CN113929570A - Myrtle ketone derivative and preparation method and application thereof - Google Patents
Myrtle ketone derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN113929570A CN113929570A CN202111286397.1A CN202111286397A CN113929570A CN 113929570 A CN113929570 A CN 113929570A CN 202111286397 A CN202111286397 A CN 202111286397A CN 113929570 A CN113929570 A CN 113929570A
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- China
- Prior art keywords
- compound
- aromatic ring
- ketone derivative
- reaction
- myrtle
- Prior art date
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- 240000005125 Myrtus communis Species 0.000 title claims abstract description 20
- 235000013418 Myrtus communis Nutrition 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 94
- 125000003118 aryl group Chemical group 0.000 claims abstract description 26
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 10
- 150000002367 halogens Chemical class 0.000 claims abstract description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 10
- 241000191967 Staphylococcus aureus Species 0.000 claims abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 claims abstract description 6
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- 229960003085 meticillin Drugs 0.000 claims abstract description 4
- 230000003287 optical effect Effects 0.000 claims abstract description 4
- -1 nitro, hydroxyl Chemical group 0.000 claims description 22
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- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 1
- 229960003907 linezolid Drugs 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- NTQYXUJLILNTFH-UHFFFAOYSA-N nonanoyl chloride Chemical compound CCCCCCCCC(Cl)=O NTQYXUJLILNTFH-UHFFFAOYSA-N 0.000 description 1
- REEZZSHJLXOIHL-UHFFFAOYSA-N octanoyl chloride Chemical compound CCCCCCCC(Cl)=O REEZZSHJLXOIHL-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 description 1
- 230000000079 pharmacotherapeutic effect Effects 0.000 description 1
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 description 1
- 229960001553 phloroglucinol Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- FPZLLRFZJZRHSY-HJYUBDRYSA-N tigecycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=C(NC(=O)CNC(C)(C)C)C(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O FPZLLRFZJZRHSY-HJYUBDRYSA-N 0.000 description 1
- 229960004089 tigecycline Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
- C07C49/83—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups polycyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C07C45/46—Friedel-Crafts reactions
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- C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
- C07C45/512—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being a free hydroxyl group
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- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
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Abstract
A myrtle ketone derivative is a compound shown in formula (I), optical isomer, enantiomer, diastereomer, raceme and pharmaceutically acceptable salt thereof,
wherein: r1、R2Independently selected from H, halogen, nitryl, hydroxyl, amino, C1-C12 straight chain, C1-C12 branched chain, C3-C12 naphthenic base, C3-C12 alkenyl, C3-C12 alkynyl, heterocyclic radical, aromatic ring, substituted aromatic ring, C2-C12 alkoxy or C2-C12 halogenated alkyl. The compound provided by the invention has better in-vitro activity of different types of pathogenic bacteria, and pharmacological experiments prove that the inhibitory activity of most of the compounds provided by the invention on various pathogenic bacteria is better than that of vancomycin, especially the compound I7Can effectively induce colony number to decrease, has good selectivity on bacterial cell membranes, and has 50 times of activity of resisting MRSA (methicillin-resistant staphylococcus aureus).
Description
Technical Field
The invention belongs to the fields of pharmaceutical chemistry and pharmacotherapeutics, and particularly relates to a myrtle ketone derivative, a preparation method and medical application thereof.
Background
Methicillin-resistant Staphylococcus aureus (MRSA) is a common multi-drug resistant pathogen in clinical practice, and its infection rate and death rate have gradually increased in recent years, seriously threatening human health. At present, MRSA infection is combined with hepatitis B and AIDS to be three most difficult infectious diseases in the world. Vancomycin (vancomycin) is the first choice drug for treating MRSA infection at present, but the antibiotic has large toxic and side effects, and the long-term large-dose use of the antibiotic causes serious damage to the kidney, is easy to cause deafness and limits the further application of the antibiotic. In addition, a few drugs such as linezolid, daptomycin, and tigecycline have been approved by the FDA in the united states and are also used for clinical treatment of MRSA infections, but in recent years MRSA has also developed resistance to these drugs. Therefore, the search and discovery of new anti-MRSA drugs or drug lead compounds are both urgent needs for clinical treatment and the primary problem in developing anti-MRSA drugs.
