CN115583932B - Xanthohumol-antibacterial peptide mimetic hybrid, preparation method and antibacterial application thereof - Google Patents

Xanthohumol-antibacterial peptide mimetic hybrid, preparation method and antibacterial application thereof Download PDF

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CN115583932B
CN115583932B CN202211360911.6A CN202211360911A CN115583932B CN 115583932 B CN115583932 B CN 115583932B CN 202211360911 A CN202211360911 A CN 202211360911A CN 115583932 B CN115583932 B CN 115583932B
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xanthohumol
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CN115583932A (en
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郭勇
秦上尚
程晚晴
杨瑞阁
闫小婷
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Zhengzhou University
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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
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Abstract

The invention discloses a series of xanthohumol-antibacterial peptide mimetic hybrids, a preparation method and antibacterial application thereof. The series of compounds take a natural compound Huang Fuchun as a substrate, hydrophilic quaternary ammonium salt fragments are introduced on phenolic hydroxyl groups through nucleophilic substitution reaction through structural optimization, so that a series of xanthohumol-antibacterial peptide mimetic hybrids are prepared, and the structural general formula of the hybrids is shown as the following formula (I). The heterozygote has stronger in-vivo and in-vitro antibacterial activity on staphylococcus aureus (S.aureus) ATCC29213 and clinically isolated methicillin-resistant Lin Jinhuan staphylococcus (MRSA), and the activity is equivalent to that of positive control vancomycin. The invention enhances the water solubility and antibacterial activity of the xanthohumol-antibacterial peptide mimetic hybrid through structural optimization, has better stability and lower in-vivo and in-vitro toxicity, and therefore, the xanthohumol-antibacterial peptide mimetic hybrid has potential value of developing a novel antibacterial drug.

Description

Xanthohumol-antibacterial peptide mimetic hybrid, preparation method and antibacterial application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a xanthohumol-antibacterial peptide mimetic hybrid, a preparation method and antibacterial application thereof.
Background
Xanthohumol (xanthohumol) is a major prenyl flavonoid characteristic of female hops, and is secreted from lupulus glands of hops, and has a formula C 21 H 22 O 5 Molecular weight 354.4. It has been found that it is present only in hops, accounting for 0.1% to 1% of the dry weight of hops. In 1931, power et al first isolated xanthohumol from hops and characterized and named it (Power F B, tutin F, rogerson H.the constituents of hops [ J)]Chemical society 1913, 103:1267-1292.). In 1957 Verzele chemically determined that XN is a chalcone structure and that the position of the oxymethyl group was 6' but the position of the isopentenyl group was not yet determined (Verzele, M.Stockx, J.Fontijn, F.Anteunis, M.Xanthohumol, a New Natural chalkodone. Bull. Soc. Chip. Belg.1957,66,452-475. Following 1960 Huebner). Further studies were performed by Haensel 1988 to confirm that the isopentenyl group is in the 3' positionThe chemical structure of xanthohumol was finally determined (Haensel R, schulz J. Desmoxyxanthohumal: isolierung aus Hopfen und Cyclisierung zu Flavanonen. (Weinheim, ger.). Arch. Pharm.1988, 321:37-40).
The special structure of the xanthohumol endows the xanthohumol with multiple physiological activities, and the main flavonoid component in hops is based on Huang Fuchun, so that the study on the physiological activity of the xanthohumol becomes a hotspot for the study on the flavonoid compounds of hops, and a great deal of researches show that the xanthohumol has various physiological activities of preventing cancers, resisting viruses, preventing diabetes, arteriosclerosis and the like. Gerhaser et al have established a series of interrelated bioassay systems and the results of the study have shown that xanthohumol can effectively modulate the activity of enzymes involved in the metabolism and detoxification of carcinogens (Gerhaser C, alt A, heiss E, et al, cancer chemopreventive activity of Xanthohumol, a natural product derived from hop [ J ]. Molecular Cancer therapeutics 2002,1 (11): 959-969.). Miranda et al have performed in vitro antiproliferative experiments on tumor cells (breast cancer cells, ovarian cancer cells, etc.) on six flavonoids in hops, and the experimental results show that xanthohumol has no damage to normal cells, but can have a remarkable inhibitory effect on the proliferation of cancer cells, wherein the inhibitory effect of xanthohumol is most remarkable (Miranda C L, stevens J F, helmrich A, et al, anti-pro-active and cytotoxic effects of prenylated flavonoids from hops (Humulus lupulus) in human cancer cell lines [ J ]. Food and Chemical Toxicology.1999,37 (4): 271-285.). In terms of its structural modification and antibacterial activity, xanthohumol has been less studied and its water solubility is relatively poor.
Disclosure of Invention
The invention aims to: aiming at the technical problems, the invention provides a xanthohumol-antibacterial peptide mimetic hybrid, a preparation method and antibacterial application thereof, wherein the two xanthohumol-antibacterial peptide mimetic hybrid has good in-vivo and in-vitro antibacterial effects on staphylococcus aureus (S.aureus) ATCC29213 and various clinically isolated gram-positive bacteria such as MRSA and the like, and solves the problems of poor water solubility and the like.
The technical scheme is as follows: in order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a xanthohumol-antimicrobial peptide mimetic hybrid having the structure shown in formula (I):
wherein n=3, 4 or 5, r isOr a six-membered nitrogen heterocyclic amine, wherein R 1 And R is 2 Independently selected from H or C1-C8 alkyl.
Preferably, said R 1 And R is 2 Independently selected from H or C2-C6 alkyl; the azacyclic amine is selected from six-membered azacyclic amines.
Preferably, when R isWhen n, R 1 And R is 2 Is one of the following combinations:
(1)n＝3,R 1 ＝H,R 2 ＝-(CH 2 ) 2 CH 3 (2)n＝3,R 1 ＝H,R 2 ＝-(CH 2 ) 3 CH 3
(3)n＝3,R 1 ＝H,R 2 ＝-(CH 2 ) 4 CH 3 (4)n＝3,R 1 ＝H,R 2 ＝-(CH 2 ) 5 CH 3
(5)n＝3,R 1 ＝R 2 ＝-(CH 2 ) 2 CH 3 (6)n＝3,R 1 ＝R 2 ＝-(CH 2 ) 3 CH 3
(7)n＝3,R 1 ＝R 2 ＝-CH(CH 3 ) 2 (8)n＝3,R 1 ＝R 2 ＝-CH 2 CH(CH 3 ) 2
(9)n＝4,R 1 ＝H,R 2 ＝-(CH 2 ) 2 CH 3 (10)n＝4,R 1 ＝H,R 2 ＝-(CH 2 ) 3 CH 3
(11)n＝4,R 1 ＝H,R 2 ＝-(CH 2 ) 4 CH 3 (12)n＝4,R 1 ＝H,R 2 ＝-(CH 2 ) 5 CH 3
(13)n＝4,R 1 ＝R 2 ＝-(CH 2 ) 2 CH 3 (14)n＝4,R 1 ＝R 2 ＝-(CH 2 ) 3 CH 3
(15)n＝4,R 1 ＝R 2 ＝-CH(CH 3 ) 2 (16)n＝4,R 1 ＝R 2 ＝-CH 2 CH(CH 3 ) 2
(17)n＝5,R 1 ＝H,R 2 ＝-(CH 2 ) 2 CH 3 (18)n＝5,R 1 ＝H,R 2 ＝-(CH 2 ) 3 CH 3
(19)n＝5,R 1 ＝H,R 2 ＝-(CH 2 ) 4 CH 3 (20)n＝5,R 1 ＝H,R 2 ＝-(CH 2 ) 5 CH 3
(21)n＝5,R 1 ＝R 2 ＝-(CH 2 ) 2 CH 3 (22)n＝5,R 1 ＝R 2 ＝-(CH 2 ) 3 CH 3
(23)n＝5,R 1 ＝R 2 ＝-CH(CH 3 ) 2 (24)n＝5,R 1 ＝R 2 ＝-CH 2 CH(CH 3 ) 2 。
preferably, when R is a six-membered azacyclic amine, n, R are one of the following combinations:
(25)n＝3,(26)n＝3,/>
(27)n＝4,(28)n＝3,/>
(29)n＝5,(30)n＝5,/>
the above selections represent Table compounds 1-30 in the examples that follow.
The invention also provides a preparation method of the xanthohumol-antibacterial peptide mimetic hybrid, which comprises the following steps:
(1) Taking xanthohumol as a substrate, and forming an intermediate a by isopentenyl and phenolic hydroxyl Guan Huange under the action of a dehydrogenation agent;
(2) Intermediate a and dibromoalkane react under alkaline conditions to synthesize an intermediate b1-3;
(3) And the intermediates b1-3 and the intermediate c undergo substitution reaction to generate a series of new xanthohumol-antibacterial peptide mimetic hybrids, wherein the reaction formula is shown as follows:
wherein R and n are as described above.
Preferably, in step (1), the dehydrogenation agent is selected from dichlorodicyanobenzoquinone (DDQ); the molar ratio of the xanthohumol to the dehydrogenation agent is 1:1.1-1:1.5, the reaction temperature is 100-110 ℃, and the reaction solvent is toluene.
Preferably, in step (2), the base in the alkaline condition is K 2 CO 3 The reaction mole ratio of the intermediate a and the alkali is 1:1.5-1:3, the mole ratio of the intermediate a and dibromoalkane is 1:2-1:4, the reaction temperature is 45-60 ℃, and the reaction solvent is acetone.
