CN113024404A - Quaternary ammonium salt type honokiol/magnolol derivative and preparation method and application thereof - Google Patents

Quaternary ammonium salt type honokiol/magnolol derivative and preparation method and application thereof Download PDF

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CN113024404A
CN113024404A CN202110264058.7A CN202110264058A CN113024404A CN 113024404 A CN113024404 A CN 113024404A CN 202110264058 A CN202110264058 A CN 202110264058A CN 113024404 A CN113024404 A CN 113024404A
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magnolol
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honokiol
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郭勇
秦上尚
柳继锋
温婷羽
程晚晴
韩美悦
侯恩花
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Abstract

The invention discloses a series of novel quaternary ammonium salt type honokiol/magnolol derivatives, and a preparation method and application thereof. The series of compounds are prepared by taking honokiol/magnolol as raw materials and performing coupling reaction on phenolic hydroxyl groups of the honokiol/magnolol to prepare a series of novel quaternary ammonium salt type honokiol/magnolol derivatives, and the structural general formula of the compounds is shown in the specification. The compound has strong antibacterial activity on staphylococcus aureus (S.aureus) ATCC 29213 and clinically-separated methicillin-resistant staphylococcus aureus (MRSA), most of derivatives are higher than parent honokiol/magnolol, and the activity of part of target derivatives is higher than that of a contrast medicament levofloxacin, so that the compound is expected to be used for preparing medicaments for resisting staphylococcus aureus and methicillin-resistant staphylococcus aureus.
Figure DDA0002968681140000011

Description

Quaternary ammonium salt type honokiol/magnolol derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of honokiol/magnolol derivatives, and particularly relates to a quaternary ammonium salt type honokiol/magnolol derivative and a preparation method and application thereof.
Background
Magnolol (Magnolol) and Honokiol (Honokiol) are polyphenol binaphthyl compounds extracted from dried bark, root bark and branch bark of Magnolia officinalis of Magnoliaceae family, Magnolia officinalis of Rhd. et. Wils. var. bioloba of Rhd. et. Wils. et. the Magnolol and Honokiol are isomers, and are linked by bipartite phenylpropanoid through 3-3' carbon atom. In the 30 s of the 20 th century, magnolol was first isolated from magnolia officinalis by the Japanese scholar Shuijingang.
Recent studies show that magnolol and honokiol have wide pharmacological effects, such as anticancer effect against gastric cancer, lung cancer, skin cancer and other tumors, cardiovascular protection effect, antidepressant effect, blood sugar lowering effect, diarrhea resistance effect, analgesic effect, gastric emptying promotion and intestinal propulsion promotion effect, and antibacterial effect.
The search for bacteriostatic active ingredients from medicinal plants is a hotspot for developing and researching novel bacteriostatic agents at present. The research shows that magnolol and honokiol have broad-spectrum antibacterial activity, have inhibition effect on candida albicans, gram positive bacteria and gram negative bacteria, and are mostly related to the permeability affecting bacterial cell membranes. Studies of bruary turmeric etc. found that MIC and MBC of honokiol against candida albicans were 16 μ g/ml and 32 μ g/ml, respectively [ bruary turmeric, zhangming, bamboos, etc.. honokiol kills candida albicans (english) by accumulation and destruction of cell membranes by ROS [ J ] microbiology report, 2018, 58 (3): 511-519.]. Studies to dawn bove et al found that magnolol 125mg/ml inhibited candida albicans by 66.32% [ dawn bove, zhou yangmeng, von linying, etc.. based on the effect of magnolol on candida albicans adhesion and biofilm formation, its anticaries effect was investigated [ J ]. proceedings of the first medical university, 2015, 36 (6): 942-945.]. Liudan and other researches find that high-concentration (0.75g/L) honokiol has an inhibiting effect on helicobacter pylori, and can effectively inhibit the formation and secretion of vacuolating toxin A when the high-concentration (0.75g/L) honokiol is far lower than the minimum inhibitory concentration (0.33g/L) [ Liudan, Liao cis flower, Wanglixin, and the like. 1657-1663.]. The researches of plum and the like find that magnolol can obviously reduce the growth activity of a streptococcus mutans biomembrane, obviously reduce the live bacteria proportion in the membrane, and inhibit the transcription expression of mRNA of gene segments such as cariogenic virulence factors ffh, gtfD, pdp and the like, so that the biomembrane structure is damaged [ the research of the effect of plum, magnolol on the cariogenic virulence factors of the streptococcus mutans biomembrane [ D ] Jiamuse: jia wood university, 2013. Georubin and the like find that the MIC of honokiol to MRSA is 64 mu g/ml, and the honokiol and the like have a synergistic effect when combined with antibiotics such as amikacin, vancomycin and the like, can greatly reduce the minimum bactericidal concentration of the honokiol and the antibiotics, and even can reverse the drug resistance of MRSA to amikacin and gentamicin in partial strains [ Georubin, Shshinkuc, Shemingjiu ] and honokiol inhibit the formation of a methicillin-resistant staphylococcus aureus biofilm [ J ]. microbiological report, 2016, 56(8):1266 ]. The antibacterial activity of Penicillium expandasum (Penicillium expandam) against Alternaria alternata causing post-harvest fruit decay was measured by a well-seedling or the like, and five concentrations of 3.13, 6.25, 12.5, 25, and 50mg/ml were set. The results show that honokiol has obvious inhibition effect on the growth of hyphae of the two fungi, the inhibition effect is enhanced along with the increase of concentration, when the concentration is 50mg/mL, the growth of the hyphae in the first two days can be completely inhibited, and when the hyphae are cultured for 3, 4, 5 and 6 days, the colony diameter is obviously smaller than that of a control and other treatments, the inhibition effect is strongest [ the inhibition effect of honokiol on fruit postharvest saprophytic fungi [ J ]. fresh-keeping and processing, 2005,28(10):613 cake 615 ]. Liu et al found that magnolol has an obvious inhibitory effect on NDM-1 positive Escherichia coli by combining with NDM-1 enzyme activity and inhibiting beta-lactamase activity, and can play a role in enhancing bacteriostasis in combination with meropenem, and the MIC is increased from 16 mu g/mL to 4 mu g/mL [ Liu S, Zhou Y L, Niu X D, Wang T T, Li J Y, Liu Z J, Wang J F, Tang S, Wang Y and Deng X M.major phenols of activity of cyclopenem inhibitor NDM-1-reducing Escherichia coli by inhibiting the activity of alpha-lactamase [ J ]. Cell Death Discovery,2018,4:28 ]. Zuo et al found that the MIC of magnolol and honokiol to MRSA was 16-64mg/L, the efficacy was similar to amikacin and gentamicin, and the combined use of conventional antibiotics showed synergistic antibacterial effect, the MIC of magnolol and honokiol was reduced to 1-2mg/L, and the MIC of antibiotics was reduced to 1-16 mg/L. The combination has no antagonism to 10 MRSA strains. The dynamic bactericidal activity of the combination on MRSA is better than that of the combination on MRSA alone under the condition of 24-hour culture [ Zuo G Y, Zhang X J, Han J, et al. in vitro synchronization of magnolol and honokiol in combination with antibacterial agents and antibiotic isolates of methicillin-resistant Staphylococcus aureus (MRSA) [ J ]. BMC comparative Alter Med, 2015, 15:425 ]
The biological activity of honokiol and magnolol as the main active ingredient of officinal magnolia is successively discovered and researched in recent years, and especially aims at the bacteriostatic action of MRSA. However, as the structure of the compound contains phenolic hydroxyl, early experiments show that the compound has high cytotoxicity to normal mammals and extremely poor water solubility, and brings difficulty to further deep research.
Disclosure of Invention
The purpose of the invention is as follows: in view of the above technical problems, the present invention provides a quaternary ammonium salt type honokiol/magnolol derivative, which has antibacterial activity against staphylococcus aureus (s. aureus) ATCC 29213 and various clinically isolated MRSA, and is highly efficient and low-toxic, and a preparation method and an application thereof.
The technical scheme is as follows: in order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:
the quaternary ammonium salt type magnolol/magnolia phenol derivative has a structural formula shown as follows:
Figure BDA0002968681120000031
wherein R is1Selected from-H or C1-C4 alkyl, R2Selected from C2-C8 alkyl, n ═ 2, 3, or 4;
R3and R4Is selected from one of the following two cases:
R3is selected from
Figure BDA0002968681120000032
Wherein R is1、R2And n is as above, R4Is selected from-H;
or, R3Is selected from-H, R4Is selected from-OH.