Myrtaceae (myrtaceae) plants are abundant in resources in China, most of the myrtaceae plants are medicinal plants, and are traditionally used for treating nasosinusitis, bronchitis, bronchiectasis, chronic obstructive pulmonary diseases, pulmonary fungal infection, pulmonary tuberculosis, silicosis and other bacterial infection related diseases. The phloroglucinol compounds serving as main characteristic chemical components and functional active substances of the phloroglucinol compounds have novel and changeable structural characteristics and obvious biological activity, and have unique advantages in the field of drug research and development. In recent years, it has been found that many phloroglucinol-based active ingredients derived from myrtaceae plants have anti-MRSA activity. In particular to phloroglucinol compounds such as rhodogyrone, rhodogyrone B, tonenonol A, tonenonol C and the like, the MRSA activity of the phloroglucinol compounds is close to or even superior to that of vancomycin.
The prior art CN 105859537B discloses ring-opening myrtle ketone analogues, a preparation method thereof and application thereof in antibacterial drugs. The ring-opening myrtle ketone analogue has a structure shown in a formula (1):
wherein R is H, C1-C15 straight chain, branched chain or naphthenic base, or aromatic group. The seco-rhodomyrtle analogue has significant activity against MRSA, Staphylococcus aureus, Bacillus cereus, B.subtilis, B.thuringiensis or Escherichia coli. The compound 11i-11n has remarkable antibacterial activity, and the MIC value is as low as 0.25-0.50 mu g/mL, which is 2-4 times of vancomycin (vancomycin, 1.0 mu g/mL) of the last barrier of the antibacterial drug.
Therefore, in view of the traditional efficacy and modern pharmacological activity of the myrtaceae plants, the structural modification and optimization of the characteristic MRSA resistant active ingredients are expected to become an effective way for finding a novel structural lead compound/medicament with more remarkable MRSA resistant curative effect.
Disclosure of Invention
The invention aims to provide a ring-opening myrtle ketone derivative with better activity than that of the existing myrtle ketone derivative, an optical isomer, an enantiomer, a diastereomer, a racemate and pharmaceutically acceptable salts thereof, and a preparation method and application thereof in medicine.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a myrtle ketone derivative, namely a compound shown as a formula (I), an optical isomer, an enantiomer, a diastereoisomer, a racemate and pharmaceutically acceptable salts thereof,
wherein:
R1、R2independently selected from H, halogen, nitryl, hydroxyl, amino, C1-C12 straight chain, C1-C12 branched chain, C3-C12 naphthenic base, C3-C12 alkenyl, C3-C12 alkynyl, heterocyclic radical, aromatic ring, substituted aromatic ring, C2-C12 alkoxy or C2-C12 halogenated alkyl.
Preferably, R1、R2Independently selected from C5-C10 straight chain, C5-C10 branched chain, C3-C6 naphthenic base, aromatic ring, substituted aromatic ring and C5-C10 halogenated alkyl.
Preferably, the aromatic ring is a benzene ring.
Preferably, the substituted aromatic ring is a substituted benzene ring.
Preferably, the substituent of the substituted aromatic ring is selected from C1-C12 straight chain, C1-C12 branched chain, aromatic ring, halogen, nitro, hydroxyl and amino.
Preferably, said R is1And R2The same is true.
Preferably, said R is1And R2Meanwhile, the substituted benzene ring is C5-C10 straight chain, C5-C10 branched chain, C3-C6 naphthenic base, C5-C10 halogenated alkyl, benzene ring or substituted benzene ring, wherein the substituent of the substituted benzene ring is selected from C1-C12 straight chain, C1-C12 branched chain, aromatic ring, halogen, nitro, hydroxyl and amino.
Preferably, said R is1And R2And is C5-C10 straight chain, C5-C10 branched chain or C5-C10 halogenated alkyl.
Preferably, the myrtle ketone derivative is selected from the following compounds:
preferably, the myrtle ketone derivative is selected from the following compounds:
the invention also provides a preparation method of the compound shown in the formula (I), and the synthetic route is as follows:
wherein:
R1、R2independently selected from H, halogen, nitryl, hydroxyl, amino, C1-C12 straight chain, C1-C12 branched chain, C3-C12 naphthenic base, C3-C12 alkenyl, C3-C12 alkynyl, heterocyclic radical, aromatic ring, substituted aromatic ring, C2-C12 alkoxy or C2-C12 halogenated alkyl.