Preferably, in step (3), the preparation method of the intermediate c comprises the following steps: the amine RH and bromoacetyl bromide undergo substitution reaction under alkaline conditions to generate bromoacetamide, and then the bromoacetamide and dimethylamine undergo continuous substitution reaction under alkaline conditions to generate an intermediate c:
wherein R is as described above.
Further preferably, the preparation method of the intermediate c is as follows:
wherein R is 1 And R is 2 As described above.
Further preferably, the molar ratio of the amine RH to bromoacetyl bromide with different carbon chain lengths is 1:1.5-1:3, the alkali selected in the reaction is K 2 CO 3 The reaction temperature is 0 ℃ to room temperature, the reaction is carried out for 2 to 8 hours, and the reaction solvent is anhydrous dichloromethane; the mol ratio of bromoamide to dimethylamine is 1:1.5-1:3, the reaction temperature is room temperature, the reaction lasts for 12-18h, and the reaction solvent is acetone.
Preferably, in the step (3), the molar ratio of the intermediate b1-3 to the intermediate c is 1:2-1:4, the reaction temperature is 70-80 ℃, and the reaction solvent is acetonitrile.
The invention finally provides application of the xanthohumol-antibacterial peptide mimetic hybrid in preparation of antibacterial drugs. Preferably, the application in preparing medicines for inhibiting staphylococcus aureus (staphylococcus aureus) ATCC29213 and various methicillin-resistant staphylococcus aureus (MRSA) by needles.
The compound designs and synthesizes a series of xanthohumol-antibacterial peptide mimic hybrids (quaternary ammonium salt type derivatives) through the structure and the function of the antibacterial peptide. The parent structure in the derivative acts as a hydrophobic moiety to facilitate insertion of the compound into the bacterial phospholipid bilayer membrane and a hydrophilic cationic moiety to facilitate interaction with the negatively charged bacterial cell membrane, resulting in bacterial cell death. According to the invention, antibacterial activity evaluation is carried out on all target compounds, and it is found that all target compounds have stronger in-vivo and in-vitro antibacterial activity on staphylococcus aureus (S.aureus) ATCC29213 and clinically separated methicillin-resistant staphylococcus aureus (MRSA), and the antibacterial effect is superior to that of a parent compound xanthohumol, and is equivalent to that of a positive control drug vancomycin. And the target compound has lower hemolytic activity, in vivo toxicity, better water solubility and stability, so the compound has wide clinical application prospect.
The technical effects are as follows: the xanthohumol-antibacterial peptide mimic hybrid prepared by the invention has better in-vivo and in-vitro antibacterial effects on gram-positive bacteria such as staphylococcus aureus ATCC29213 and various methicillin-resistant staphylococcus aureus (MRSA), improves the water solubility, reduces the biotoxicity, has higher yield, and is expected to be further developed into potential antibacterial drugs in clinic.
Drawings
FIG. 1 is a dynamic sterilization curve of compound 13.
FIG. 2 is a graph of blood normative and blood biochemical index in vivo for Compound 13.
FIG. 3 shows the change in the skin load of mice containing Compound 13.
FIG. 4 is a 1H-NMR chart of compound 13.
FIG. 5 is a 13C-NMR chart of compound 13.
Detailed Description
The invention is further illustrated by the following examples.
Example 1 preparation of intermediate a
Appropriate amounts of substrate xanthohumol (1 mmol) and dichlorodicyanobenzoquinone (DDQ) (1.3 mmol) were weighed into a 25mL round bottom flask, 3mL of anhydrous toluene was added to dissolve the materials, the mixture was heated under reflux and stirred at 110℃until the reaction was completed, the reaction solution was filtered by Thin Layer Chromatography (TLC), dichloromethane was sufficiently washed, the filtrate was concentrated under reduced pressure, and the column chromatography was separated to obtain intermediate a.
Example 2 preparation of intermediates b1-3
Appropriate amounts of intermediate a (1 mmol) and potassium carbonate (3 mmol) were weighed into a 25mL round bottom flask, 3mL of acetone was added to dissolve the mixture, 1, 3-dibromoethane/1, 4-dibromopropane/1, 5-dibromobutane (3 mmol) was added, the mixture was heated and stirred at 50 ℃, the reaction was detected by Thin Layer Chromatography (TLC), ethyl acetate (3X 30 mL) was used for extraction, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the intermediate b1-3 was isolated by column chromatography.
The physicochemical properties of intermediate b1 are as follows:
1) Yellow solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak is assigned to be YIeld 65%, 1 H NMR(600MHz CDCl 3 )δ:14.58(s,1H,-OH),7.71-7.78(m,2H,-CH＝CH-),7.53(d,J＝8.4Hz,2H,-Ph),6.89(d,J＝8.4Hz,2H,-Ph),6.66(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.13-4.16(m,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.80-3.83(m,2H,-CH 2 -),2.23-2.28(s,2H,-CH 2 -),1.45(s,6H,-CH 3 )；MS(ESI)C 24 H 26 BrO 5 [M+H] + calcd＝473.10；found＝473.18.
the physicochemical properties of intermediate b2 are as follows:
1) Yellow solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak is assigned to be YIeld 70%, 1 H NMR(600MHz CDCl 3 )δ:14.59(s,1H,-OH),7.72-7.78(m,2H,-CH＝CH-),7.53(d,J＝8.4Hz,2H,-Ph),6.89(d,J＝8.4Hz,2H,-Ph),6.66(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.12-4.15(m,2H,-CH 2 -),3.90(s,3H,-OCH 3 ),3.78-3.80(m,2H,-CH 2 -),2.22-2.26(s,2H,-CH 2 -),1.45(s,6H,-CH 3 )；MS(ESI)C 25 H 28 BrO 5 [M+H] + calcd＝487.11；found＝487.15.
the physicochemical properties of intermediate b3 are as follows:
1) Yellow solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak is assigned to be YIeld 70%, 1 H NMR(600MHz CDCl 3 )δ:14.58(s,1H,-OH),7.71-7.78(m,2H,-CH＝CH-),7.53(d,J＝8.4Hz,2H,-Ph),6.89(d,J＝8.4Hz,2H,-Ph),6.66(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.13-4.16(m,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.79-3.82(m,2H,-CH 2 -),2.23-2.26(s,2H,-CH 2 -),1.45(s,6H,-CH 3 )；MS(ESI)C 26 H 30 BrO 5 [M+H] + calcd＝500.13；found＝500.17.
example 3 preparation of intermediate c
The corresponding amine (1 mmol) was weighed into a 50mL round bottom flask, 2mL of anhydrous dichloromethane was added to dissolve the amine, potassium carbonate (1.5 mmol) was added, bromoacetyl bromide (1.5 mmol) was slowly added dropwise to the reaction solution at 0℃and the reaction was continued for half an hour, then the reaction was transferred to room temperature for reaction, the reaction was detected to be finished by Thin Layer Chromatography (TLC), extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain the corresponding bromoacetamide.
Dimethylamine (1.5 mmol) and the corresponding bromoacetamide (1 mmol) were weighed and placed in a 25mL round bottom flask, 3mL of acetone was added to dissolve the mixture, a proper amount of potassium carbonate (1.5 mmol) was added to react at room temperature, the reaction was detected to be finished by Thin Layer Chromatography (TLC), ethyl acetate extraction, anhydrous sodium sulfate drying, reduced pressure concentration and column chromatography separation were performed to obtain intermediate c.
Example 4 Compound 1
Intermediate b1-3 (1 mmol)) and intermediate c (3 mmol) were weighed into a 25mL round bottom flask, dissolved in 2mL of anhydrous acetonitrile, and reacted under stirring at 78 ℃, and detected by Thin Layer Chromatography (TLC) until the reaction was completed, to prepare a thin layer chromatography (dichloromethane: methanol=10:1) to obtain the pure product of the target compound.
The physicochemical properties of compound 1 are as follows:
1) Brown solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak belongs to the range of 48.3 percent of Yield, 1 H NMR(600MHz CDCl 3 )δ:14.59(s,1H,-OH),8.80(s,1H,-NH-),7.71-7.78(m,2H,-CH＝CH-),7.53(d,J＝8.4Hz,2H,-Ph),6.89(d,J＝8.4Hz,2H,-Ph),6.66(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.67(s,2H,-CH 2 -),4.14(s,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.88(d,J＝4.2Hz,2H,-CH 2 -),3.45(s,6H,N-CH 3 ),3.21-3.25(m,2H,-CH 2 -),2.38(s,2H,-CH 2 -),1.58(q,J＝7.2Hz,2H,-CH 2 -),1.45(s,6H,-CH 3 ),0.93(t,J＝7.2Hz,3H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.5,162.5,160.2,159.5,141.7,130.1,129.1,125.8,125.4,116.0,114.8,106.0,103.0,91.5,78.2,64.1,64.0,63.1,55.9,52.4,41.5,29.7,28.4,23.3,22.2,11.6；HRMS(ESI)C 31 H 41 BrN 2 O 6 [M-Br] + calcd＝537.2959；found＝537.2963.
EXAMPLE 5 Compound 2
Compound 2 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 2 as follows:
1) Brown solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization
With CDCl 3 Is solvent, wherein each peak belongs to the range of 55.6 percent of Yield, brownsol, 1 H NMR(600MHz CDCl 3 )δ:14.58(s,1H,-OH),8.85(t,J＝5.4Hz,1H,-NH-),7.72-7.79(m,2H,-CH＝CH-),7.53(d,J＝9Hz,2H,-Ph),6.89(d,J＝8.4Hz,2H,-Ph),6.67(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.70(s,2H,-CH 2 -),4.14(t,J＝5.4Hz,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.88-3.90(m,2H,-CH 2 -),3.45(s,6H,N-CH 3 ),3.26-3.29(m,J＝13.2,7.2Hz,2H,-CH 2 -),2.37-2.42(m,2H,-CH 2 -),1.55-1.60(m,2H,-CH 2 -),1.45(s,6H,-CH 3 ),1.35-1.39(m,2H,-CH 2 -),0.89(t,J＝7.8Hz,3H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.5,162.5,162.4,160.2,159.4,141.7,130.1,129.2,125.9,125.4,116.0,114.8,106.0,103.0,91.5,78.2,64.2,64.1,63.1,55.9,52.4,39.6,30.9,28.4,23.3,20.2,13.6,HRMS(ESI)C 32 H 43 BrN 2 O 6 [M-Br] + calcd＝551.3116；found＝551.3131.