Preferably, R3Is selected from
Figure BDA0002968681120000033
R4When selected from-H, R1、R2And n is selected as follows:
(1)：n＝2,R1＝-H,R2＝-CH2CH3；(2)：n＝2,R1＝-H,R2＝-(CH2)2CH3；
(3)：n＝2,R1＝-H,R2＝-(CH2)3CH3；(4)：n＝2,R1＝-H,R2＝-(CH2)5CH3；
(5)：n＝2,R1＝-(CH2)3CH3,R2＝-(CH2)3CH3；(6)：n＝3,R1＝-H,R2＝-CH2CH3；
(7)：n＝3,R1＝-H,R2＝-(CH2)2CH3；(8)：n＝3,R1＝-H,R2＝-(CH2)3CH3；
(9)：n＝3,R1＝-H,R2＝-(CH2)4CH3；(10)：n＝3,R1＝-H,R2＝-(CH2)5CH3；
(11)：n＝3,R1＝R2＝-(CH2)3CH3；(12)：n＝4,R1＝-H,R2＝-CH2CH3；
(13)：n＝4,R1＝-H,R2＝-(CH2)2CH3；(14)：n＝4,R1＝-H,R2＝-(CH2)3CH3；
(15)：n＝4,R1＝-H,R2＝-(CH2)4CH3；(16)：n＝4,R1＝-H,R2＝-(CH2)5CH3；
(17)：n＝4,R1＝R2＝-(CH2)3CH3。
preferably, R3Is selected from-H, R4When selected from-OH, R1、R2And n is selected as follows:
(18)：n＝2,R1＝-H,R2＝-(CH2)3CH3；(19)：n＝2,R1＝-H,R2＝-(CH2)4CH3；
(20)：n＝2,R1＝-H,R2＝-(CH2)5CH3；(21)：n＝2,R1＝R2＝-(CH2)3CH3；
(22)：n＝3,R1＝-H,R2＝-(CH2)3CH3；(23)：n＝3,R1＝-H,R2＝-(CH2)4CH3；
(24)：n＝3,R1＝-H,R2＝-(CH2)5CH3；(25)：n＝3,R1＝R2＝-(CH2)3CH3；
(26)：n＝4,R1＝-H,R2＝-(CH2)3CH3；(27)：n＝4,R1＝-H,R2＝-(CH2)4CH3；
(28)：n＝4,R1＝-H,R2＝-(CH2)5CH3；(29)：n＝4,R1＝R2＝-(CH2)3CH3。
the preparation method of the quaternary ammonium salt type magnolol/magnolia phenol derivative comprises the steps of introducing bromoalkane into hydroxyl of honokiol/magnolol serving as a raw material to synthesize an intermediate a/b, and performing substitution reaction with the intermediate c and the like to generate a series of new quaternary ammonium salt type honokiol/magnolia phenol derivatives:
Figure BDA0002968681120000041
wherein R is1、R2And n is as described above.
Preferably, the molar ratio of the intermediate a/b to the intermediate c is 1:2-1:4, and the reaction temperature is 70-80 ℃.
Preferably, the preparation method of the intermediate a/b is as follows: reacting magnolol/honokiol with dibromoalkane under alkaline condition to generate an intermediate a/b;
Figure BDA0002968681120000042
further preferably, the base in the alkaline condition is selected from potassium carbonate, the molar ratio of magnolol/honokiol to base is 1:1.5-1:3, the molar ratio of magnolol/honokiol to dibromoalkane is 1:2-1:4, and the reaction temperature is 45-55 ℃.
Preferably, the preparation method of the intermediate c is as follows: reacting amine with various carbon chains with bromoacetyl bromide under an alkaline condition to generate bromoacetamide with various carbon chains, and reacting the bromoacetamide with different carbon chains with dimethylamine under the alkaline condition to generate an intermediate c;
Figure BDA0002968681120000051
wherein R is1、R2As described above.
Further preferably, the molar ratio of the amine with various carbon chains to the bromoacetyl bromide is 1:1.5-1:3, and the reaction temperature is 0 ℃; the molar ratio of the bromoacetamide and dimethylamine with different carbon chains is 1:1.5-1:3, and the reaction temperature is room temperature.
The invention finally provides the application of the quaternary ammonium salt type magnolol/magnolol derivative in preparing antibacterial drugs. Preferably, use in the preparation of an antibacterial medicament against staphylococcus aureus (s. aureus) ATCC 29213 and various MRSAs.
The technical effects are as follows: compared with the prior art, the quaternary ammonium salt type magnolol/magnolol quaternary ammonium salt type derivative prepared by the invention has excellent antibacterial activity on staphylococcus aureus (S.aureus) ATCC 29213 and various MRSAs, and is expected to be used for preparing excellent natural product antibacterial agents. And the preparation method is simple and has high yield.
Drawings
FIG. 1 is a scheme of Compound 8(HEH-47)1H-NMR spectrum.
FIG. 2 is a drawing showing the preparation of Compound 8(HEH-47)1C-NMR spectrum.
FIG. 3 is a bactericidal curve for Compound 8, where a is the bactericidal effect of Compound 8 on early log phase MRSA-16; compound 8 has bactericidal effect on late logarithmic growth stage MRSA-16.
Detailed Description
The present invention is further illustrated by the following examples.
EXAMPLE 1 preparation of intermediates a/b
Weighing magnolol/honokiol (1mmol) and potassium carbonate (4.5mmol), placing in a 25mL round-bottom flask, adding 3mL absolute ethyl alcohol to dissolve, adding 1, 2-dibromoethane/1, 3-dibromopropane/1, 4-dibromobutane (3mmol), heating and stirring at 50 ℃, detecting by thin-layer chromatography (TLC), after the reaction is finished, decompressing and evaporating the reaction liquid, extracting with dichloromethane (30mL) for three times, combining organic layers, drying with anhydrous sodium sulfate to remove water, and separating by column chromatography to obtain an intermediate a/b.
EXAMPLE 2 preparation of intermediate c
Weighing various corresponding amines (1mmol) in a 50mL round-bottom flask, adding 5mL anhydrous dichloromethane to dissolve the corresponding amines, adding potassium carbonate (1.5mmol), stirring at 0 ℃ for half an hour, slowly adding bromoacetyl bromide (1.5mmol) into the reaction solution, continuing stirring for half an hour, detecting by Thin Layer Chromatography (TLC), after the reaction is finished, evaporating the reaction solution under reduced pressure, extracting with ethyl acetate (30mL) for three times, combining organic layers, drying anhydrous sodium sulfate to remove water, evaporating ethyl acetate under reduced pressure, and separating by column chromatography to obtain corresponding bromoacetamide. Finally weighing dimethylamine (1.5mmol) and corresponding bromoacetamide (1mmol), placing the dimethylamine and the corresponding bromoacetamide in a 25mL round-bottom flask, adding 3mL acetone to dissolve the acetone, adding potassium carbonate (1.5mmol), stirring at room temperature, detecting by thin-layer chromatography (TLC), after the reaction is finished, evaporating the reaction solution under reduced pressure, extracting with dichloromethane (30mL) for three times, combining organic layers, drying with anhydrous sodium sulfate to remove water, and separating by column chromatography to obtain an intermediate c.
EXAMPLE 3 Compound 1
Weighing the intermediate a (1mmol) and the intermediate c (3mmol) in a tween bottle, adding 2mL of absolute ethyl alcohol to dissolve the intermediate a and the intermediate c, stirring the mixture at 78 ℃ for reaction, detecting the reaction by thin-layer chromatography (TLC), decompressing and evaporating the reaction liquid after the reaction is finished, and preparing the pure product of the target compound by thin-layer chromatography (dichloromethane: methanol ═ 10: 1).