The invention also provides a preparation method of the compound shown in the formula (I), which comprises the following steps:
(1) carrying out hydroxyl oxidation and selective carbon methylation reaction on the compound II and methyl iodide under an alkaline environment to obtain a compound III;
(2) thermally promoting a reverse Friedel Crafts acylation reaction on the compound III to obtain a compound IV;
(3) the compound IV and isovaleraldehyde react under the catalysis of proline to obtain a compound V;
(4) carrying out Friedel Crafts acylation reaction on the compound VI and substituted acyl chloride under an acidic condition to obtain a compound VII;
(5) carrying out Michael addition reaction on the compound V and a compound VII under the catalysis of sodium hydride to finally obtain a compound with a structural formula (I);
wherein R in the compound of formula (I)1、R2Independently selected from H, halogen, nitryl, hydroxyl, amino, C1-C12 straight chain, C1-C12 branched chain, C3-C12 naphthenic base, C3-C12 alkenyl, C3-C12 alkynyl, heterocyclic radical, aromatic ring, substituted aromatic ring, C2-C12 alkoxy or C2-C12 halogenated alkyl.
Preferably, in the reaction for preparing the compound III from the compound II, the solvent is one or more selected from anhydrous dichloromethane, chloroform, ethyl acetate, ethanol, methanol, tetrahydrofuran, acetone, dimethyl sulfoxide, N, N-dimethylformamide or dioxane; the base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, and lithium amide.
Preferably, in the reaction for preparing the compound IV from the compound III, the solvent is selected from hydrochloric acid aqueous solutions with different equivalent weights; the reaction temperature is-10 ℃ to heating reflux.
Preferably, in the reaction for preparing the compound V from the compound IV, the solvent is one or more selected from the group consisting of anhydrous dichloromethane, chloroform, ethyl acetate, ethanol, methanol, tetrahydrofuran, acetone, dimethyl sulfoxide, N-dimethylformamide and dioxane.
Preferably, in the reaction for preparing the compound VII from the compound VI, the reaction temperature is from-10 ℃ to heating reflux.
Preferably, in the reaction for preparing the compound VII from the compound V, the solvent is one or more selected from the group consisting of anhydrous dichloromethane, chloroform, ethyl acetate, ethanol, methanol, tetrahydrofuran, acetone, dimethyl sulfoxide, N, N-dimethylformamide and dioxane.
These intermediates or the target compounds can be purified according to conventional isolation techniques, separated into monomers if necessary according to conventional isolation techniques, and further converted into addition salts of pharmaceutically acceptable bases if necessary.
The invention also provides application of the compound shown in the formula (I) in preparing a medicament or a medicinal composition for treating or preventing infectious diseases, wherein the infectious diseases specifically comprise but are not limited to MRSA, gram-positive coccal infection and gram-positive bacilli infection.
An antibacterial agent contains any one compound of the above seco-myrtle analogs as an active ingredient, and a pharmaceutically acceptable carrier.
The antibacterial agent is preferably an agent against Methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, Bacillus cereus, P.acnes, E.faecalis, S.epidermides, E.coli, S.typhimurium or S.dysenteriae bacteria.
"drug" in the present invention refers to one, more or a pharmaceutically acceptable salt, solvate, hydrate or prodrug of a compound of the present invention in admixture with another chemical component, e.g., a pharmaceutically acceptable carrier. Or a pharmaceutical composition, the purpose of which is to facilitate the administration process to an animal.
"pharmaceutical carrier" in the present invention refers to an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, such as, but not limited to: starch, water, polyethylene glycol, castor oil, cyclodextrin, sesame oil, peanut oil, various sugars (such as mannitol, glucose, and the like), acrylic acid polymers, and the like.
In the present invention, when the compound I and pharmaceutically acceptable salts thereof, and solvates of these compounds are administered to a mammal, they may be used alone or, preferably, in combination with a pharmaceutically acceptable carrier or diluent in accordance with standard pharmaceutical practice. The mode of administration can be by various routes, including oral, parenteral, or topical administration. Parenteral administration as used herein includes, but is not limited to, intravenous, intramuscular, intraperitoneal, subcutaneous, and transdermal administration.