EXAMPLE 6 Compound 3
Compound 3 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 3 as follows:
1) Yellow solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak is belonged to be YIeld 48.6%, yellow solid, 1 H NMR(600MHz CDCl 3 )δ:14.59(s,1H,-OH),8.86(s,1H,-NH-),7.72-7.79(m,2H,-CH＝CH-),7.53(d,J＝9Hz,2H,-Ph),6.89(d,J＝8.4Hz,2H,-Ph),6.66(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝9.6Hz,1H,-CH＝CH-),4.67(s,2H,-CH 2 -),4.13(m,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.88(d,J＝6.6Hz,2H,-CH 2 -),3.44(s,6H,N-CH 3 ),3.25-3.28(m,2H,-CH 2 -),2.38(d,J＝4.2Hz,2H,-CH 2 -),1.54-1.59(m,2H,-CH 2 -),1.45(s,6H,-CH 3 ),1.34-1.38(m,2H,-CH 2 -),1.25-1.28(m,2H,-CH 2 -),0.89(t,J＝7.2Hz,3H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.5,162.57,162.5,162.4,160.2,159.5,141.7,130.1,129.2,125.8,125.4,116.0,114.8,106.0,103.0,91.5,78.2,64.1,64.0,63.1,55.9,52.4,39.6,30.9,28.4,23.3,20.2,13.6,HRMS(ESI)C 33 H 45 BrN 2 O 6 [M-Br] + calcd＝565.3272；found＝565.3293.
EXAMPLE 7 Compound 4
Compound 4 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 4 as follows:
1) Yellow solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) specialThe sign is as follows:
with CDCl 3 Is solvent, wherein each peak is assigned to be YIeld 65.6%, yellow solid, 1 H NMR(600MHz CDCl 3 )δ:14.59(s,1H,-OH),8.84(t,J＝5.4Hz,1H,-NH-),7.72-7.79(m,2H,-CH＝CH-),7.53(d,J＝8.4Hz,2H,-Ph),6.89(d,J＝9Hz,2H,-Ph),6.66(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.69(s,2H,-CH 2 -),4.13(t,J＝5.4Hz,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.88(d,J＝8.4Hz,2H,-CH 2 -),3.45(s,6H,N-CH 3 ),3.24-3.45(m,2H,-CH 2 -),2.37-2.41(m,2H,-CH 2 -),1.55-1.60(m,2H,-CH 2 -),1.45(s,6H,-CH 3 ),1.31-1.34(m,2H,-CH 2 -),1.26-1.28(m,4H,-CH 2 -),0.85(t,J＝7.2Hz,3H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.5,162.57,162.5,162.4,160.2,159.4,141.7,130.1,129.2,125.8,125.4,116.0,114.8,106.0,103.0,91.5,78.2,64.1,64.1,63.1,55.9,52.4,39.9,31.3,28.8,26.7,23.3,22.5,14.0,HRMS(ESI)C 34 H 47 BrN 2 O 6 [M-Br] + calcd＝579.3429；found＝579.3439.
example 8 Compound 5
Compound 5 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 5 as follows:
1) Yellow solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak is belonged to 62.4% of Yield, 1 H NMR(600MHz CDCl 3 )δ:14.59(s,1H,-OH),7.72-7.79(m,2H,-CH＝CH-),7.53(d,J＝9Hz,2H,-Ph),6.89(d,J＝8.4Hz,2H,-Ph),6.67(d,J＝9.6Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.94(s,2H,-CH 2 -),4.11-4.15(m,4H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.62(s,6H,N-CH 3 ),3.41-3.43(m,2H,-CH 2 -),3.25(t,J＝7.8Hz,2H,-CH 2 -),2.29-2.34(m,2H,-CH 2 -),1.64(t,J＝7.8Hz,2H,-CH 2 -),1.54-1.58(m,2H,-CH 2 -),1.45(s,6H,-CH 3 ),0.98(t,J＝7.2Hz,3H,-CH 3 ),0.89(t,J＝7.2Hz,3H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.5,162.6,162.57,162.5,160.2,159.6,141.8,130.1,129.1,125.8,125.3,116.0,114.8,106.0,103.0,91.5,78.2,64.2,63.1,61.2,55.9,52.8,49.3,48.2,28.4,23.4,22.2,20.7,11.38,11.3,HRMS(ESI)C 34 H 47 BrN 2 O 6 [M-Br] + calcd＝579.3429；found＝579.3433.
EXAMPLE 9 Compound 6
Compound 6 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 6 as follows:
1) Yellow solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak belongs to the field of 86.0 percent, pale yellow solid, 1 H NMR(600MHz CDCl 3 )δ:14.59(s,1H,-OH),7.72-7.79(m,2H,-CH＝CH-),7.53(d,J＝9Hz,2H,-Ph),6.89(d,J＝8.4Hz,2H,-Ph),6.67(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.93(s,2H,-CH 2 -),4.12-4.15(m,4H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.62(s,6H,N-CH 3 ),3.44-3.46(m,2H,-CH 2 -),3.28(t,J＝7.8Hz,2H,-CH 2 -),2.29-2.34(m,2H,-CH 2 -),1.57-1.62(m,2H,-CH 2 -),1.50-1.53(m,2H,-CH 2 -),1.45(s,6H,-CH 3 ),1.38-1.42(m,2H,-CH 2 -),1.29-1.33(m,2H,-CH 2 -),0.95(t,J＝7.2Hz,3H,-CH 3 ),0.91(t,J＝7.2Hz,3H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.5,162.56,162.5,160.2,159.5,141.8,130.1,129.1,125.8,125.3,116.0,114.8,106.0,103.0,91.5,78.2,64.2,63.1,61.2,55.9,52.7,47.7,46.4,31.1,29.5,28.4,23.4,20.2,20.1,13.9,13.7,HRMS(ESI)C 36 H 51 BrN 2 O 6 [M-Br] + calcd＝607.3742；found＝607.3770.
EXAMPLE 10 Compound 7
Compound 7 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 7 as follows:
1) Yellow solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak is belonged to be YIeld:52.6%, yellow solid, 1 H NMR(600MHz CDCl 3 )δ:14.60(s,1H,-OH),7.72-7.79(m,2H,-CH＝CH-),7.53(d,J＝9Hz,2H,-Ph),6.89(d,J＝8.4Hz,2H,-Ph),6.67(d,J＝9.6Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝9.6Hz,1H,-CH＝CH-),4.96(s,2H,-CH 2 -),4.13(t,J＝5.4Hz,2H,-CH 2 -),4.09-4.12(m,3H,-CH 2 -,-CH-),3.91(s,3H,-OCH 3 ),3.61(s,6H,N-CH 3 ),3.45-3.50(m,1H,-CH-),2.29-2.34(m,2H,-CH 2 -),1.45(s,6H,-CH 3 ),1.38(d,J＝6.6Hz,6H,-CH 3 -),1.27(d,J＝6.6Hz,6H,-CH 3 -)； 13 C NMR(150MHz CDCl 3 )δ:192.5,162.58,162.5,161.5,160.2,159.6,141.8,130.1,129.0,125.7,125.3,116.0,114.8,106.0,103.0,91.5,78.2,64.3,62.9,62.2,55.9,52.8,48.9,46.8,28.3,23.4,21.0,20.3,HRMS(ESI)C 34 H 47 BrN 2 O 6 [M-Br] + calcd＝579.3429；found＝579.3427.
EXAMPLE 11 Compound 8
Compound 8 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 8 as follows:
1) Yellow solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak is belonged to be Yield 46.8%, yellow solid, 1 H NMR(600MHz CDCl 3 )δ:14.59(s,1H,-OH),7.72-7.79(m,2H,-CH＝CH-),7.53(d,J＝9Hz,2H,-Ph),6.89(d,J＝9Hz,2H,-Ph),6.67(d,J＝9.6Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.93(s,2H,-CH 2 -),4.11-4.15(m,4H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.63(s,6H,N-CH 3 ),3.37(d,J＝7.8Hz,2H,-CH 2 -),3.20(d,J＝7.8Hz,2H,-CH 2 -),2.29-2.34(m,2H,-CH 2 -),1.96-2.01(m,2H,-CH-),1.45(s,6H,-CH 3 ),0.99(d,J＝6.6Hz,6H,-CH 3 -),0.89(d,J＝6.6Hz,6H,-CH 3 -)； 13 C NMR(150MHz CDCl 3 )δ:192.5,163.5,162.58,162.5,160.2,159.6,141.8,130.1,129.1,125.7,125.3,116.0,114.8,106.0,103.0,91.5,78.2,64.2,63.1,61.3,55.9,54.8,53.4,52.9,28.4,27.8,26.4,23.5,20.2,19.9,HRMS(ESI)C 36 H 51 BrN 2 O 6 [M-Br] + calcd＝607.3742；found＝607.3749.