The physicochemical properties of compound 1 are as follows:
1) a light yellow liquid;
2) NMR spectrum of the compound (A)1H NMR, 600MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(600MHz DMSO-d6)δ:8.78(t,J＝4.8Hz,1H,-NH-),8.73-8.75(t,J＝5.4Hz,1H,-NH-),7.30-7.33(m,1H,-Ar),7.24(d,J＝1.8Hz,1H,-Ar),7.15-7.16(m,1H,-Ar),7.13(d,J＝8.4Hz,1H,-Ar),7.09(d,J＝8.4Hz,1H,-Ar),7.06(d,J＝1.8Hz,1H,-Ar),5.94-6.00(m,2H,-CH2-),5.06-5.10(m,2H,-CH2-),5.03-5.05(m,2H,-CH2-),4.53-4.54(m,2H,-CH2-),4.43-4.44(m,2H,-CH2-),4.31(s,2H,-CH2-),4.18(s,2H,-CH2-),4.09-4.11(m,2H,-CH2-),3.91-3.93(m,2H,-CH2-),3.36(s,12H,-CH3),3.18(s,4H,-CH2-),3.12-3.17(m,4H,-CH2-),1.03-1.08(m,6H,-CH3)；13C NMR(150MHz DMSO-d6)δ:171.8,155.7,153.2,137.3,133.1,131.0,128.7,128.5,127.8,66.6,63.8,56.4,52.3,39.0,34.4,33.4,15.3.
EXAMPLE 4 Compound 2
Compound 2 was synthesized using the method described in example 3, with the physicochemical properties of compound 2 as follows:
1) and yellow liquid.
2) NMR spectrum of the compound (A)1H NMR, 600MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(600MHz DMSO-d6)δ:8.58(s,1H,-NH-),8.53(s,1H,-NH-),7.29-7.31(m,1H,-Ar),7.24(s,1H,-Ar),7.14(d,J＝2.4Hz,1H,-Ar),7.10(d,J＝8.4Hz,1H,-Ar),7.05(d,J＝8.4Hz,2H,-Ar)5.94-5.97(m,2H,-CH-),5.02-5.09(m,4H,-CH2-),4.49-4.50(m,2H,-CH2-),4.41-4.42(m,2H,-CH2-),4.23(s,2H,-CH2-),4.11(m,2H,-CH2-),4.07(m,4H,-CH2-),3.21(s,12H,-CH2-，-CH3),3.15(s,4H,-CH2-,-CH3),3.06-3.08(m,4H,-CH2-),1.43(d,J＝7.2Hz,4H,-CH2-),0.84-0.87(m,6H,-CH3)；13C NMR(150MHz DMSO-d6)δ:169.9,163.1,155.7,153.2,138.4,137.3,131.0,130.9,130.5,128.7,128.5,127.8,116.0,113.6,111.7,66.6,63.8,63.4,62.5,61.9,61.6,52.3,43.5,39.0,34.0,33.4,33.3,14.6.
EXAMPLE 5 Compound 3
Compound 3 was synthesized using the method described in example 3, and the physicochemical properties of compound 3 were as follows:
1) yellow liquid;
2) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(400MHz DMSO-d6)δ:9.27(s,1H,-NH-),8.65(s,1H,-NH-),7.36(dd,J＝3.0,2.0Hz,1H,-Ar),7.30(d,J＝2.0Hz,1H,-Ar),7.04(d,J＝8.4Hz,1H,-Ar),6.98(d,J＝2.0Hz,1H,-Ar),6.91(dd,J＝8.0,1.6Hz,1H,-Ar),6.84(d,J＝8.0Hz,1H,-Ar),5.92(m,2H,-CH-),5.01(m,4H,-CH2-),4.50(s,2H,-CH2-),4.26(s,2H,-CH2-),4.07(s,2H,-CH2-),3.34(s,4H,-CH2-),3.27(d,J＝6.4Hz,12H,-CH3),3.12(d,J＝6.4Hz,2H,-CH2-),3.07-3.13(m,8H,-CH2-,-CH3),1.34-1.46(m,4H,-CH2-),1.25-1.34(m,4H,-CH2-),1.17(t,J＝7.6Hz,3H,-CH3),0.859(t,J＝7.2Hz,3H,-CH3)；13C NMR(100MHz DMSO-d6)δ:162.9,153.8,152,4,136.9,131.6,130.4,130.2,127.9,127.1,127.1,115.7,115.2,111.3,63.4,62.7,61.6,51.9,45.5,39.4,38.6,38.3,33.7,30.6,19.5,13.5.
EXAMPLE 6 Compound 4
Compound 4 was synthesized using the method described in example 3, and the physicochemical properties of compound 4 were as follows:
1) light yellow liquid;
2) NMR spectrum of the compound (A)1H NMR, 600MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(600MHz DMSO-d6)δ:8.62(s,1H,-NH-),8.56(s,1H,-NH-),7.29-7.31(m,1H,-Ar),7.24(d,J＝2.4Hz,1H,-Ar),7.14-7.16(m,1H,-Ar),7.11(d,J＝7.8Hz,1H,-Ar),7.05-7.07(m,2H,-Ar),5.94-5.97(m,2H,-CH-),5.06-5.09(m,2H,-CH2-),5.02-5.04(m,2H,-CH2-),4.50(t,J＝4.2Hz,2H,-CH2-),4.40(t,J＝4.8Hz,2H,-CH2-),4.25(s,2H,-CH2-),4.13(s,2H,-CH2-),4.07-4.08(m,2H,-CH2-),3.89(t,J＝4.8Hz,2H,-CH2-),3.33(s,10H,-CH2-,-CH3),3.16(s,6H,-CH3),3.07-3.12(m,4H,-CH2-),1.39-1.44(m,4H,-CH2-),1.24-1.26(m,12H,-CH2-),0.84-0.86(s,6H,-CH3)；13C NMR(150MHz DMSO-d6)δ:163.4,163.2,154.8,153.2,138.4,133.4,131.3,131.1,130.3,128,5.127.8,116.1,113.7,112.0,63.8,63.6,63.4,62.5,62.1,52.4,52.3,39.9,39.0,34.1,29.0,28.9,28.7,22.2.
EXAMPLE 7 Compound 5
Compound 5 was synthesized using the method described in example 3, and the physicochemical properties of compound 5 were as follows:
1) a light yellow liquid;
2) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(400MHz DMSO-d6)δ:7.29(dd,J＝2.0,8.4Hz,1H,-Ar),7.26(d,J＝2.0Hz,1H,-Ar),7.13(s,2H,-Ar),7.08(s,1H,-Ar),7.05(d,J＝4.2Hz,1H,-Ar),5.93-5.98(m,2H,-CH-),5.03-5.05(m,4H,-CH2-),4.61(s,2H,-CH2-),4.50(m,4H,-CH2-),4.40(s,2H,-CH2-),4.17(s,2H,-CH2-),4.00(s,2H,-CH2-),3.38(s,6H,-CH2-),3.23-3.29(m,4H,-CH2-),3.19(s,6H,-CH3),3.11-3.18(m,8H,-CH2-,-CH3),1.42-1.46(m,8H,-CH2-),1.19-1.27(m,8H,-CH2-),0.86-0.88(m,12H,-CH3)；13C NMR(150MHz DMSO-d6)δ:163.4,163.2,154.8,153.3,138.4,137.3,133.5,130.2,128.5,127.8,116.0,114.0,112.1,63.3,63.0,62.8,62.3,61.5,61.4,52.6,46.9,39.0,34.1,29.5,20.0,14.1.
EXAMPLE 8 Compound 6
Compound 6 was synthesized using the method described in example 3, and the physicochemical properties of compound 6 were as follows:
1) a light yellow liquid;
2) NMR spectrum of the compound (A)1H NMR, 600MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(600MHz DMSO-d6)δ:8.57-8.62(m,2H,-NH-),7.26(d,J＝1.8Hz,1H,-Ar),7.13(d,J＝1.8Hz,1H,-Ar),7.00-7.06(m,4H,-Ar),5.94-5.98(m,2H,-CH-),5.02-5.08(m,4H,-CH2-),4.08-4.12(m,4H,-CH2-),4.00-4.04(m,4H,-CH2-),3.70-3.73(m,2H,-CH2-),3.55-3.58(m,2H,-CH2-),3.38(d,J＝4.2Hz,4H,-CH2-),3.26(s,6H,-CH3),3.11-3.17(m,6H,-CH3),3.09-3.10(m,4H,-CH2-),2.20-2.24(m,4H,-CH2-),1.01-1.07(m,6H,-CH3)；13C NMR(150MHz DMSO-d6)δ:163.2,163.1,155.3,153.7,138.4,137.6,133.0,130.9,130.2,128.7,127.9,116.1,113.8,111.7,65.8,65.2,62.6,62.5,53.7,39.1,34.0,23.0,14.7.
