several times, combine the organic phases, wash, dry, rotary evaporate the organic solvent, and separate and purify by column chromatography to obtain the target product.

[0024] Furthermore, in the step 1, the molar ratio of crotonic acid to compound III is 1:(0.8-1), and in the step 2, the molar ratio of quinoline-6-carboxaldehyde to (2E)-but-2-enamide is 1:(1-1.2).

[0025] Furthermore, the solvent in step one is dichloromethane, and the solvent in step two is dimethyl sulfoxide.

[0026] Furthermore, an application of the above-mentioned 5-quinolinepenta-2,4-dienamide derivative is provided, and the 5-quinolinepenta-2,4-dienamide derivative is applied to the preparation of a drug for treating bacterial infection.

[0027] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: Compared with the prior art, the above-mentioned 5-quinoline penta-2,4-dienamide derivatives prepared by the present invention have a brand-new chemical structure, and the preparation method is simple and easy to produce. The compounds have excellent antibacterial effects on Escherichia coli and Staphylococcus aureus, and the activity of some compounds is better than that of the positive control norfloxacin, which has important guiding significance for the development of new antibacterial drugs. DETAILED DESCRIPTION

[0028] The technical solution of the present invention is further described below. The specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0029] Example 1: Preparation of (2E)-but-2-enamide (IV)

[0030]

[0031] 16.5mmol crotonic acid (II) was added to an eggplant-shaped bottle, 100mL DCM was added to dissolve, 18mmol EDCI, 3mmol DMAP, and 15mmol corresponding amine (III) were added in sequence, stirred for 16h, water was added, and DCM was extracted three times. The organic phases were combined, washed with saturated brine, and anhydrous NaSO 4 Drying, rotary evaporation of the organic solvent to obtain a crude product, separation and purification by column chromatography to obtain (2E)-but-2-enamide (IV). The following compounds can be prepared according to the above method with a yield of 54%-85%.

[0032]

[0033] Example 2: Preparation of 5-quinolinepenta-2,4-dienamide derivatives (I)

[0034]

[0035] 0.8 mmol of quinoline-6-carboxaldehyde ((V)) was added to an eggplant-shaped bottle, 2 mL of DMSO was added as a solvent, 0.2 mL of 50% KOH solution was added, and 0.96 mmol of compound (IV) was added, and the reaction was stirred for 3 hours. Water was added to the reaction system, and dichloromethane was used for extraction. The organic phases were combined, washed with saturated brine, and anhydrous NaSO 4 After drying, the organic solvent was evaporated and purified by column chromatography to obtain the target product (I) with a yield of 55%-80%.

[0036] 1. (2E,4E)-1-(hexahydropyridin-1-yl)-5-(quinolin-6-yl)penta-2,4-dien-1-one

[0037]

[0038] 1H-NMR (CDCl 3 ,400MHz)δ8.88(dd,J=4.3,1.7Hz,1H),8.25–8.01(m,2H),7.89(dd,J=8.9,2.0Hz,1H),7.77(d,J=2.0Hz,1H),7. 59–7.34(m,2H),7.18–6.88(m,2H),6.57(d,J=14.7Hz,1H),3.61(dt,J=42.2,5.2Hz,4H),1.79–1.45(m,6H); 13C NMR (101MHz, CDCl3) δ165.20,150.58,148.38,142.01,137.51,136.16,134.72,129.91 ,128.48,128.44,127.19,126.95,121.77,121.71,47.00,43.32,26.78,25.64,24.66.

[0039] 2. (2E,4E)-N-ethyl-N-methyl-5-(quinolin-6-yl)penta-2,4-dienamide

[0040]

[0041] 1H NMR (CDCl 3,400MHz)δ8.88(dd,J=4.3,1.8Hz,1H),8.22–8.05(m,2H),7.90(dd,J=8.9,2.0Hz,1H),7.79(d,J=2.0Hz,1H),7.66–7.49(m,1H),7.41(dd,J=8.3,4 .2Hz,1H),7.20–6.90(m,2H),6.52(dd,J=14.7,2.5Hz,1H),3.50(dq,J=2 1.9,7.2Hz,2H),3.08(d,J=29.6Hz,3H),1.21(dt,J=30.3,7.1Hz,3H); 13C NMR (101MHz, CDCl3) δ166.23,150.60,148.40,142.09,137.82,136.18,134.71,129.92,12 8.49,128.37,127.24,126.98,121.72,121.46,44.75,42.86,34.85,33.60,14.16,12.37.

[0042] 3. (2E,4E)-N,N-diethyl-5-(quinolin-6-yl)penta-2,4-dienamide

[0043]

[0044] 1H NMR (CDCl 3 ,400MHz)δ8.88(dd,J=4.3,1.8Hz,1H),8.21–8.03(m,2H),7.90(dd,J=8.9,2.0Hz,1H),7.78(d,J=2.0Hz,1H),7.54(dd,J=1 13C NMR (101MHz, CDCl3) δ165.68,150.52,148.29,142.07,137.74,136.24,134.75,129 .81,128.50,128.43,127.21,127.02,121.88,121.72,42.30,41.08,15.07,13.25.