EXAMPLE 12 Compound 9
Compound 9 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 9 as follows:
1) Brown solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,400 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak is belonged to be YIeld 48.9%, brown solid, 1 H NMR(600MHz CDCl 3 )δ:14.61(s,1H,-OH),8.84(t,J＝5.4Hz,1H,-NH-),7.73-7.79(m,2H,-CH＝CH-),7.53(d,J＝9Hz,2H,-Ph),6.90(d,J＝9Hz,2H,-Ph),6.67(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.65(s,2H,-CH 2 -),4.07(t,J＝5.4Hz,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.75-3.78(m,2H,-CH 2 -),3.40(s,6H,N-CH 3 ),3.21-3.25(m,2H,-CH 2 -),2.04-2.07(m,2H,-CH 2 -),1.89-1.93(m,2H,-CH 2 -),1.58-1.62(m,2H,-CH 2 -),1.45(s,6H,-CH 3 ),0.93(t,J＝7.2Hz,3H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.6,162.57,162.5,160.2,160.0,142.0,130.1,128.8,125.5,125.4,116.0,114.8,106.0,103.0,91.5,78.2,66.6,65.8,63.4,55.9,51.9,41.6,29.7,28.4,25.8,22.2,20.1,11.6,HRMS(ESI)C 32 H 43 BrN 2 O 6 [M-Br] + calcd＝551.3116；found＝551.3133.
EXAMPLE 13 Compound 10
Compound 10 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 10 as follows:
1) Orange solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak is belonged to be YIeld 48.5%, orangesol, 1 H NMR(600MHz CDCl 3 )δ:14.60(s,1H,-OH),8.85(t,J＝5.4Hz,1H,-NH-),7.73-7.79(m,2H,-CH＝CH-),7.54(d,J＝9Hz,2H,-Ph),6.90(d,J＝9Hz,2H,-Ph),6.67(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.64(s,2H,-CH 2 -),4.07-4.09(m,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.75-3.77(m,2H,-CH 2 -),3.39(s,6H,N-CH 3 ),3.25-3.28(m,2H,-CH 2 -),2.03-2.09(m,2H,-CH 2 -),1.89-1.93(m,2H,-CH 2 -),1.54-1.59(m,2H,-CH 2 -),1.45(s,6H,-CH 3 ),1.35-1.39(m,2H,-CH 2 ),0.90(t,J＝7.2Hz,3H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.6,162.57,162.5,162.4,160.2,160.0,142.0,130.1,128.8,125.6,125.4,116.0,114.8,106.0,103.0,91.5,78.2,66.6,65.9,63.5,55.9,51.9,39.6,30.9,28.4,25.8,20.2,20.1,13.6,HRMS(ESI)C 33 H 45 BrN 2 O 6 [M-Br] + calcd＝565.3272；found＝565.3278.
EXAMPLE 14 Compound 11
Compound 11 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 11 as follows:
1) Yellow solid.
3) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak is belonged to be YIeld 45.6 percent, yellow solid, 1 H NMR(600MHz CDCl 3 )δ:14.60(s,1H,-OH),8.87(t,J＝4.8Hz,1H,-NH-),7.73-7.79(m,2H,-CH＝CH-),7.54(d,J＝8.4Hz,2H,-Ph),6.90(d,J＝9Hz,2H,-Ph),6.67(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝9.6Hz,1H,-CH＝CH-),4.63(s,2H,-CH 2 -),4.07(t,J＝5.4Hz,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.75(t,J＝8.4Hz,2H,-CH 2 -),3.39(s,6H,N-CH 3 ),3.23-3.27(m,2H,-CH 2 -),2.04-2.08(m,2H,-CH 2 -),1.90-1.93(m,2H,-CH 2 -),1.57-1.59(m,2H,-CH 2 -),1.45(s,6H,-CH 3 ),1.31(t,J＝3.6Hz,4H,-CH 2 ),0.87(t,J＝7.2Hz,3H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.6,162.57,162.55,162.5,160.2,160.0,142.0,130.1,128.8,125.6,125.4,116.0,114.8,106.0,103.0,91.5,78.2,66.6,65.9,63.5,55.9,51.9,39.9,29.1,28.5,28.4,25.8,22.5,20.1,13.9,HRMS(ESI)C 34 H 47 BrN 2 O 6 [M-Br] + calcd＝579.3429；found＝579.3436.
EXAMPLE 15 Compound 12
Compound 12 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 12 as follows:
1) Orange solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak belongs to the range of 48.4 percent, orange solid, 1 H NMR(600MHz CDCl 3 )δ:14.60(s,1H,-OH),8.85(t,J＝5.4Hz,1H,-NH-),7.73-7.79(m,2H,-CH＝CH-),7.54(d,J＝9Hz,2H,-Ph),6.90(d,J＝9Hz,2H,-Ph),6.67(d,J＝9.6Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝9.6Hz,1H,-CH＝CH-),4.65(s,2H,-CH 2 -),4.07-4.09(m,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.75-3.78(m,2H,-CH 2 -),3.40(s,6H,N-CH 3 ),3.24-3.27(m,2H,-CH 2 -),2.03-2.08(m,2H,-CH 2 -),1.89-1.93(m,2H,-CH 2 -),1.55-1.60(m,2H,-CH 2 -),1.45(s,6H,-CH 3 ),1.31-1.34(m,2H,-CH 2 ),1.26-1.29(m,2H,-CH 2 ),0.85(t,J＝7.2Hz,3H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.6,162.57,162.5,162.4,160.2,160.0,142.0,130.1,128.8,125.6,125.4,116.0,114.8,106.0,103.0,91.5,78.2,66.6,65.9,63.4,55.9,51.9,39.9,31.3,29.7,28.8,28.4,26.7,25.8,22.5,20.1,14.0,HRMS(ESI)C 35 H 49 BrN 2 O 6 [M-Br] + calcd＝593.3585；found＝593.3586.
EXAMPLE 16 Compound 13
Compound 13 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 13 as follows:
1) Orange solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak belongs to the field of 52.6 percent, the orange solid, 1 H NMR(600MHz CDCl 3 )δ:14.61(s,1H,-OH),7.73-7.79(m,2H,-CH＝CH-),7.53(d,J＝9Hz,2H,-Ph),6.90(d,J＝9Hz,2H,-Ph),6.67(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.89(s,2H,-CH 2 -),4.06(t,J＝5.4Hz,2H,-CH 2 -),3.98-4.01(m,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.58(s,6H,N-CH 3 ),3.39(t,J＝7.8Hz,2H,-CH 2 ),3.23(t,J＝7.8Hz,2H,-CH 2 ),1.95-2.00(m,2H,-CH 2 -),1.89-1.92(m,2H,-CH 2 -),1.63-1.66(m,2H,-CH 2 -),1.53-1.56(m,2H,-CH 2 -),1.45(s,6H,-CH 3 ),0.97(t,J＝7.2Hz,3H,-CH 3 ),0.87(t,J＝7.2Hz,3H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.6,162.7,162.57,162.5,160.2,142.0,130.1,128.7,125.5,125.3,116.0,114.8,106.0,103.0,91.5,78.2,66.6,64.8,61.2,55.9,52.4,49.3,48.2,28.3,25.8,22.1,20.7,20.0,11.3,11.2,HRMS(ESI)C 35 H 49 BrN 2 O 6 [M-Br] + calcd＝593.3585；found＝593.3605.
EXAMPLE 17 Compound 14
Compound 14 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 14 as follows:
1) Orange solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak is belonged to be YIeld 37.0%, orange solid, 1 H NMR(600MHz CDCl 3 )δ:14.61(s,1H,-OH),7.73-7.79(m,2H,-CH＝CH-),7.53(d,J＝9Hz,2H,-Ph),6.90(d,J＝8.4Hz,2H,-Ph),6.67(d,J＝9.6Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.86(s,2H,-CH 2 -),4.06-4.08(m,2H,-CH 2 -),3.98-4.01(m,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.57(s,6H,N-CH 3 ),3.41(t,J＝7.8Hz,2H,-CH 2 ),3.26(t,J＝7.8Hz,2H,-CH 2 ),1.95-2.00(m,2H,-CH 2 -),1.89-1.92(m,2H,-CH 2 -),1.57-1.60(m,2H,-CH 2 -),1.48-1.51(m,2H,-CH 2 -),1.45(s,6H,-CH 3 ),1.37-1.41(m,2H,-CH 2 -),1.28-1.32(m,2H,-CH 2 ),0.94(t,J＝7.2Hz,3H,-CH 3 ),0.91(t,J＝7.2Hz,3H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.6,162.57,162.5,160.2,142.0,130.1,128.7,125.5,125.3,116.1,114.8,106.0,103.0,91.5,78.2,66.6,64.8,61.2,55.9,52.4,47.7,46.4,31.0,29.5,28.3,25.8,20.2,20.08,20.0,13.9,13.7,HRMS(ESI)C 37 H 53 BrN 2 O 6 [M-Br] + calcd＝621.3898；found＝621.3895.
EXAMPLE 18 Compound 15
Compound 15 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 15 as follows:
1) Yellow solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak is attributed to a yellow:55.3%, 1 H NMR(600MHz CDCl 3 )δ:14.61(s,1H,-OH),7.73-7.79(m,2H,-CH＝CH-),7.53(d,J＝9Hz,2H,-Ph),6.90(d,J＝9Hz,2H,-Ph),6.67(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.90(s,2H,-CH 2 -),4.06-4.08(m,3H,-CH 2 -,-CH-),3.96-3.99(m,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.55(s,6H,N-CH 3 ),3.45-3.49(m,1H,-CH-),1.95-2.00(m,2H,-CH 2 -),1.89-1.92(m,2H,-CH 2 -)1.45(s,6H,-CH 3 ),1.37(d,J＝6.6Hz,6H,-CH 3 -),1.26(d,J＝6.6Hz,6H,-CH 3 -)； 13 C NMR(150MHz CDCl 3 )δ:192.6,162.57,162.5,161.6,160.2,142.0,130.1,128.7,125.5,125.3,116.1,114.8,106.0,103.0,91.5,78.2,66.7,64.7,62.2,55.9,52.3,48.8,46.8,28.4,25.9,20.9,20.2,20.0,HRMS(ESI)C 35 H 49 BrN 2 O 6 [M-Br] + calcd＝593.3585；found＝593.3604.