EXAMPLE 9 Compound 7
Compound 7 was synthesized using the method described in example 3, and the physicochemical properties of compound 7 were as follows:
1) yellow liquid;
2) NMR spectrum of the compound (A)1H NMR, 600MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(600MHz DMSO-d6)δ:8.67-8.71(m,2H,-NH-),7.33(dd,J＝2.4,8.4Hz,1H,-Ar),7.24(d,J＝2.4Hz,1H,-Ar),7.09(dd,J＝2.4,8.4Hz,1H,-Ar),7.06(d,J＝2.4Hz,1H,-Ar),7.02(dd,J＝3.6,8.4Hz,2H,-Ar),5.95-5.99(m,2H,-CH-),5.06-5.12(m,2H,-CH2-),5.02-5.05(m,2H,-CH2-),4.20(s,1H,-CH2-),4.12(s,1H,-CH2-),4.08-4.10(m,1H,-CH2-),3.99-4.01(m,1H,-CH2-),3.73-3.75(m,2H,-CH2-),3.34(s,12H,-CH3),3.27(s,4H,-CH2-),3.19(s,4H,-CH2-),3.03-3.10(m,4H,-CH2-),2.10-2.27(m,4H,-CH2-),1.39-1.48(m,4H,-CH2-),0.83-0.88(m,6H,-CH3)；13C NMR(150MHz DMSO-d6)δ:163.4,155.3,153.7,138.4,137.6,133.0,130.8,130.2,128.7,128.5,127.9,116.0,113.9,111.7,65.9,65.2,62.6,62.5,51.8,51.7,40.8,39.1,34.3,23.1,22.9,22.4,11.8.
EXAMPLE 10 Compound 8
Compound 8 was synthesized using the method described in example 3, and the physicochemical properties of compound 8 were as follows:
1) yellow liquid;
2) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, whereinThe peak assignments were:1H NMR(400MHz DMSO-d6)δ:8.67(d,J＝5.6Hz,2H,-NH-),7.25(dd,J＝2.0,6.4Hz,1H,-Ar),7.15(d,J＝2.0Hz,1H,-Ar),6.99(s,2H,-Ar),6.85(dd,J＝9.0,22.0Hz,2H,-Ar),5.86-5.94(m,2H,-CH-),4.97(s,4H,-CH2-),4.32(s,2H,-CH2-),4.08(s,2H,-CH2-),3.93(s,2H,-CH2-),3.84(s,2H,-CH2-),3.82(s,2H,-CH2-),3.53(t,J＝8.0Hz 2H,-CH2-),3.33(s,6H,-CH2-),3.27(t,J＝6.8Hz,4H,-CH2),3.18(s,6H,-CH3),3.08(dd,J＝6.8,13.6Hz,4H,-CH2-),2.29-2.30(m,2H,-CH2-),2.11-2.12(m,2H,-CH2-),1.39-1.43(m,4H,-CH2-),1.17-1.28(m,4H,-CH2-),4.97(m,6H,-CH3),；13C NMR(150MHz DMSO-d6)δ:163.2,155.5,153.8,138.4,137.5,130.9,130.8,130.6,130.3,128.8,128.5,127.9,116.0,115.9,113.8,111.6,65.9,64.7,62.7,62.5,51.7,42.6,39.9,39.1,38.7,34.5,32.3,31.1,22.9,19.9,14.0.
EXAMPLE 11 Compound 9
Compound 9 was synthesized using the method described in example 3, and the physicochemical properties of compound 9 were as follows:
1) yellow liquid;
2) NMR spectrum of the compound (A)1H NMR, 600MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(600MHz DMSO-d6)δ:8.69-8.76(m,2H,-NH-),7.32-7.34(m,1H,-Ar),7.23-7.24(m,1H,-Ar),7.08(t,J＝2.4Hz,2H,-Ar),7.02-7.03(m,2H,-Ar),5.95-5.98(m,2H,-CH-),5.02-5.09(m,4H,-CH2-),4.09-4.13(m,4H,-CH2-),3.83-3.99(m,4H,-CH2-),3.56(t,J＝7.8Hz,4H,-CH2-),3.34(s,6H,-CH3),3.26-3.27(m,4H,-CH2-),3.22(s,6H,-CH3),3.07-3.09(m,4H,-CH2-),2.11-2.20(m,4H,-CH2-),1.39-1.41(m,4H,-CH2-),1.22(t,J＝8.4Hz,8H,-CH2-),0.83-0.85(m,6H,-CH3)；13C NMR(150MHz DMSO-d6)δ:163.2,155.5,155.3,138.4,133.0,130.8,130.3,128.8,128.7,127.9,116.0,113.8,111.6,65.8,64.7,62.5,51.7,39.1,32.2,31.3,28.9,22.4,22.2,14.3.
EXAMPLE 12 Compound 10
Compound 10 was synthesized using the method described in example 3, and the physicochemical properties of compound 10 were as follows:
1) yellow liquid;
2) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(400MHz DMSO-d6)δ:8.69(s,2H,-NH-),7.24(s,1H,-Ar),7.06(s,1H,-Ar),7.03(s,4H,-Ar),5.94(t,J＝6.8Hz,2H,-；H-),5.01-5.09(m,4H,-CH2-),3.99-4.18(m,8H,-CH2-),3.70(t,J＝6.8Hz,2H,-CH2-),3.55(t,J＝8.0Hz,2H,-CH2-),3.39(s,4H,-CH2-),3.26(s,6H,-CH3),3.18(s,6H,-CH3),3.06-3.11(m,4H,-CH2-),2.23(d,2H,J＝5.2Hz,-CH2-),2.12(d,J＝5.6Hz,2H,-CH2-),1.23-1.41(m,16H,-CH2-),0.83-0.86(m,6H,-CH3)；13C NMR(100MHz DMSO-d6)δ:163.3,163.27,155.3,153.7,138.4,133.0,130.8,128.7,127.9,116.0,113.8,111.6,65.8,65.2,62.5,51.8,51.7,39.1,39.0,39.0,34.3,28.9,28.7,28.6,23.0,22.9,22.2,14.3.
EXAMPLE 13 Compound 11
Compound 11 was synthesized using the method described in example 3, and the physicochemical properties of compound 11 were as follows:
1) yellow liquid;
2) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(400MHz DMSO-d6)δ:7.50-7.52(m,1H,-Ar),7.38(d,J＝5.6Hz,1H,-Ar),7.25-7.26(m,1H,-Ar),7.13(s,1H,-Ar),7.05-7.09(m,2H,-Ar),5.93-5.98(m,2H,-CH-),5.01-5.09(m,4H,-CH2-),4.40-4.64(m,4H,-CH2-),4.01-4.17(m,4H,-CH2-),3.39(s,8H,-CH2-),3.21-3.26(m,12H,-CH3),3.11-3.16(m,8H,-CH2-),1.40-1.45(m,4H,-CH2-),1.29(s,8H,-CH2-),1.23(d,J＝9.2Hz,8H,-CH2-),0.84-0.88(m,12H,-CH3).
EXAMPLE 14 Compound 12
Compound 12 was synthesized using the method described in example 3, and the physicochemical properties of compound 12 were as follows:
1) and yellow liquid.
2) NMR spectrum of the compound (A)1HNMR, 600MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(600MHz DMSO-d6)δ:8.70-8.72(m,2H,-NH-),7.33(dd,J＝1.8,8.4Hz,1H,-Ar),7.27(d,J＝2.4Hz,1H,-Ar),7.08(dd,J＝1.8,7.8Hz,1H,-Ar),7.06(d,J＝2.4Hz,1H,-Ar),6.99-7.02(m,2H,-Ar),5.94-6.01(m,2H,-CH2-),5.06-5.10(m,2H,-CH2-),5.02-5.06(m,2H,-CH2-),4.13(s,2H,-CH2-),4.06(s,2H,-CH2-),4.04(t,J＝12.0Hz,2H,-CH2-),3.95(t,J＝12.6Hz,2H,-CH2-),3.60-3.63(m,2H,-CH2-),3.46-3.49(m,2H,-CH2-),3.35(m,12H,-CH3),3.23(s,4H,-CH2-),3.13(s,4H,-CH2-),1.90-1.95(m,2H,-CH2-),1.76-1.80(m,4H,-CH2-),1.64-1.68(m,2H,-CH2-),1.19(t,J＝9.0Hz,2H,-CH3),1.03-1.07(m,4H,-CH3)；13C NMR(150MHz DMSO-d6)δ:170.4,155.6,154.0,137.4,132.6,131.0,128.7,128.4,127.6,116.0 115.9,113.5,67.7,67.2,64.7,49.5,40.0,39.1,34.5,34.0,27.9,16.2,12.3.