The compound provided by the invention has better inhibitory activity to different types of pathogenic bacteria in vitro, pharmacological experiments prove that the inhibitory activity of most of the compounds provided by the invention to various pathogenic bacteria is better than that of vancomycin, especially the compound I7Can effectively induce colony number to decrease, has good selectivity on bacterial cell membrane, and has about vancom activity against MRSA50 times ycin. I is7The compound has obvious anti-MRSA activity in vivo and in vitro by destroying the structure of bacterial cell membranes, the hydrophobic acyl group of the compound can be an important pharmacophore of the compound, and compared with the prior art, the modified disubstituted acyl compound can enhance the capability of the compound of penetrating the MRSA cell walls and destroying the cell membranes.
Detailed description of the invention
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention are described below clearly and completely, and it is obvious that the described embodiments are a part of the embodiments of the present invention, not all of the embodiments of the present invention. All other embodiments obtained by those skilled in the art without any creative effort based on the embodiments of the present invention belong to the protection scope of the present invention.
Example 1:
a compound:
4- (1- (3,5-Diacetyl-2,4,6-trihydroxyphenyl) -3-methylbutanyl) -5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione, i.e. I1The preparation of (1):
compound II (100mmol) was dissolved in 300mL of anhydrous methanol under ice bath conditions, followed by slow addition of sodium hydroxide (600 mmol). After stirring in an ice bath for 10 minutes, methyl iodide (600mmol) was slowly added dropwise to the reaction system. After stirring for a further 30 minutes under ice-bath conditions, the reaction mixture was then left to stir at room temperature for 12 hours. After the reaction was completed, 300mL of 2N aqueous hydrochloric acid was added to terminate the reaction, and the mixture was extracted 4 times with ethyl acetate (500mL), and the organic phases were combined. The organic phase was washed with 500mL of saturated brine 2 times, dried over anhydrous sodium sulfate, filtered and concentrated to give compound III in 90% yield.
Compound III (100mmol) was placed in a 500mL round-bottom flask, and then 300mL of 6N aqueous hydrochloric acid was added thereto. The reaction was then placed in a 120 ℃ oil bath, vigorously stirred and heated to reflux for 12 hours. And after the reaction system is gradually cooled to room temperature, filtering, washing a filter cake for 3 times by 50mL of tap water, and drying to obtain a light black powdery solid compound IV with the yield of 80%.
To a 100mL round-bottom flask containing compound IV (30mmol) and isovaleraldehyde (90mmol) was added anhydrous dichloromethane (50mL), and after stirring well for 5 minutes, proline (3mmol) was added thereto in one portion at room temperature. The reaction system was further stirred for half an hour, 200mL of n-hexane was added at a time, and then washed twice with saturated brine, dried and concentrated to obtain Compound V with a yield of 90%.
Compound VI (100mmol) and methanesulfonic acid (300mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, acetyl chloride (300mmol) was slowly added dropwise to the reaction system. After dropping, the reaction system was stirred for 10 minutes while being kept at the temperature, cooled to room temperature after the reaction was sufficiently carried out, and the reaction mixture was poured into 150mL of ice water and extracted 3 times with n-hexane (150mL), and the organic phases were combined, washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then washed once with saturated brine. Drying the organic phase with anhydrous sodium sulfate, filtering, and spin-drying the filtrate under reduced pressure to obtain compound VII1，R1＝CH3，R2＝CH3The yield was 85%.
Sodium hydride (30mmo) was slowly added to the solution of VII1To a solution (250mL) of intermediate V (20mmol) in tetrahydrofuran was added a solution (50mL) of intermediate V (20mmol), and the mixture was stirred at room temperature for half an hour. The reaction was checked by TCL and 150mL of 1N aqueous hydrochloric acid was added. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate (150mL), washed with saturated brine (150mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure light yellow powder (I)1)，R1＝CH3，R2＝CH3The yield was 80%.