EXAMPLE 19 Compound 16
Compound 16 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 16 as follows:
1) Brown solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak belongs to 62.4 percent of Yield, brown solid, 1 H NMR(600MHz CDCl 3 )δ:14.61(s,1H,-OH),7.73-7.79(m,2H,-CH＝CH-),7.53(d,J＝9Hz,2H,-Ph),6.90(d,J＝9Hz,2H,-Ph),6.67(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.88(s,2H,-CH 2 -),4.06-4.08(m,2H,-CH 2 -),3.98-4.01(m,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.58(s,6H,N-CH 3 ),3.34(d,J＝7.8Hz,2H,-CH 2 -),3.18(d,J＝7.2Hz,2H,-CH 2 -),1.95-1.99(m,4H,-CH 2 -,-CH-),1.89-1.92(m,2H,-CH 2 -),1.45(s,6H,-CH 3 ),0.97(d,J＝6.6Hz,6H,-CH 3 -),0.88(d,J＝6.6Hz,6H,-CH 3 -)； 13 C NMR(150MHz CDCl 3 )δ:192.6,163.5,162.57,162.5,160.2,142.0,130.1,128.7,125.5,125.3,116.1,114.8,106.0,103.0,91.5,78.2,66.7,64.8,61.2,55.9,54.8,53.4,52.5,28.4,27.8,26.4,25.8,20.2,20.1,19.9,HRMS(ESI)C 37 H 53 BrN 2 O 6 [M-Br] + calcd＝621.3898；found＝621.3916.
EXAMPLE 20 Compound 17
Compound 17 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 17 as follows:
1) Yellow solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak is belonged to be YIeld:54.6%, yellow solid, 1 H NMR(600MHz CDCl 3 )δ:14.62(s,1H,-OH),8.87-8.89(m,1H,-NH-),7.73-7.79(m,2H,-CH＝CH-),7.53(d,J＝9Hz,2H,-Ph),6.89(d,J＝8.4Hz,2H,-Ph),6.67(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.66(s,2H,-CH 2 -),4.02-4.04(m,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.65-3.68(m,2H,-CH 2 -),3.38(s,6H,N-CH 3 ),3.22(q,J＝6.6Hz,2H,-CH 2 -),1.88-1.93(m,4H,-CH 2 -),1.58-1.63(m,4H,-CH 2 -),1.45(s,6H,-CH 3 ),0.93(t,J＝7.2Hz,3H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.6,162.57,162.5,160.4,160.1,142.1,130.1,128.4,125.3,116.0,114.8,106.0,103.0,91.5,78.2,67.2,66.2,63.3,55.9,52.0,41.6,28.5,28.3,23.0,22.7,22.2,11.6,HRMS(ESI)C 33 H 45 BrN 2 O 6 [M-Br] + calcd＝565.3272；found＝565.3290.
EXAMPLE 21 Compound 18
Compound 18 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 18 as follows:
1) Yellow solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak is belonged to be YIeld 59.6%, yellow solid, 1 H NMR(600MHz CDCl 3 )δ:14.62(s,1H,-OH),8.86(t,J＝5.4Hz,1H,-NH-),7.73-7.79(m,2H,-CH＝CH-),7.53(d,J＝9Hz,2H,-Ph),6.89(d,J＝8.4Hz,2H,-Ph),6.67(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.64(s,2H,-CH 2 -),4.02(t,J＝6Hz,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.65-3.68(m,2H,-CH 2 -),3.38(s,6H,N-CH 3 ),3.25-3.29(m,2H,-CH 2 -),1.88-1.93(m,4H,-CH 2 -),1.56-1.62(m,4H,-CH 2 -),1.45(s,6H,-CH 3 ),1.35-1.39(m,2H,-CH 2 ),0.90(t,J＝7.2Hz,3H,-CH 3 -)； 13 C NMR(150MHz CDCl 3 )δ:192.6,162.57,162.55,162.5,160.4,160.1,142.1,130.1,128.5,125.3,116.1,114.8,106.0,103.0,91.5,78.2,67.2,66.2,63.3,55.9,52.0,39.6,30.9,28.5,28.3,23.0,22.7,20.2,13.6,HRMS(ESI)C 34 H 47 BrN 2 O 6 [M-Br] + calcd＝579.3429；found＝579.3435.
EXAMPLE 22 Compound 19
Compound 19 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 19 as follows:
1) Orange solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak belongs to 62.4 percent of Yield, orange solid, 1 H NMR(600MHz CDCl 3 )δ:14.62(s,1H,-OH),8.87(s,1H,-NH-),7.74-7.79(m,2H,-CH＝CH-),7.53(d,J＝9Hz,2H,-Ph),6.89(d,J＝9Hz,2H,-Ph),6.67(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.65(s,2H,-CH 2 -),4.02(t,J＝6Hz,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.65(t,J＝8.4Hz,2H,-CH 2 -),3.38(s,6H,N-CH 3 ),3.24-3.27(m,2H,-CH 2 -),1.87-1.94(m,4H,-CH 2 -),1.57-1.62(m,4H,-CH 2 -),1.45(s,6H,-CH 3 ),1.30-1.32(m,4H,-CH 2 ),0.87(t,J＝7.2Hz,3H,-CH 3 -)； 13 C NMR(150MHz CDCl 3 )δ:192.6,162.57,162.5,162.4,160.4,160.1,142.1,130.1,128.5,125.3,116.1,114.8,106.0,103.0,91.5,78.2,67.2,66.2,63.3,55.9,52.0,39.9,29.1,28.59,28.5,28.3,23.0,22.7,22.2,13.9,HRMS(ESI)C 35 H 49 BrN 2 O 6 [M-Br] + calcd＝593.3585；found＝593.3605.
EXAMPLE 23 Compound 20
Compound 20 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 20 as follows:
1) Yellow solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak is belonged to be YIeld:54.3%, yellow solid, 1 H NMR(600MHz CDCl 3 )δ:14.62(s,1H,-OH),8.86(t,J＝5.4Hz,1H,-NH-),7.73-7.79(m,2H,-CH＝CH-),7.53(d,J＝8.4Hz,2H,-Ph),6.89(d,J＝8.4Hz,2H,-Ph),6.67(d,J＝9.6Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.65(s,2H,-CH 2 -),4.01(t,J＝6Hz,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.65-3.68(m,2H,-CH 2 -),3.38(s,6H,N-CH 3 ),3.24-3.27(m,2H,-CH 2 -),1.87-1.94(m,4H,-CH 2 -),1.55-1.63(m,4H,-CH 2 -),1.45(s,6H,-CH 3 ),1.32-1.34(m,2H,-CH 2 ),1.27-1.29(m,4H,-CH 2 ),0.85(t,J＝7.2Hz,3H,-CH 3 -)； 13 C NMR(150MHz CDCl 3 )δ:192.6,162.57,162.56,162.5,160.4,160.1,142.1,130.1,128.4,125.3,116.1,114.8,106.0,103.0,91.5,78.2,67.2,66.2,63.3,55.9,52.0,39.9,31.3,28.8,28.5,28.3,26.7,23.0,22.7,22.5,14.0,HRMS(ESI)C 36 H 51 BrN 2 O 6 [M-Br] + calcd＝607.3742；found＝607.3758.
EXAMPLE 24 Compound 21
Compound 21 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 21 as follows:
1) Yellow solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak is belonged to 62.3% of Yield, 1 H NMR(600MHz CDCl 3 )δ:14.63(s,1H,-OH),7.74-7.79(m,2H,-CH＝CH-),7.53(d,J＝8.4Hz,2H,-Ph),6.88(d,J＝8.4Hz,2H,-Ph),6.67(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝9.6Hz,1H,-CH＝CH-),4.87(s,2H,-CH 2 -),4.00-4.02(m,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.87-3.90(m,2H,-CH 2 -),3.57(s,6H,N-CH 3 ),3.38-3.41(m,2H,-CH 2 ),3.24-3.27(m,2H,-CH 2 ),1.85-1.89(m,4H,-CH 2 -),1.63-1.67(m,2H,-CH 2 -),1.59(d,J＝7.2Hz,2H,-CH 2 -),1.53(t,J＝7.8Hz,2H,-CH 2 -),1.45(s,6H,-CH 3 ),0.97(t,J＝7.2Hz,3H,-CH 3 ),0.88(t,J＝7.2Hz,3H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.6,162.8,162.57,162.55,160.5,160.1,142.2,130.1,128.4,125.37,125.3,116.1,114.8,106.0,103.0,91.5,78.2,67.3,64.9,61.1,55.9,52.6,49.3,48.2,28.5,28.3,23.0,22.7,22.1,20.7,11.3,11.2,HRMS(ESI)C 36 H 51 BrN 2 O 6 [M-Br] + calcd＝607.3742；found＝607.3748.