[0045] 4. (2E,4E)-N-Benzyl-5-(quinolin-6-yl)penta-2,4-dienamide

[0046]

[0047] 1H NMR (400MHz, DMSO-d6) δ8.87(dd,J=4.2,1.7Hz,1H),8.68(s,1H),8.44–8.29(m,1H),8.15–8.04(m,2H),7.99(d,J=8.7Hz,1H),7.54 13C NMR (101MHz, DMSO) δ165.52,151.16,148.22,139.92,139.86,137.84,136.61,134.96,1 29.84,128.90,128.82,128.58,127.85,127.81,127.68,127.32,126.40,122.50,42.73.

[0048] Example 3: In order to evaluate the antibacterial activity of the compound prepared in Example 2, an in vitro antibacterial activity evaluation was carried out:

[0049] Norfloxacin was used as a positive control, and the activity test method of the reference (Journal of Chemistry in Universities. 2024, 45(07): 115-124) was used to determine the minimum inhibitory concentration (MIC) of the target compound against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) by the two-fold dilution method. The test results are shown in Table 1.

[0050] Table 1:

[0051]

[0052] The above tests show that the 5-quinolinepenta-2,4-dienamide derivatives prepared by the present invention can effectively inhibit the growth of Escherichia coli and Staphylococcus aureus, and the antibacterial activity of some compounds is equivalent to or better than that of the positive drug norfloxacin, indicating that the 5-quinolinepenta-2,4-dienamide derivatives prepared by the present invention may have a good inhibitory effect on bacterial infection.

Claims

1. A 5-quinolinepenta-2,4-dienamide derivative, characterized in that: The general structural formula of the derivative is as follows (I): Wherein, R1 and R2 groups are each independently selected from -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, hydrogen, straight chain or branched C1-C5 alkyl, substituted or unsubstituted benzyl.

2. The 5-quinolinepenta-2,4-dienamide derivative according to claim 1, characterized in that The R1 and R2 are one of -CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2-; when the R1 and R2 are both alkyl groups, the R1 and R2 are one of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, n-pentyl and isopentyl; when the R1 is hydrogen, the R2 is one of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, substituted or unsubstituted benzyl.

3. The 5-quinolinepenta-2,4-dienamide derivative according to claim 1 or 2, characterized in that The substituent group of the substituted benzyl group is selected from at least one of an alkyl group, a halogen group, an alkoxy group, a nitro group, a carboxyl group, and a cyano group.

4. The 5-quinolinepenta-2,4-dienamide derivative according to claim 3, characterized in that The substitution sites of the substituent groups of the substituted benzyl group include at least one of the 2nd, 3rd or 4th positions on the benzene ring; the substituent groups of the benzyl group are selected from the methyl or ethyl group in the alkyl group; the halogen includes fluorine, chlorine and bromine; the alkoxy includes methoxy and ethoxy.

5. The 5-quinolinepenta-2,4-dienamide derivative according to claim 1, characterized in that It is selected from the following compounds: (2E,4E)-1-(hexahydropyridin-1-yl)-5-(quinolin-6-yl)penta-2,4-dien-1-one (I-1); (2E,4E)-N-ethyl-N-methyl-5-(quinolin-6-yl)penta-2,4-dienamide (I-2); (2E,4E)-N,N-diethyl-5-(quinolin-6-yl)penta-2,4-dienamide (I-3); (2E,4E)-N-Benzyl-5-(quinolin-6-yl)penta-2,4-dienamide (I-4); The structural formula is as follows:

6. A method for preparing the 5-quinolinepenta-2,4-dienamide derivative according to any one of claims 1 to 4, characterized in that: Quinoline-6-carboxaldehyde and crotonic acid are used as the starting materials and synthesized through a two-step condensation reaction. The synthetic route is as follows: Wherein, R1 and R2 groups are each independently selected from -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, hydrogen, straight chain or branched C1-C5 alkyl, substituted or unsubstituted benzyl.

7. The method for preparing the 5-quinolinepenta-2,4-dienamide derivative according to claim 6, characterized in that: The specific steps include: Step 1: Add crotonic acid to a solvent to dissolve, then add reagents EDCI, DMAP and compound III in sequence, stir sufficiently to complete the reaction, add water to the reaction system, extract with dichloromethane several times, combine the organic phases, wash and dry, and rotary evaporate the organic solvent to obtain a crude product, which is separated and purified by column chromatography to obtain (2E)-but-2-enamide; Step 2: Add quinoline-6-carboxaldehyde to a solvent to dissolve it, add 50% KOH solution, add the compound (2E)-but-2-enamide obtained in step 1, stir to complete the reaction, add water to the reaction system, extract with dichloromethane several times, combine the organic phases, wash, dry, rotary evaporate the organic solvent, and separate and purify by column chromatography to obtain the target product.

8. The method for preparing the 5-quinolinepenta-2,4-dienamide derivative according to claim 7, characterized in that: In the step 1, the molar ratio of crotonic acid to compound III is 1:(0.8-1), and in the step 2, the molar ratio of quinoline-6-carboxaldehyde to (2E)-but-2-enamide is 1:(1-1.2).

9. The method for preparing a 5-quinolinepenta-2,4-dienamide derivative according to claim 7, characterized in that: The solvent in step 1 is dichloromethane, and the solvent in step 2 is dimethyl sulfoxide.

10. Use of the 5-quinolinepenta-2,4-dienamide derivative according to any one of claims 1 to 5, characterized in that: The 5-quinolinepenta-2,4-dienamide derivative is used for preparing drugs for treating bacterial infections.

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