1H NMR(500MHz,CD3OD):δ0.91-0.84(m,6H),1.45-1.31(m,10H),1.52(s,3H),2.15-1.76(m,2H),2.78(s,6H),4.35-4.40(t,J＝7.6Hz,2H),further peaks show a pair of atropisomers in a ratio of 1:2；major:δ＝10.27(s,0.67H),12.96(s,0.66H)；minor:δ＝11.13(s,1H),12.07(s,1H)；13C NMR(100MHz,CD3OD):major:δ211.7,205.4,205.1,203.9,177.3,170.9,167.8,167.5,114.5,107.3,105.7,103.7,55.0,48.7,38.2,33.5,32.3,27.6,27.1,26.9,26.2,24.2,22.5,22.3,22.3；minor:δ212.2,205.5,205.4,204.2,178.1,170.9,168.8,166.9,114.5,107.4,105.5,104.1,54.1,49.1,39.0,33.4,29.4,27.1,25.8,25.8,24.7,24.2,22.5,22.4,22.3。
Example 2:
a compound:
4- (1- (3, 5-dibutyl-2, 4,6-trihydroxyphenyl) -3-methylbutanyl) -5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione, i.e. I2The preparation of (1):
examples the synthesis of compounds I-VI in the following examples is the same as in example 1.
Compound VI (100mmol) and methanesulfonic acid (300mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, butyryl chloride (300mmol) was slowly added dropwise to the reaction system. After dropping, the reaction system was kept stirred at the temperature for 15 minutes, cooled to room temperature after the reaction proceeded sufficiently, and the reaction mixture was poured into 150mL of ice water and extracted with n-hexane (150mL) for 3 times, and the organic phases were combined, washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then washed once with saturated brine. Drying the organic phase with anhydrous sodium sulfate, filtering, and spin-drying the filtrate under reduced pressure to obtain compound VII2，R1＝n-C3H7，R2＝n-C3H7The yield was 80%.
Sodium hydride (30mmol) was slowly added to the dissolved VII2To a solution (250mL) of intermediate V (20mmol) in tetrahydrofuran was added a solution (50mL) of intermediate V (20mmol), and the mixture was stirred at room temperature for half an hour. The reaction was checked by TCL and 150mL of 1N aqueous hydrochloric acid was added. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate (150mL), washed with saturated brine (150mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure light yellow powder (I)2)，R1＝n-C3H7，R2＝n-C3H7To obtain a light yellow powder with the yield of 87 percent.
1H NMR(500MHz,CDCl3)δ12.89(s,0.67H,major),12.01(s,0.33H,minor),11.24(s,0.33H,minor),10.39(s,0.67H,major),4.39(t,J＝7.7Hz,0.67H,major),4.36(t,7.7Hz,0.33H,minor),3.29-3.11(m,4H),2.1-1.97(m,1H),1.83-1.69(m,4H),1.52(s,3H),1.47-1.32(m,10H),1.03(t,J＝6.7Hz,6H),0.95-0.79(m,6H)；13C NMR(125MHz,CDCl3):major:δ211.8,208.1,207.9,203.8,177.4,170.8,167.8,167.1,114.6,107.3,105.4,103.5,55.0,48.7,46.5,45.6,38.2,27.8,27.0,26.9,26.2,24.2,22.6,22.5,22.3,18.1,18.0,14.0,13.9；minor:δ212.3,208.3,208.0,204.2,178.2,170.8,168.8,166.5,114.6,107.5,105.3,103.8,54.1,54.1,49.1,46.5,45.6,39.0,29.5,27.1,25.7,25.7,24.5,22.5,22.4,18.1,18.0,14.0,13.9。
Example 3:
a compound:
5-Hydroxy-2,2,6,6-tetramethyl-4- (3-methyl-1- (2,4,6-trihydroxy-3, 5-diisobutylphenyl) butyl) cyclohex-4-ene-1,3-dione, i.e. I3The preparation of (1):
compound VI (100mmol) and methanesulfonic acid (300mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, isobutyryl chloride (300mmol) was slowly added dropwise to the reaction system. After dropping, the reaction system was kept stirred at the temperature for 15 minutes, cooled to room temperature after the reaction proceeded sufficiently, and the reaction mixture was poured into 150mL of ice water and extracted with n-hexane (150mL) for 3 times, and the organic phases were combined, washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then washed once with saturated brine. Drying the organic phase with anhydrous sodium sulfate, filtering, and spin-drying the filtrate under reduced pressure to obtain compound VII3，R1＝i-C3H7，R2＝i-C3H7The yield was 82%.