EXAMPLE 25 Compound 22
Compound 22 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 22 as follows:
1) Yellow solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak is belonged to be YIeld:55.3%, yellow solid, 1 H NMR(600MHz CDCl 3 )δ:14.62(s,1H,-OH),7.74-7.79(m,2H,-CH＝CH-),7.53(d,J＝8.4Hz,2H,-Ph),6.88(d,J＝8.4Hz,2H,-Ph),6.67(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝9.6Hz,1H,-CH＝CH-),4.87(s,2H,-CH 2 -),4.00(t,J＝6Hz,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.88-3.90(m,2H,-CH 2 -),3.57(s,6H,N-CH 3 ),3.42(t,J＝7.8Hz,2H,-CH 2 ),3.27(t,J＝7.8Hz,2H,-CH 2 ),1.85-1.90(m,2H,-CH 2 -),1.80-1.84(m,2H,-CH 2 -),1.57-1.61(m,4H,-CH 2 -),1.49-1.52(m,2H,-CH 2 -),1.45(s,6H,-CH 3 ),1.37-1.41(m,2H,-CH 2 -),1.28-1.32(m,2H,-CH 2 -),0.95(t,J＝7.2Hz,3H,-CH 3 ),0.91(t,J＝7.2Hz,3H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.6,162.6,162.57,162.5,160.5,160.1,142.2,130.1,128.4,125.37,125.3,116.1,114.8,106.0,103.0,91.5,78.2,67.3,64.9,61.2,55.8,52.5,47.7,46.4,31.0,29.5,28.5,28.3,23.0,22.7,20.2,20.0,13.9,13.7,HRMS(ESI)C 38 H 55 BrN 2 O 6 [M-Br] + calcd＝635.4055；found＝635.4072.
EXAMPLE 26 Compound 23
Compound 23 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 23 as follows:
1) Orange solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak belongs to 62.3 percent of Yield, orange solid, 1 H NMR(600MHz CDCl 3 )δ:14.62(s,1H,-OH),7.74-7.79(m,2H,-CH＝CH-),7.53(d,J＝8.4Hz,2H,-Ph),6.88(d,J＝9Hz,2H,-Ph),6.67(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.90(s,2H,-CH 2 -),4.07-4.11(m,1H,-CH-),4.01-4.02(m,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.86-3.89(m,2H,-CH 2 -),3.54(s,6H,N-CH 3 ),3.44-3.49(m,1H,-CH-),1.85-1.90(m,2H,-CH 2 -),1.80-1.84(m,2H,-CH 2 -),1.57-1.62(m,2H,-CH 2 -),1.45(s,6H,-CH 3 ),1.37(d,J＝7.2Hz,6H,-CH 3 -),1.26(d,J＝6.6Hz,6H,-CH 3 -)； 13 C NMR(150MHz CDCl 3 )δ:192.6,162.57,162.5,161.6,160.5,160.1,142.2,130.1,128.4,125.37,125.3,116.1,114.8,106.0,103.0,91.5,78.2,67.3,64.9,62.2,55.9,52.5,48.8,46.7,28.5,28.3,23.0,22.7,20.9,20.2,HRMS(ESI)C 36 H 51 BrN 2 O 6 [M-Br] + calcd＝607.3742；found＝607.3741.
EXAMPLE 27 Compound 24
Compound 24 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 24 as follows:
1) Orange solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak belongs to the range of 55.8 percent, orange solid, 1 H NMR(600MHz CDCl 3 )δ:14.62(s,1H,-OH),7.74-7.79(m,2H,-CH＝CH-),7.53(d,J＝9Hz,2H,-Ph),6.88(d,J＝8.4Hz,2H,-Ph),6.67(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),4.87(s,2H,-CH 2 -),4.00(t,J＝6Hz,2H,-CH 2 ),3.91(s,3H,-OCH 3 ),3.87-3.90(m,2H,-CH 2 -),3.56(s,6H,N-CH 3 ),3.35(d,J＝7.2Hz,2H,-CH 2 -),3.19(d,J＝7.8Hz,2H,-CH 2 -),1.92-2.01(m,2H,-CH-),1.86-1.89(m,2H,-CH 2 -),1.81-1.85(m,2H,-CH 2 -),1.57-1.62(m,2H,-CH 2 -),1.45(s,6H,-CH 3 ),0.98(d,J＝6.6Hz,6H,-CH 3 -),0.88(d,J＝6.6Hz,6H,-CH 3 -)； 13 C NMR(150MHz CDCl 3 )δ:192.6,163.5,162.57,162.5,160.5,160.1,142.2,130.1,128.4,125.3,125.3,116.1,114.8,106.0,103.0,91.5,78.2,67.3,65.0,61.2,55.9,54.8,53.4,52.7,28.5,28.3,27.8,26.4,23.0,22.8,20.2,19.9,HRMS(ESI)C 38 H 55 BrN 2 O 6 [M-Br] + calcd＝635.4055；found＝635.4069.
EXAMPLE 28 Compound 25
Compound 25 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 25 as follows:
1) Orange solid;
2) Nuclear magnetic resonance spectrum of the compound 1 HNMR,600 MHz) characteristics:
with CDCl 3 Is solvent, wherein each peak is belonged to the original solid of which the Yield is 58.6 percent, 1 H NMR(600MHz CDCl 3 )δ:14.58(s,1H,-OH),7.72-7.79(m,2H,-CH＝CH-),7.53(d,J＝9Hz,2H,-Ph),6.89(d,J＝9Hz,2H,-Ph),6.66(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),5.23(s,2H,-CH 2 -),4.13(t,J＝5.4Hz,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.78(t,J＝4.8Hz,2H,-CH 2 -),3.72-3.73(m,2H,-CH 2 -),3.68-3.70(m,2H,-CH 2 -),3.58(s,8H,N-CH 3 ,-CH 2 ),2.32-2.36(m,2H,-CH 2 -),1.45(s,6H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.5,162.57,162.5,161.8,160.2,159.5,141.7,130.1,129.1,125.8,125.4,116.0,114.8,106.0,103.0,91.5,78.2,66.6,66.3,64.2,63.2,61.6,55.9,52.7,45.8,42.0,28.4,23.4,HRMS(ESI)C 32 H 41 BrN 2 O 7 [M-Br] + calcd＝565.2908；found＝565.2903.
EXAMPLE 29 Compound 26
Compound 26 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 26 as follows:
1) Orange solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak is belonged to the original solid of which the Yield is 51.4 percent, 1 H NMR(600MHz CDCl 3 )δ:14.58(s,1H,-OH),7.72-7.79(m,2H,-CH＝CH-),7.54(d,J＝9Hz,2H,-Ph),6.89(d,J＝9Hz,2H,-Ph),6.67(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),5.23(s,2H,-CH 2 -),4.13(t,J＝5.4Hz,2H,-CH 2 -),4.08-4.10(m,2H,-CH 2 -),3.92(t,J＝4.8Hz,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.83-3.85(m,2H,-CH 2 -),3.57(s,6H,N-CH 3 ),2.80(t,J＝4.8Hz,2H,-CH 2 -),2.61(t,J＝4.8Hz,2H,-CH 2 -),2.31-2.35(m,2H,-CH 2 -),1.45(s,6H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.5,162.5,161.6,160.2,159.4,141.7,130.1,129.2,125.9,125.4,116.0,114.8,106.0,103.0,91.5,78.2,64.1,63.3,61.7,55.9,52.7,48.3,44.6,28.4,27.2,23.4,HRMS(ESI)C 32 H 41 BrN 2 O 6 SM-Br] + calcd＝581.2680；found＝581.2684.
EXAMPLE 30 Compound 27
Compound 27 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 27 as follows:
1) Orange solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak belongs to the range of 45.3 percent, orange solid, 1 H NMR(600MHz CDCl 3 )δ:14.60(s,1H,-OH),7.73-7.79(m,2H,-CH＝CH-),7.54(d,J＝9Hz,2H,-Ph),6.91(d,J＝8.4Hz,2H,-Ph),6.67(d,J＝9.6Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),5.17(s,2H,-CH 2 -),4.07(t,J＝5.4Hz,2H,-CH 2 -),3.95-3.98(m,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.77-3.79(m,2H,-CH 2 -),3.67-3.71(m,4H,-CH 2 -),3.55(t,J＝4.8Hz,2H,-CH 2 -),3.53(s,6H,N-CH 3 ),1.98-2.03(m,2H,-CH 2 -),1.88-1.92(m,2H,-CH 2 -),1.45(s,6H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.6,162.57,162.5,161.8,160.2,160.1,142.0,130.1,128.7,125.5,125.4,116.0,114.8,106.0,103.0,91.5,78.2,66.67,66.6,66.3,64.9,61.6,55.9,52.2,45.8,42.0,28.4,25.8,20.0,HRMS(ESI)C 33 H 43 BrN 2 O 7 [M-Br] + calcd＝579.3065；found＝579.3083.
EXAMPLE 31 Compound 28
Compound 28 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 28 as follows:
1) Orange solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak belongs to the range of 45.2 percent, orange solid, 1 H NMR(600MHz CDCl 3 )δ:14.60(s,1H,-OH),7.73-7.79(m,2H,-CH＝CH-),7.54(d,J＝9Hz,2H,-Ph),6.91(d,J＝9Hz,2H,-Ph),6.67(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝10.2Hz,1H,-CH＝CH-),5.16(s,2H,-CH 2 -),4.07-4.09(m,2H,-CH 2 -),3.94-3.97(m,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.89-3.91(m,2H,-CH 2 -),3.81-3.83(m,2H,-CH 2 -),3.53(s,6H,N-CH 3 ),2.79-2.80(m,2H,-CH 2 -),2.60-2.61(m,2H,-CH 2 -),1.97-2.02(m,2H,-CH 2 -),1.88-1.92(m,2H,-CH 2 -),1.45(s,6H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.6,162.5,161.7,160.2,160.1,142.0,130.1,128.7,125.6,125.3,116.0,114.8,106.0,103.0,91.5,78.2,66.6,64.9,61.8,55.9,52.2,48.3,44.5,28.4,28.3,27.2,25.8,20.0,HRMS(ESI)C 33 H 43 BrN 2 O 6 S[M-Br] + calcd＝595.2836；found＝595.2846.