EXAMPLE 15 Compound 13
Compound 13 was synthesized using the method described in example 3, and the physicochemical properties of compound 13 were as follows:
1) and yellow liquid.
2) NMR spectrum of the compound (A)1H NMR, 600MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(600MHz DMSO-d6)δ:8.59-8.62(m,1H,-NH-),7.31(dd,J＝2.4,7.8Hz,1H,-Ar),7.26(d,J＝1.8Hz,1H,-Ar),7.08(dd,J＝2.4,8.4Hz,1H,-Ar),7.05(d,J＝2.4Hz,1H,-Ar),6.97-7.01(m,2H,-Ar),5.92-5.99(m,2H,-CH2-),5.01-5.09(m,4H,-CH2-),4.09(s,2H,-CH2-),4.03(d,J＝5.4Hz,2H,-CH2-),4.02(s,2H,-CH2-),3.94(t,J＝12.6Hz,2H,-CH2-),3.57-3.59(m,2H,-CH2-),3.43-3.46(m,2H,-CH2-),3.32(s,4H,-CH2-),3.21(s,6H,-CH3),3.11(s,6H,-CH3),3.04-3.08(m,2H,-CH2-),1.87-1.93(m,2H,-CH2-),1.75-1.79(m,4H,-CH2-),1.64-1.67(m,2H,-CH2-),1.40-1.45(m,4H,-CH2-),0.83-0.87(m,6H,-CH3)；13C NMR(150MHz DMSO-d6)δ:163.4,163.3,155.5,154.0,137.5,132.6,130.7,128.7,128.5,127.7,116.0,113.5,111.5,67.7,67.2,64.6,64.6,62.3,62.2,51.7,51.5,40.5,39.1,34.4,31.6,26.3,26.1,22.4,22.3,19.6,19.4,11.8.
EXAMPLE 16 Compound 14
Compound 14 was synthesized using the method described in example 3, and the physicochemical properties of compound 14 were as follows:
1) and yellow liquid.
2) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(400MHz DMSO-d6)δ:8.78(s,2H,-NH-),7.25-7.32(m,2H,-Ar),6.97-7.01(m,4H,-Ar),5.93-5.97(m,2H,-CH-),5.02-5.09(m,4H,-CH2-),4.17(s,4H,-CH2-),3.94(d,J＝33.0Hz,4H,-CH2-),3.31-3.36(m,4H,-CH2-),3.23(s,6H,-CH3),3.12(s,6H,-CH3),3.07-3.10(m,4H,-CH2-),2.83-2.94(m,4H,-CH2-),1.64-1.88(m,8H,-CH2-),1.12-1.40(m,16H,-CH2-),0.84(s,6H,-CH3)；13C NMR(100MHz DMSO-d6)δ:162.8,162.7,155.0,153.5,137.0,132.0,128.2,127.8,127.2,115.4,113.1,111.0,67.2,66.7,64.1,61.7,51.2,51.0,39.4,38.6,38.2,33.9,30.5,30.5,25.8,25.6,19.4,19.1,18.9,13.5.
EXAMPLE 17 Compound 15
Compound 15 was synthesized using the method described in example 3, and the physicochemical properties of compound 15 were as follows:
1) yellow liquid;
2) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(400MHz DMSO-d6)δ:8.78(s,2H,-NH-),7.31(dd,J＝2.0,8.4Hz,1H,-Ar),7.27(s,1H,-Ar),7.05-7.07(m,2H,-Ar),6.97-7.01(m,2H,-Ar),5.94-5.99(m,2H,-CH-),5.04-5.10(m,4H,-CH2-),3.95-4.14(m,8H,-CH2-),3.61(s,2H,-CH2-),3.59(s,2H,-CH2-),3.57(s,4H,-CH2-),3.24(s,6H,-CH3),3.12(s,6H,-CH3),3.07-3.12(m,4H,-NH2),1.77-1.79(m,4H,-CH2-),1.40(t,J＝6.0Hz,4H,-CH2-),1.23-1.25(t,J＝3.6Hz,12H,-CH2-),0.83-0.87(m,6H,-CH3)；13C NMR(100MHz DMSO-d6)δ:163.5,163.2,154.8,153.2 137.3,131.3,128.8,128.6,127.6,116.3,113.6,111.9,64.2,62.4,53.7,52.4,40.9,40.5,39.0,34.1,31.6,30.3,22.8,22.4,22.3,11.8.
EXAMPLE 18 Compound 16
Compound 16 was synthesized using the method described in example 3, and the physicochemical properties of compound 16 were as follows:
1) and yellow liquid.
3) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(400MHz DMSO-d6)δ:8.67(s,2H,-NH-),7.26-7.33(m,2H,-Ar),7.05-7.09(m,2H,-Ar),5.94-5.98(m,2H,-Ar),5.05-5.09(m,4H,-CH-),4.11(s,2H,-CH2-),4.03(d,J＝6.0Hz,4H,-CH2-),3.95(s,2H,-CH2-),3.56(t,J＝8.0Hz,2H,-CH2-),3.42-3.47(m,2H,-CH2-),3.32(s,2H,-CH2-),3.21(s,8H,-CH2-,CH3),3.11(s,10H,-CH3),1.63-1.91(s,8H,-CH2-),1.23-1.42(m,16H,-CH2-),0.83-0.86(s,6H,-CH3)；13C NMR(150MHz DMSO-d6)δ:163.3,163.2,155.5,154.0,137.5,132.6,130.7,128.7,128.5,127.7,116.0,113.5,111.5,67.7,67.2,64.6,64.5,62.3,62.2,51.7,51.5,39.9,39.1,39.0,34.4,28.9,28.7,28.6,26.1,22.1,19.6,19.4,14.3.
EXAMPLE 19 Compound 17
Compound 17 was synthesized using the method described in example 3, and the physicochemical properties of compound 17 were as follows:
1) yellow liquid;
2) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(400MHz DMSO-d6)δ:7.31-7.33(m,1H,-Ar),7.26(d,J＝6.0Hz,1H,-Ar),7.05-7.08(m,1H,-Ar),6.99-7.05(m,1H,-Ar),6.97-7.00(m,2H,-Ar),5.95-5.97(m,2H,-CH-),5.02-5.09(m,4H,＝CH2),4.48(s,2H,-CH2-),4.43(s,2H,-CH2-),4.01(t,J＝4.0Hz,2H,-CH2-),3.93(t,J＝4.0Hz,2H,-CH2-),3.69(t,J＝5.6Hz,2H,-CH2-),3.42-3.47(m,2H,-CH2-),3.32(s,2H,-CH2-),3.21(s,8H,-CH2-,-CH3),3.11(s,10H,-CH3),1.63-1.91(s,8H,-CH2-),1.23-1.42(m,16H,-CH2-),0.83-0.86(s,6H,-CH3)；13C NMR(150MHz DMSO-d6)δ:162.3,154.3,152.9,137.4,136.3,131.4,129.8,129.6,129.0,115.0,110.3,66.6,66.0,62.8,50.8,50.5,38.8,38.0,33.3,28.6,28.4,28.4,18.8,18.6,18.3,13.3.
EXAMPLE 20 Compound 18
Compound 18 was synthesized using the method described in example 3, and the physicochemical properties of compound 18 were as follows:
1) white powder, melting point 154-.
2) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(400MHz DMSO-d6)δ:8.23-8.26(m,1H,-NH),7.11-7.17(m,2H,-Ar),6.97-7.06(m,2H,-Ar),6.86-6.91(m,2H,-Ar),5.87-5.98(m,2H,-CH-),5.02-5.10(m,4H,＝CH2),3.86-4.42(m,6H,-CH2-),3.33(d,J＝6.8Hz,2H,-CH2-),3.29(d,J＝6.8Hz,2H,-CH2-),3.17-3.21(m,8H,-CH3 and-CH2-),1.47-1.55(m,2H,-CH2-),1.29-1.38(m,2H,-CH2-),0.88(t,J＝7.2Hz,3H,-CH3)；13C NMR(100MHz,DMSO-d6)δ:162.7,153.2,151.9,137.7,137.2,134.4,131.8,131.6,131.0,129.1,129.0,128.3,125.5,116.05,116.03,115.5,112.5,64.5,63.5,63.1,53.3,39.5,39.3,39.2,30.9,20.1,13.6.