Sodium hydride (30mmol) was slowly added to the dissolved VII3To a solution (250mL) of intermediate V (20mmol) in tetrahydrofuran was added a solution (50mL) of intermediate V (20mmol), and the mixture was stirred at room temperature for half an hour. The reaction was checked by TCL and 150mL of 1N aqueous hydrochloric acid was added. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate (150mL), washed with saturated brine (150mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure light yellow powder (I)3)，R1＝i-C3H7，R2＝i-C3H7To obtain light yellow powder with a yield of 77%.
1H NMR(500MHz,CDCl3)δ12.90(s,0.67H,major),12.02(s,0.33H,minor),11.21(s,0.33H,minor),10.35(s,1H,major),4.38(m,1H),3.35-3.14(m,2H),2.17-1.93(m,1H),2.12-1.74(m,1H),1.54-1.47(m,3H),1.45-1.30(m,10H),1.20(m,12H),0.89(m,6H).；13C NMR(100MHz,CDCl3):major:δ211.8,208.7,208.5,203.9,177.3,170.7,167.4,167.1,114.6,107.3,105.3,103.4,55.0,48.7,38.2,38.0,37.2,27.7,27.1,26.9,26.2,24.2,22.6,22.4,22.3,8.7,8.5.minor:δ212.3,208.9,208.6,204.1,178.1,170.6,168.4,166.5,114.6,107.4,105.2,103.8,54.1,49.1,39.0,38.0,37.2,29.4,27.1,25.8,25.7,24.7,24.3,22.5,22.3,8.7,8.4。
Example 4:
5-Hydroxy-2,2,6, 6-tetramethylyl-4- (3-methyl-1- (2,4, 6-trihydroxy-3-pentanylphenyl) butyl) cyclohex-4-ene-1,3-dione, i.e. I4The preparation of (1):
compound VI (100mmol) and methanesulfonic acid (300mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, valeryl chloride (300mmol) was slowly added dropwise to the reaction system. The reaction was stirred for 10 minutes while continuing to maintain the temperature until the reaction was complete, cooled to room temperature, and the reaction mixture was poured into 150mL of ice waterThe mixture was extracted 3 times with n-hexane (150mL), and the organic phases were combined, washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then washed once with saturated brine. Drying the organic phase with anhydrous sodium sulfate, filtering, and spin-drying the filtrate under reduced pressure to obtain compound VII4，R1＝n-C4H9，R2＝n-C4H9The yield was 80%.
Sodium hydride (30mmol) was slowly added to the dissolved VII4To a solution (250mL) of intermediate V (20mmol) in tetrahydrofuran was added a solution (50mL) of intermediate V (20mmol), and the mixture was stirred at room temperature for half an hour. The reaction was checked by TCL and 150mL of 1N aqueous hydrochloric acid was added. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate (150mL), washed with saturated brine (150mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure light yellow powder (I)4)，R1＝n-C4H9，R2＝n-C4H9To obtain light yellow powder with the yield of 89 percent.
1H NMR(400MHz,CDCl3):δ12.89(s,1H,major),12.01(s,1H,minor),11.25(s,1H,minor),10.39(s,1H,major),4.38(m,1H),3.29-3.11(m,4H),2.16-1.95(m,1H),1.82-1.63(m,5H),1.55-1.48(m,3H),1.45-1.30(m,22H),0.99-0.91(m,6H),0.91-0.84(m,6H)；13C NMR(125MHz,CDCl3)δ211.8,208.3,208.1,203.8,177.4,170.8,167.8,167.1,114.6,107.3,105.4,103.5,54.9,48.7,44.6,43.7,38.2,31.6,27.8,27.0,26.9,26.2,24.6,24.3,24.2,22.6,22.6,22.5,22.5,22.3,14.0,14.0；minor:δ212.3,208.5,208.3,204.1,178.2,170.8,168.8,166.5,114.6,107.5,105.2,103.8,54.1,49.1,44.6,43.7,39.0,31.6,31.6,29.5,27.1,25.7,25.6,24.8,24.5,24.4,24.3,22.6,22.5,22.4,14.0,14.0。
Example 5:
4-Hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-trihydroxy-3-propionylphenyl)butyl)cyclohex-4-ene-1,3-dione, i.e. I5The preparation of (1):
compound VI (100mmol) and methanesulfonic acid (300mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, isovaleryl chloride (300mmol) was slowly added dropwise to the reaction system. The reaction system was stirred for 10 minutes while continuing to maintain the temperature after the dropwise addition, cooled to room temperature after the reaction proceeded sufficiently, and the reaction mixture was poured into 150mL of ice water and extracted 3 times with n-hexane (150mL), and the organic phases were combined, washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then washed once with saturated brine. Drying the organic phase with anhydrous sodium sulfate, filtering, and spin-drying the filtrate under reduced pressure to obtain compound VII5，R1＝i-C4H9，R2＝i-C4H9The yield was 70%.