EXAMPLE 32 Compound 29
Compound 29 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 29 as follows:
1) Yellow solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak is belonged to be YIeld:57.6%, yellow solid, 1 H NMR(600MHz CDCl 3 )δ:14.63(s,1H,-OH),7.73-7.79(m,2H,-CH＝CH-),7.53(d,J＝8.4Hz,2H,-Ph),6.89(d,J＝8.4Hz,2H,-Ph),6.66(d,J＝10.2Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝9.6Hz,1H,-CH＝CH-),5.15(s,2H,-CH 2 -),4.00(t,J＝6Hz,2H,-CH 2 -),3.91(s,3H,-OCH 3 ),3.84(t,J＝8.4Hz,2H,-CH 2 -),3.77-3.78(m,2H,-CH 2 -),3.68-3.70(m,4H,-CH 2 -),3.56-3.57(m,2H,-CH 2 -),3.52(s,6H,N-CH 3 ),1.85-1.89(m,4H,-CH 2 -),1.57-1.59(m,2H,-CH 2 -),1.45(s,6H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.6,162.57,162.5,162.0,160.5,160.1,142.2,130.1,128.4,127.5,125.39,125.3,116.0,114.8,106.0,103.0,91.5,78.2,67.3,66.6,66.3,64.9,61.6,55.9,52.3,45.8,42.0,28.3,23.0,22.7,HRMS(ESI)C 34 H 45 BrN 2 O 7 [M-Br] + calcd＝593.3221；found＝593.3242.
EXAMPLE 33 Compound 30
Compound 30 was synthesized using the procedure described in example 4, with the physicochemical properties of compound 30 as follows:
1) Orange solid;
2) Nuclear magnetic resonance spectrum of the compound 1 H NMR,600 MHz) characterization:
with CDCl 3 Is solvent, wherein each peak belongs to the spectrum of 49.3 percent, orange solid, 1 H NMR(600MHz CDCl 3 )δ:14.65(s,1H,-OH),7.74-7.80(m,2H,-CH＝CH-),7.54(d,J＝8.4Hz,2H,-Ph),6.89(d,J＝8.4Hz,2H,-Ph),6.67(d,J＝9.6Hz,1H,-CH＝CH-),5.92(s,1H,-Ph),5.45(d,J＝9.6Hz,1H,-CH＝CH-),5.19(s,2H,-CH 2 -),4.01(t,J＝6Hz,2H,-CH 2 -),3.92(s,3H,-OCH 3 ),3.89-3.91(m,2H,-CH 2 -),3.84-3.87(m,2H,-CH 2 -),3.82-3.84(m,2H,-CH 2 -),3.53(s,6H,N-CH 3 ),2.80-2.81(m,2H,-CH 2 -),2.61(t,J＝4.8Hz,2H,-CH 2 -),1.83-1.90(m,4H,-CH 2 -),1.56-1.61(m,2H,-CH 2 -),1.45(s,6H,-CH 3 )； 13 C NMR(150MHz CDCl 3 )δ:192.6,162.5,161.8,160.4,160.1,142.2,130.1,128.4,125.37,125.3 116.0,114.7,106.0,103.0,91.4,78.2,67.2,65.0,61.7,55.8,52.3,48.2,44.5,28.5,28.3,27.2,23.0,22.7,HRMS(ESI)C 34 H 45 BrN 2 O 6 S[M-Br] + calcd＝609.2993；found＝609.3004.
application example 1: in vitro antibacterial Activity assay
1. Test bacteria:
staphylococcus aureus (Staphylococcus aureus ATCC 29213); methicillin-resistant staphylococcus aureus (MRSA).
2. Sample and reagent:
the samples are: xanthohumol, vancomycin, meropenem and the compounds 1-30 prepared in examples.
3. The testing method comprises the following steps:
the in vitro antibacterial activity of xanthohumol and the compounds 1 to 30 of the present invention and the clinical antibacterial drug vancomycin were tested by a double dilution method using 96 well plates according to the national Clinical Laboratory Standards Institute (CLSI) standard, and the drug concentration of the smallest completely clarified well was visually observed as MIC value.
TABLE 1 in vitro bacteriostatic Activity of the xanthohumol-antibacterial peptide mimetic hybrid 1-30 of the invention (μg/mL)
Note that: HFC: xanthohumol, van: vancomycin, MEM: meropenem, S.a a : staphylococcus aureus ATCC29213, M.l d : micrococcus luteus, S.s c : streptococcus suis, E.c d : coli ATCC 29522, K.p e : klebsiella pneumoniae 18-227, K.p f : klebsiella pneumoniae 18-29.
As can be seen from table one: the xanthohumol-antibacterial peptide mimetic hybrid prepared by the invention has better antibacterial effect on gram-positive bacteria. Compared with the parent compound, the antibacterial activity of all xanthohumol-antibacterial peptide mimetic hybrids to gram-positive bacteria is improved, wherein the improvement of the compounds 5, 13, 15 and 24 is most obvious, the Minimum Inhibitory Concentration (MIC) reaches 1-2 mug/mL, the antibacterial activity is stronger, and the MIC value of the compound 13 to staphylococcus aureus is 1 mug/mL. At the same time, relative to the parent xanthohumol, erythrocyte hemolytic toxicity HC of Compound 13 50 Also improved and reduced hemolytic toxicity.
TABLE 2 MIC values of xanthohumol-antimicrobial peptide mimetic hybrids of the invention 1-30 vs. 10 clinical isolates of MRSA
/>
As can be seen from Table 2, the xanthohumol-antibacterial peptide mimetic hybrid prepared by the invention has better antibacterial activity on methicillin-resistant staphylococcus aureus (MRSA), and compounds 2, 5-8, 13-16, 18, 21, 23 and 24 all have better antibacterial activity than parent compounds, the minimum antibacterial concentration is less than or equal to 4 mug/mL, and especially the antibacterial effect of compounds 6 and 13 is optimal, the MIC value is 1-2 mug/mL, and the active pharmaceutical composition is close to vancomycin which is a positive drug, and has more stable antibacterial activity on clinically isolated 10 strains of MRSA, so the active pharmaceutical composition is expected to be a clinical antibacterial drug for methicillin-resistant staphylococcus aureus.
Application example 2: time sterilization kinetics experiments:
1. test bacteria:
staphylococcus aureus (Staphylococcus aureus ATCC 29213); MRSA-3 (clinical isolate).
2. Sample and reagent:
the samples are: vancomycin and compound 13 prepared in the examples.
3. The testing method comprises the following steps:
single colonies of the Staphylococcus aureus resistant strain MRSA-3 were picked up and cultured in 1mL LB liquid medium in a shaker (200 rpm,37 ℃) for 16-18h. Diluting the bacterial liquid with LB liquid culture medium 10000 times, culturing for 2.5 hr, and diluting the bacterial liquid to 1×10 5 CFU/mL. Then, compound 13 (4×mic, 8×mic) was added to the bacterial solution at various concentrations, vancomycin (8×mic) was used as a positive control, and a blank group without drug was set. Placing into a shaker (200 rpm,37 ℃) for continuous culture, taking 100 mu L of each group at each time point of 0h,0.5h,1h,2h,4h,6h and 8h after dosing, centrifuging for 3min at 4 ℃ at 3500rpm, removing supernatant, washing for three times, re-suspending with 100 mu L of 1 XPBS buffer solution, diluting by multiple ratio, counting by dropping plate, setting three parallel controls for each group, culturing overnight in a constant temperature incubator at 37 ℃, counting colony number in the next day, and obtaining unit log 10 CFU/mL, plotted, results are shown in FIG. 1.
FIG. 1 shows that the compound 13 kills staphylococcus aureus ATCC29213 and MRSA-3 completely within 1-2 hours under the action of 8 xMIC, and has stronger bactericidal effect compared with vancomycin which is a positive control drug at the same concentration. In addition, under the condition of 4 XMIC, the colony numbers of staphylococcus aureus ATCC29213 and MRSA-3 also gradually decrease along with the time, and the better inhibition effect is shown. The result shows that the hybrid 13 of the xanthohumol-antibacterial peptide mimic has strong bactericidal effect on staphylococcus aureus ATCC29213 and MRSA-3, has dose dependency, and is expected to be developed into a clinical rapid antibacterial medicament.
Application example 3: in vivo safety evaluation experiment
1. Reagent:
compound 13, 0.9% NaCl prepared in example.
2. Test animal
SPF grade KM mice (purchased from Beijing Bei Fu Biotechnology Co., ltd., body mass 19-22g,4-6 weeks old).
3. Test method
30 mice were grouped, 5 mice in each group were respectively Control group (0.9% NaCl), 13 (5 mg/kg), 13 (10 mg/kg), 13 (20 mg/kg), 13 (40 mg/kg) and 13 (80 mg/kg), the backs of the mice were dehaired, and then 60. Mu.L of 0.9% NaCl and different concentrations of the compounds 13 were respectively injected, and after 24 hours, the skin of the mice was observed for abnormalities (e.g., redness, hardening, ulceration, etc.). Mice in the maximum dose group that did not cause adverse reactions were sacrificed, and their blood was taken for conventional blood tests and blood biochemical index tests to evaluate whether compound 13 caused toxicity in vivo to mice, and the results are shown in fig. 2.