EXAMPLE 21 Compound 19
Compound 19 was synthesized using the method described in example 3, and the physicochemical properties of compound 19 were as follows:
1) yellow powder, melting point 147-.
2) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(400MHz DMSO-d6)δ:8.23(s,1H,-NH),7.63(s,1H,-OH),7.16-7.18(m,1H,-Ar),7.11-7.13(m,1H,-Ar),7.06(s,1H,-Ar),6.96-6.98(m,1H,-Ar),6.92(s,1H,-Ar),6.86-6.88(m,1H,-Ar),5.87-5.98(m,2H,-CH-),5.02-5.10(m,4H,＝CH2),3.84-4.37(m,6H,-CH2-),3.33(d,J＝6.8Hz,2H,-CH2-),3.29(d,J＝6.8Hz,2H,-CH2-),3.16-3.17(m,8H,-CH3,-CH2-),1.51-1.54(m,2H,-CH2-),1.27-1.29(m,4H,-CH2-),0.85(t,J＝6.4Hz,3H,-CH3)；13C NMR(100MHz,DMSO-d6)δ:162.7,153.2,151.9,137.7,137.2,134.4,131.8,131.6,131.0,129.1,129.0,128.3,125.5,116.08,116.03,115.5,112.6,64.6,63.5,63.1,53.4,39.8,39.3,39.2,29.1,28.6,22.2,13.9.
EXAMPLE 22 Compound 20
Compound 20 was synthesized using the method described in example 3, and the physicochemical properties of compound 20 were as follows:
1) yellow powder, melting point 144-145 ℃;
2) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(400MHz DMSO-d6)δ:8.20(s,1H,-NH),7.66(s,1H,-OH),7.16-7.18(m,1H,-Ar),7.11-7.13(m,1H,-Ar),7.06(s,1H,-Ar),6.96-6.98(m,1H,-Ar),6.91(s,1H,-Ar),6.86-6.88(m,1H,-Ar),5.87-5.97(m,2H,-CH-),5.02-5.10(m,4H,＝CH2),3.84-4.36(m,6H,-CH2-),3.33(d,J＝6.8Hz,2H,-CH2-),3.29(d,J＝6.8Hz,2H,-CH2-),3.16-3.17(m,8H,-CH3 and-CH2-),1.50-1.53(m,2H,-CH2-),1.26(s,6H,-CH2-),0.84(t,J＝6.4Hz,3H,-CH3)；13C NMR(100MHz,DMSO-d6)δ:162.7,153.2,151.9,137.7,137.2,134.4,131.8,131.6,131.0,129.1,129.0,128.3,125.5,116.08,116.03,115.5,112.5,64.5,63.5,63.1,53.4,39.8,39.3,39.2,31.3,28.9,26.6,22.5,14.0.
EXAMPLE 23 Compound 21
Compound 21 was synthesized using the method described in example 3, and the physicochemical properties of compound 21 were as follows:
1) yellow liquid;
2) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(400MHz DMSO-d6)δ:8.43(s,1H,-OH),7.33-7.35(m,1H,-Ar),7.06-7.12(m,2H,-Ar),6.89-6.98(m,2H,-Ar),6.72-6.74(m,1H,-Ar),5.88-6.00(m,2H,-CH-),5.01-5.10(m,4H,＝CH2),4.02-4.21(m,6H,-CH2-),3.42(s,6H,-CH3),3.34(d,J＝6.8Hz,2H,-CH2-),3.29(d,J＝6.8Hz,2H,-CH2-),3.14(t,J＝8.0Hz,2H,-CH2-),3.05(s,2H,-CH2-),1.42-1.54(m,4H,-CH2-),1.25-1.33(m,4H,-CH2-),0.91(t,J＝7.2Hz,6H,-CH3-)；13C NMR(100MHz,DMSO-d6)δ:163.3,153.1,152.2,137.9,137.3,134.0,132.2,131.0,129.1,128.5,128.4,125.1,116.2,115.8,115.3,110.5,63.2,62.8,61.5,47.5,47.3,46.0,42.9,39.34,39.30,30.9,30.7,29.58,29.51,20.2,20.1,20.0,19.7,13.7,13.6.
EXAMPLE 24 Compound 22
Compound 22 was synthesized using the method described in example 3, and the physicochemical properties of compound 22 were as follows:
1) yellow liquid;
2) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(400MHz DMSO-d6)δ:8.67-8.70(m,1H,-NH),6.95-7.17(m,5H,-Ar),6.79-6.82(m,1H,-Ar),5.89-5.99(m,2H,-CH-),5.02-5.10(m,4H,＝CH2),4.42(s,2H,-CH2-),3.99(t,J＝5.2Hz,2H,-CH2-),3.62(t,J＝8.0Hz,2H,-CH2-),3.31-3.36(m,4H,-CH2-),3.21-3.26(m,2H,-CH2-),3.12(s,6H,-CH3),2.10-2.11(m,2H,-CH2-),1.51-1.57(m,2H,-CH2-),1.31-1.38(m,2H,-CH2-),0.89(t,J＝7.2Hz,3H,-CH3-)；13C NMR(100MHz,DMSO-d6)δ:162.4,153.4,152.2,137.7,137.3,133.6,131.8,131.6,131.4,128.9,128.8,128.1,125.8,115.9,115.5,112.4,64.4,64.3,63.8,51.2,51.0,39.6,39.3,30.8,23.1,20.2,13.6.
EXAMPLE 25 Compound 23
Compound 23 was synthesized using the procedure described in example 3, and the physicochemical properties of compound 23 were as follows:
1) yellow liquid;
2) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(400MHz DMSO-d6)δ:8.66(s,1H,N-H),7.44(s,1H,-OH),7.16-7.18(m,1H,-Ar),7.10-7.12(m,1H,-Ar),7.05(s,1H,-Ar),7.00-7.02(m,1H,-Ar),6.95(s,1H,-Ar),6.79-6.81(m,1H,-Ar),5.89-5.99(m,2H,-CH-),5.02-5.10(m,4H,＝CH2),4.42(s,2H,-CH2-),4.00(s,2H,-CH2-),3.64(t,J＝8.0Hz,2H,-CH2-),3.31-3.35(m,4H,-CH2-),3.19-3.24(m,2H,-CH2-),3.12(s,6H,-CH3),2.10(s,2H,-CH2-),1.54-1.58(m,2H,-CH2-),1.28-1.32(m,4H,-CH2-),0.85-0.89(m,3H,-CH3)；13C NMR(100MHz,DMSO-d6)δ:162.4,153.4,152.2,137.7,137.4,133.6,131.8,131.6,131.3,128.9,128.8,128.1,125.8,115.8,115.5,112.4,64.5,64.2,63.8,51.2,39.8,39.3,29.1,28.5,23.1,22.2,13.9.
EXAMPLE 26 Compound 24
Compound 24 was synthesized using the method described in example 3, and the physicochemical properties of compound 24 were as follows:
1) yellow liquid;
2) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(400MHz DMSO)δ:8.69(s,1H,-NH),7.53(s,1H,-OH),7.17-7.19(m,1H,-Ar),7.09-7.11(m,1H,-Ar),7.05(s,1H,-Ar),6.99-7.01(m,1H,-Ar),6.95(s,1H,-Ar),6.79-6.81(m,1H,-Ar),5.89-5.99(m,2H,-CH-),5.02-5.10(m,4H,＝CH2),4.41(s,2H,-CH2-),3.98-4.00(m,2H,-CH2-),3.64(t,J＝7.6Hz,2H,-CH2-),3.31-3.35(m,4H,-CH2-),3.19-3.24(m,2H,-CH2-),3.12(s,6H,-CH3),2.09(s,2H,-CH2-),1.52-1.59(m,2H,-CH2-),1.28-1.33(m,6H,-CH2-),0.85(t,J＝6.4Hz,3H,-CH3)；13C NMR(100MHz,DMSO-d6)δ:162.4,153.4,152.3,137.8,137.4,133.6,131.8,131.6,131.3,128.9,128.8,128.1,125.8,115.8,115.6,115.5,112.3,64.4,64.3,63.9,51.1,39.9,39.3,31.3,28.8,26.6,23.1,22.5,14.0.