As a result, it was found that when the concentration of the compound 13 was not more than 20mg/kg, the skin of the mice did not show any adverse reaction (e.g., redness, hardening, ulceration, etc.) by subcutaneous injection of the compound at various concentrations into the mice, and thus conventional blood tests and blood biochemical index tests were conducted on the mice at the administered doses. FIG. 2 shows that blood samples were subjected to both routine and biochemical blood analysis, test items including white blood cell count (WBC), red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), mean red blood cell volume (MCV) and platelet count (PLT). The statistical results showed that there was no significant difference between the results after subcutaneous injection of compound 13 (20 mg/kg) into KM mice compared to the Control group (0.9% NaCl). Meanwhile, blood biochemical tests including Albumin (ALB), UREA (UREA) and Creatinine (CREA) were performed by collecting serum, and after compound 13 (20 mg/kg) was subcutaneously injected into KM mice compared with the Control group (0.9% NaCl), there was no obvious difference in the corresponding index of liver and kidney functions of the mice, and the results showed that compound 13 had a certain in vivo safety.
Application example 4: in vivo anti-MRSA infection Activity assay of Compound 13
1. Test bacteria:
MRSA-3 (clinical isolate)
2. Sample and reagent:
the samples are: vancomycin and compound 13 prepared in the examples, 0.9% NaCl.
3. Test animals:
SPF grade KM mice (purchased from Beijing Bei Fu Biotechnology Co., ltd., body mass 19-22g,4-6 weeks old).
4. The testing method comprises the following steps:
30 KM mice were subjected to dehairing treatment on their backs, and 6 mice each were grouped into a blank group (no MRSA-16 bacteria solution injected, no drug solution injected), a model group (only MRSA-16 bacteria solution injected), compound 13 (10 mg/kg), compound 13 (5 mg/kg), and positive control vancomycin (5 mg/kg). Mice were anesthetized and MRSA-3 bacteria solution (60. Mu.L, 6X 10) was subcutaneously injected into the backs thereof 8 CFU/mL), 60 μl of each of the compound, vancomycin, and 0.9% NaCl at different concentrations were injected to the skin infection site after 2 hours, mice were euthanized by dislocation and then the infected skin of the mice was aseptically separated, followed by grinding, counting by dropping plate, and the skin-borne bacteria amount of the mice was read for 24 hours, and the results are shown in fig. 3.
The results show that: compared to the model group, the number of MRSA cells in the skin of mice after treatment with compound 13 and vancomycin was significantly reduced (P<0.0001 And compound 13 (10 mg/kg) was most significant in therapeutic effect (P)<0.0001 About 4.5log reduction in tissue load relative to model group 10 CFU/g; while the tissue load of compound 13 (5 mg/kg) and vancomycin was reduced by about 3.0log, respectively 10 CFU/g and 2.2log 10 CFU/g, shows moderate antibacterial effect, and the antibacterial effect of Compound 13 is slightly better than that of vancomycin (P)<0.05). Therefore, the xanthohumol-antibacterial peptide mimetic hybrid 13 has a good treatment effect on the skin abscess of mice infected by MRSA, is superior to a control drug vancomycin, and is expected to be developed into a clinical antibacterial drug.

Claims (9)

1. A xanthohumol-antimicrobial peptide mimetic hybrid having the structure shown in formula (I):
wherein n=3, 4 or 5, r isOr an azacyclic amine, wherein R 1 And R is 2 Independently selected from H or C1-C8 alkyl; when R is an azacyclic amine, n and R are one of the following combinations:
(25)n＝3,(26)n＝3,/>
(27)n＝4,(28)n＝3,/>
(29) n ＝ 5,(30) n ＝ 5,/>
2. the xanthohumol-antibacterial peptide mimetic hybrid of claim 1, wherein R 1 And R is 2 Independently selected from H or C2-C6 alkyl; the azacyclic amine is selected from six-membered azacyclic amines.
3. The xanthohumol-antibacterial peptide mimetic hybrid of claim 1, wherein when R isWhen n, R 1 And R is 2 For example asOne of the following combinations:
(1) n ＝3, R 1 ＝ H, R 2 ＝ -(CH 2 ) 2 CH 3 (2) n ＝ 3, R 1 ＝ H, R 2 ＝ -(CH 2 ) 3 CH 3
(3) n ＝ 3, R 1 ＝ H, R 2 ＝ -(CH 2 ) 4 CH 3 (4) n ＝ 3, R 1 ＝ H, R 2 ＝ -(CH 2 ) 5 CH 3
(5) n ＝ 3, R 1 ＝ R 2 ＝ -(CH 2 ) 2 CH 3 (6) n ＝ 3, R 1 ＝ R 2 ＝ -(CH 2 ) 3 CH 3
(7) n ＝ 3, R 1 ＝ R 2 ＝ -CH(CH 3 ) 2 (8) n ＝ 3, R 1 ＝ R 2 ＝ -CH 2 CH(CH 3 ) 2
(9) n ＝4, R 1 ＝ H, R 2 ＝ -(CH 2 ) 2 CH 3 (10) n ＝ 4, R 1 ＝ H, R 2 ＝ -(CH 2 ) 3 CH 3
(11) n ＝ 4, R 1 ＝ H, R 2 ＝ -(CH 2 ) 4 CH 3 (12) n ＝ 4, R 1 ＝ H, R 2 ＝ -(CH 2 ) 5 CH 3
(13) n ＝ 4, R 1 ＝ R 2 ＝ -(CH 2 ) 2 CH 3 (14) n ＝ 4, R 1 ＝ R 2 ＝ -(CH 2 ) 3 CH 3
(15) n ＝ 4, R 1 ＝ R 2 ＝ -CH(CH 3 ) 2 (16) n ＝ 4, R 1 ＝ R 2 ＝ -CH 2 CH(CH 3 ) 2
(17) n ＝5, R 1 ＝ H, R 2 ＝ -(CH 2 ) 2 CH 3 (18) n ＝ 5, R 1 ＝ H, R 2 ＝ -(CH 2 ) 3 CH 3
(19) n ＝ 5, R 1 ＝ H, R 2 ＝ -(CH 2 ) 4 CH 3 (20) n ＝ 5, R 1 ＝ H, R 2 ＝ -(CH 2 ) 5 CH 3
(21) n ＝ 5, R 1 ＝ R 2 ＝ -(CH 2 ) 2 CH 3 (22) n ＝ 5, R 1 ＝ R 2 ＝ -(CH 2 ) 3 CH 3
(23) n ＝ 5, R 1 ＝ R 2 ＝ -CH(CH 3 ) 2 (24) n ＝ 5, R 1 ＝ R 2 ＝ -CH 2 CH(CH 3 ) 2 。
4. the method for preparing a hybrid of xanthohumol-antibacterial peptide mimetic of claim 1, comprising the steps of:
(1) Taking xanthohumol as a substrate, and forming an intermediate a by isopentenyl and phenolic hydroxyl Guan Huange under the action of a dehydrogenation agent;
(2) Intermediate a and dibromoalkane react under alkaline conditions to synthesize an intermediate b1-3;
(3) And the intermediates b1-3 and the intermediate c undergo substitution reaction to generate a series of new xanthohumol-antibacterial peptide mimetic hybrids, wherein the reaction formula is shown as follows:
wherein R and n are as defined in claim 1.
5. The method of preparing a xanthohumol-antimicrobial peptide mimetic hybrid according to claim 4, wherein in step (1), the dehydrogenating agent is selected from the group consisting of dichlorodicyanobenzoquinone (DDQ); the molar ratio of the xanthohumol to the dehydrogenation agent is 1:1.1-1:1.5, the reaction temperature is 100-110 ℃, and the reaction solvent is toluene.
6. Preparation of a hybrid of xanthohumol-antibacterial peptide mimetic according to claim 4The method is characterized in that in the step (2), the alkali in the alkaline condition is K 2 CO 3 The reaction mole ratio of the intermediate a and the alkali is 1:1.5-1:3, the mole ratio of the intermediate a and dibromoalkane is 1:2-1:4, the reaction temperature is 45-60 ℃, and the reaction solvent is acetone.
7. The method for preparing a hybrid of xanthohumol and antimicrobial peptide mimetic according to claim 4, wherein in step (3), the method for preparing intermediate c comprises the steps of: the amine RH and bromoacetyl bromide undergo substitution reaction under alkaline conditions to generate bromoacetamide, and then the bromoacetamide and dimethylamine undergo continuous substitution reaction under alkaline conditions to generate an intermediate c:
wherein R is as defined in claim 1.
8. The method for preparing a hybrid of xanthohumol and antimicrobial peptide mimetic according to claim 4, wherein in the step (3), the molar ratio of the intermediate b1-3 to the intermediate c is 1:2-1:4, the reaction temperature is 70-80 ℃, and the reaction solvent is acetonitrile.
9. Use of a xanthohumol-antibacterial peptide mimetic hybrid according to claim 1 in the manufacture of an antibacterial medicament.
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CN112715541A (en) * 2019-10-28 2021-04-30 兰州大学 Application of xanthohumol and isoxanthohumol in hops in prevention and treatment of agricultural diseases
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CN108558682A (en) * 2018-05-21 2018-09-21 郑州大学 Fragrant phenol quaternary ammonium salt antibacterial peptide mimics with antibacterial activity and preparation method thereof
CN112715541A (en) * 2019-10-28 2021-04-30 兰州大学 Application of xanthohumol and isoxanthohumol in hops in prevention and treatment of agricultural diseases
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