EXAMPLE 27 Compound 25
Compound 25 was synthesized using the method described in example 3, and the physicochemical properties of compound 25 were as follows:
1) white powder, melting point 188-;
2) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(400MHz DMSO)δ:7.63(s,1H,-OH),7.18-7.20(m,1H,-Ar),7.06-7.11(m,2H,-Ar),6.95-7.00(m,2H,-Ar),6.81-6.83(m,1H,-Ar),5.89-6.00(m,2H,-CH-),5.02-5.10(m,4H,＝CH2),4.68(s,2H,-CH2-),4.02(t,J＝4.8Hz,2H,-CH2-),3.85(t,J＝8.0Hz,2H,-CH2-),3.32-3.36(m,10H,-CH3,-CH2-),3.23(t,J＝8.0Hz,4H,-CH2-),2.07(s,2H,-CH2-),1.44-1.57(m,4H,-CH2-),1.25-1.35(m,4H,-CH2-),0.89-0.94(m,6H,-CH3)；13C NMR(100MHz,DMSO-d6)δ:162.5,153.5,152.5,137.9,137.4,133.6,131.8,131.28,131.24,128.8,128.7,128.4,125.8,115.8,115.7,115.4,112.8,64.9,63.5,61.5,52.0,47.6,46.3,39.3,30.9,29.5,23.4,20.2,20.0,13.8,13.7.
EXAMPLE 28 Compound 26
Compound 26 was synthesized using the method described in example 3, and the physicochemical properties of compound 26 were as follows:
1) yellow liquid;
2) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(400MHz DMSO-d6)δ:8.77(s,1H,-NH),6.90-7.17(m,5H,-Ar),6.68(s,1H,-Ar),5.89-6.00(m,2H,-CH-),5.04-5.11(m,4H,＝CH2),4.38(s,2H,-CH2-),4.04(t,J＝4.8Hz,2H,-CH2-),3.41-3.45(m,2H,-CH2-),3.35(d,J＝6.8Hz,2H,-CH2-),3.32(d,J＝6.8Hz,2H,-CH2-),3.20-3.25(m,2H,-CH2-),3.10(s,6H,-CH3),1.75-1.84(m,4H,-CH2-),1.50-1.56(m,2H,-CH2-),1.32-1.37(m,2H,-CH2-),0.88(t,J＝7.2Hz,3H,-CH3)；13C NMR(100MHz,DMSO-d6)δ:162.4,153.5,152.1,137.6,137.3,133.8,132.2,132.0,131.4,129.2,128.9,127.4,126.1,116.1,115.9,115.7,112.8,67.9,66.0,62.8,51.7,39.5,39.37,39.33,30.9,25.7,20.1,19.9,13.6.
EXAMPLE 29 Compound 27
Compound 27 was synthesized using the method described in example 3, and the physicochemical properties of compound 27 were as follows:
1) yellow liquid;
3) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(400MHz DMSO-d6)δ:8.73(s,1H,-NH),7.14-7.17(m,1H,-Ar),7.08(s,1H,-Ar),7.00-7.05(m,2H,-Ar),6.90-6.92(m,1H,-Ar),6.72(s,1H,-Ar),5.89-6.00(m,2H,-CH-),5.04-5.10(m,4H,＝CH2),4.37(s,2H,-CH2-),4.04(t,J＝4.8Hz,2H,-CH2-),3.41-3.45(m,2H,-CH2-),3.35(d,J＝6.8Hz,2H,-CH2-),3.32(d,J＝6.8Hz,2H,-CH2-),3.18-3.23(m,2H,-CH2-),3.10(s,6H,-CH3),1.85-1.86(m,2H,-CH2-),1.75-1.78(m,2H,-CH2-),1.53-1.57(m,2H,-CH2-),1.25-1.31(m,4H,-CH2-),0.85(t,J＝6.8Hz,3H,-CH3)；13C NMR(100MHz,DMSO-d6)δ:162.4,153.4,152.1,137.6,137.3,133.8,132.3,132.0,131.4,129.2,129.0,127.3,126.1,116.1,115.9,115.7,112.8,67.9,66.0,62.8,51.7,39.8,39.38,39.33,29.1,28.5,25.7,22.2,19.9,13.9.
EXAMPLE 30 Compound 28
Compound 28 was synthesized using the method described in example 3, and the physicochemical properties of compound 28 were as follows:
1) yellow powder, melting point 100-;
2) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(400MHz DMSO)δ:8.74(s,1H,-NH),7.14-7.17(m,1H,-Ar),7.07-7.08(m,1H,-Ar),7.02(s,2H,-Ar),6.90-6.92(m,1H,-Ar),6.76(s,1H,-Ar),5.89-6.00(m,2H,-CH-),5.04-5.10(m,4H,＝CH2),4.37(s,2H,-CH2-),4.03(t,J＝5.2Hz,2H,-CH2-),3.41-3.45(m,2H,-CH2-),3.35(d,J＝6.8Hz,2H,-CH2-),3.32(d,J＝6.8Hz,2H,-CH2-),3.18-3.23(m,2H,-CH2-),3.10(s,6H,-CH3),1.81-1.86(m,2H,-CH2-),1.74-1.77(m,2H,-CH2-),1.51-1.58(m,2H,-CH2-),1.27-1.32(m,6H,-CH2-),0.84-0.88(m,3H,-CH3-)；13C NMR(100MHz,DMSO-d6)δ:162.4,153.5,152.1,137.6,137.3,133.8,132.2,132.0,131.4,129.2,128.9,127.3,126.1,116.1,115.9,115.7,112.9,67.9,66.0,62.8,51.7,39.8,39.38,39.34,31.3,28.8,26.6,25.7,22.5,19.9,14.0.
EXAMPLE 31 Compound 29
Compound 29 was synthesized using the procedure described in example 3, and the physicochemical properties of compound 29 were as follows:
1) yellow liquid;
2) NMR spectrum of the compound (A)1H NMR, 400MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows:1H NMR(400MHz DMSO-d6)δ:7.01-7.15(m,5H,-Ar),6.90-6.92(m,1H,-Ar),5.90-6.00(m,2H,-CH-),5.04-5.10(m,4H,＝CH2),4.64(s,2H,-CH2-),4.05(s,2H,-CH2-),3.72(s,2H,-CH2-),3.32-3.37(m,8H,-CH2-),3.28(s,6H,-CH3),1.76(s,4H,-CH2-),1.46-1.54(m,4H,-CH2-),1.26-1.36(m,4H,-CH2-),0.90-0.93(m,6H,-CH3-)；13C NMR(100MHz,DMSO-d6)δ:162.6,153.6,152.3,137.7,137.4,132.3,131.4,129.0,128.9,126.0,116.2,115.8,115.6,112.7,67.8,64.8,61.0,52.2,47.6,46.3,39.4,39.3,31.0,29.5,25.7,20.2,20.0,19.9,13.9,13.7.
application example 1: in vitro antimicrobial Activity assay
1. Test bacteria:
staphylococcus aureus (Staphylococcus aureus ATCC 29213); MRSA 11-20 (clinical isolate)
2. Sample and reagent:
the samples were: honokiol, magnolol, levofloxacin, tigecycline, and compounds 1-29 prepared in the examples.
3. The test method comprises the following steps:
according to the national clinical laboratory standard, the in vitro antibacterial activity of the compounds magnolol and honokiol, the compounds 1 to 29 of the invention and the standard drugs levofloxacin and tigecycline is tested by using a 96-well plate and adopting a double-ratio dilution method, and the drug concentration of a completely clear well is observed by naked eyes to be an MIC value.
TABLE 1 in vitro bacteriostatic activity (μ g/mL) of quaternary ammonium salt type honokiol/magnolol derivatives 1-29 of the present invention
Figure BDA0002968681120000191
Figure BDA0002968681120000201
Note: VAN: vancomycin; LEV-levofloxacin; s.a Staphylococcus aureus; e.f enterococcus faecalis; b.s Bacillus subtilis; m.l Micrococcus luteus; e.c. Escherichia coli; s.m. stenotrophomonas maltophilia; s.e Salmonella H9812; s.ebSalmonella 8389.
As shown in table 1, the quaternary ammonium salt type honokiol/magnolol derivative compounds 3, 5 to 8, 11 to 15, and 21 to 29 prepared by the invention all show certain antibacterial activity against gram-positive bacteria, and the Minimum Inhibitory Concentration (MIC) is between 0.5 and 8 μ g/mL, which is obviously improved compared with the antibacterial activity of a parent compound of magnolol (MIC is 16 to 128 μ g/mL) and honokiol (MIC is 32 to 128 μ g/mL). Most notably, the compound 8 has good activity on four selected gram-positive bacteria, the MIC is 0.5-1 mug/mL, the compound also has certain activity on gram-negative bacteria escherichia coli, and the MIC is 4-8 mug/mL, so that the compound shows good broad-spectrum antibacterial property. Therefore, the quaternary ammonium salt type honokiol/magnolol derivatives prepared by the invention can be used for developing novel antibacterial drugs.
TABLE 2 MRSA activity (μ g/mL) of the quaternary ammonium salt type honokiol/magnolol derivatives 1-29 of the present invention
Figure BDA0002968681120000202
Figure BDA0002968681120000211
Note: VAN: vancomycin; TGC: tigecycline; MRSA 11-21: a clinical isolate of Methicillin-resistant Staphylococcus aureus (Methicilin-resistant Staphylococcus aureus).
As shown in Table 2, magnolol and magnolol quaternary ammonium salt type derivatives 1-29 prepared by the invention have good inhibitory activity on clinically isolated MRSA, and the MIC value is 0.5-16 mug/mL. The best performance is that the MIC value of the compound 8 to MRSA is basically 0.5-1 mu g/mL, the effect is close to that of the positive medicament tigecycline, and the compound has better bacteriostatic activity. Therefore, the quaternary ammonium salt type honokiol/magnolol derivatives prepared by the invention can be used for developing potential antibacterial drugs aiming at MRSA infection.
Application example 2: time sterilization kinetics experiment:
1. test bacteria:
MRSA-16 (clinical isolate)
2. Sample and reagent:
the samples were: tigecycline and compound 8 prepared in the examples.
The test method comprises the following steps:
MRSA-16 was shaken overnight at 225rpm and 37 ℃ in a shaker, diluted 10000-fold with MHB medium, and then shaken at 225rpm and 37 ℃ for 2.5h (initial logarithmic growth phase) and 5h (middle logarithmic growth phase), the drug to be tested was added at concentrations of 2. mu.g/mL, 3. mu.g/mL and 4. mu.g/mL, respectively, tigecycline (4. mu.g/mL) was used as a positive control, and a blank group without drug addition was set. Centrifuging each group at 3500rpm in 96-well plate at 4 deg.C for 3min at 0h, 0.5h, 1h, 2h, 4h, 6h, and 8h after adding medicine, removing supernatant, adding 100 μ L of 1 × PBS solution for resuspension, diluting with 1 × PBS solution with ten-fold gradient, dropping diluted 10 μ L of bacteria on MHA agar plate, making parallel control under three drops of each concentration, culturing overnight in 37 deg.C constant temperature incubator, counting colony number the next day, and unit log10CFU/mL, plotted, and the results are shown in FIG. 3.
The result shows that for MRSA-16 in the early logarithmic growth phase, when the concentration of the compound 8 is 4 mug/mL (8 multiplied by MIC), complete elimination effect can be achieved within 0.5h, and the effect is obviously better than that of the positive control drug tigecycline. For the late log phase MRSA-16, Compound 8 at a concentration of 4 μ g/mL (8 × MIC) completely cleared the bacteria within 4h while the positive control drug tigecycline did not clear the bacteria at 6 h. The bactericidal effect of compound 8 on MRSA-16 at both early and late logarithmic growth phases was superior to that of the positive control tigecycline. Therefore, the quaternary ammonium salt type honokiol/magnolol derivatives prepared by the invention can be used for developing novel antibacterial drugs.

Claims (10)

1. The quaternary ammonium salt type magnolol/magnolia phenol derivative has a structural formula shown as follows:
Figure FDA0002968681110000011
wherein R is1Selected from-H or C1-C4 alkyl, R2Selected from C2-C8 alkyl, n ═ 2, 3, or 4;
R3and R4Is selected from one of the following two cases:
R3is selected from
Figure FDA0002968681110000012
Wherein R is1、R2And n is as above, R4Is selected from-H;
or, R3Is selected from-H, R4Is selected from-OH.
2. The magnolol and magnolol derivative of quaternary ammonium salt type of claim 1, wherein R is3Is selected from
Figure FDA0002968681110000013
R4When selected from-H, R1、R2And n is selected as follows:
(1)：n＝2,R1＝-H,R2＝-CH2CH3；(2)：n＝2,R1＝-H,R2＝-(CH2)2CH3；
(3)：n＝2,R1＝-H,R2＝-(CH2)3CH3；(4)：n＝2,R1＝-H,R2＝-(CH2)5CH3；
(5)：n＝2,R1＝-(CH2)3CH3,R2＝-(CH2)3CH3；(6)：n＝3,R1＝-H,R2＝-CH2CH3；
(7)：n＝3,R1＝-H,R2＝-(CH2)2CH3；(8)：n＝3,R1＝-H,R2＝-(CH2)3CH3；
(9)：n＝3,R1＝-H,R2＝-(CH2)4CH3；(10)：n＝3,R1＝-H,R2＝-(CH2)5CH3；
(11)：n＝3,R1＝R2＝-(CH2)3CH3；(12)：n＝4,R1＝-H,R2＝-CH2CH3；
(13)：n＝4,R1＝-H,R2＝-(CH2)2CH3；(14)：n＝4,R1＝-H,R2＝-(CH2)3CH3；
(15)：n＝4,R1＝-H,R2＝-(CH2)4CH3；(16)：n＝4,R1＝-H,R2＝-(CH2)5CH3；
(17)：n＝4,R1＝R2＝-(CH2)3CH3。
3. the magnolol and magnolol derivative of quaternary ammonium salt type of claim 1, wherein R is3Is selected from-H, R4When selected from-OH, R1、R2And n is selected as follows:
(18)：n＝2,R1＝-H,R2＝-(CH2)3CH3；(19)：n＝2,R1＝-H,R2＝-(CH2)4CH3；
(20)：n＝2,R1＝-H,R2＝-(CH2)5CH3；(21)：n＝2,R1＝R2＝-(CH2)3CH3；
(22)：n＝3,R1＝-H,R2＝-(CH2)3CH3；(23)：n＝3,R1＝-H,R2＝-(CH2)4CH3；
(24)：n＝3,R1＝-H,R2＝-(CH2)5CH3；(25)：n＝3,R1＝R2＝-(CH2)3CH3；
(26)：n＝4,R1＝-H,R2＝-(CH2)3CH3；(27)：n＝4,R1＝-H,R2＝-(CH2)4CH3；
(28)：n＝4,R1＝-H,R2＝-(CH2)5CH3；(29)：n＝4,R1＝R2＝-(CH2)3CH3。
4. the method for preparing the quaternary ammonium salt type magnolol/magnolol derivative of claim 1, wherein the method comprises the steps of introducing bromoalkane into hydroxyl of honokiol/magnolol as a raw material to synthesize an intermediate a/b, and performing substitution reaction with the intermediate c to generate a series of novel quaternary ammonium salt type honokiol/magnolol derivatives:
Figure FDA0002968681110000021
wherein R is1、R2And n is as defined in claim 1.
5. The method of claim 4, wherein the molar ratio of intermediate a/b to intermediate c is 1:2 to 1:4, and the reaction temperature is 70 to 80 ℃.
6. The method of claim 4, wherein the intermediate a/b is prepared by the following steps: reacting magnolol/honokiol with dibromoalkane under alkaline condition to generate an intermediate a/b;
Figure FDA0002968681110000022
7. the method of claim 6, wherein the base under basic conditions is selected from potassium carbonate, the mole ratio of magnolol/honokiol to base is 1:1.5-1:3, the mole ratio of magnolol/honokiol to dibromoalkane is 1:2-1:4, and the reaction temperature is 45-55 ℃.
8. The method of claim 4, wherein intermediate c is prepared by the following steps: reacting amine with various carbon chains with bromoacetyl bromide under an alkaline condition to generate bromoacetamide with various carbon chains, and reacting the bromoacetamide with different carbon chains with dimethylamine under the alkaline condition to generate an intermediate c;
Figure FDA0002968681110000031
wherein R is1、R2The method of claim 1.
9. The method of claim 8, wherein the molar ratio of amine to bromoacetyl bromide for each carbon chain is 1:1.5 to 1:3, the reaction temperature is 0 ℃; the molar ratio of the bromoacetamide and dimethylamine with different carbon chains is 1:1.5-1:3, and the reaction temperature is room temperature.
10. The use of magnolol and magnolol derivatives of the quaternary ammonium salt type of claim 1 in the preparation of antibacterial agents.
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