Sodium hydride (30mmol) was slowly added to the dissolved VII5To a solution (250mL) of intermediate V (20mmol) in tetrahydrofuran was added a solution (50mL) of intermediate V (20mmol), and the mixture was stirred at room temperature for half an hour. The reaction was checked by TCL and 150mL of 1N aqueous hydrochloric acid was added. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate (150mL), washed with saturated brine (150mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure light yellow powder (I)5)，R1＝i-C4H9，R2＝i-C4H9To obtain light yellow powder with the yield of 88 percent.
1H NMR(400MHz,CDCl3):δ12.90(s,0.67H,major),12.01(s,0.33H,minor),11.25(s,0.33H,minor),10.40(s,1H,major),4.39(m,1H),3.23-3.14(m,4H),2.10(m,1H),1.78-1.66(m,5H),1.53-1.48(m,3H),1.47-1.31(m,14H),0.97(m,6H),0.93-0.83(m,6H).；13C NMR(100MHz,CDCl3):major:δ211.8,208.3,208.1,203.8,177.4,170.8,167.8,167.1,114.6,107.3,105.4,103.5,55.0,48.7,44.4,43.4,38.2,27.8,27.0,27.0,26.9,26.7,26.2,24.2,22.6,22.6,22.5,22.4,22.3,14.1,14.0.minor:δ212.4,208.5,208.3,204.1,178.2,170.8,168.8,166.5,114.6,107.5,105.2,103.9,54.1,49.1,44.4,43.5,38.7,30.4,29.5,28.9,27.1,26.7,25.7,25.7,24.8,24.4,23.8,23.0,22.4,14.1,14.1。
Example 6:
5-Hydroxy-2,2,6,6-tetramethyl-4- (3-methyl-1- (2,4,6-trihydroxy-3- (3-methylbutanyl) phenyl) butyl) cyclohex-4-ene-1,3-dione, i.e. I6The preparation of (1):
compound VI (100mmol) and methanesulfonic acid (300mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, hexanoyl chloride (300mmol) was slowly added dropwise to the reaction system. The reaction system was stirred for 10 minutes while continuing to maintain the temperature after the dropwise addition, cooled to room temperature after the reaction proceeded sufficiently, and the reaction mixture was poured into 150mL of ice water and extracted 3 times with n-hexane (150mL), and the organic phases were combined, washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then washed once with saturated brine. Drying the organic phase with anhydrous sodium sulfate, filtering, and spin-drying the filtrate under reduced pressure to obtain compound VII6，R1＝n-C5H11，R2＝n-C5H11Yield 78%.
Sodium hydride (30mmol) was slowly added to the dissolved VII6To a solution (250mL) of intermediate V (20mmol) in tetrahydrofuran was added a solution (50mL) of intermediate V (20mmol), and the mixture was stirred at room temperature for half an hour. The reaction was checked by TCL and 150mL of 1N aqueous hydrochloric acid was added. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate (150mL), washed with saturated brine (150mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure light yellow powder (I)6)，R1＝n-C5H11，R2＝n-C5H11To obtain a light yellow powder with a yield of 81%.
1H NMR(500MHz,CDCl3)δ12.90(s,0.67H,major),12.03(s,0.33H,minor),11.28(s,0.67H,major),10.42(s,1H,minor),4.38(m,1H),3.20-2.92(m,4H),2.35-2.19(m,2H),2.13-1.75(m,2H),1.52(m,3H),1.46-1.31(m,10H),1.08-0.97(m,12H),0.93-0.83(m,6H)；13C NMR(126MHz,CDCl3)δ211.8,207.8,207.5,203.8,177.4,170.9,168.0,167.1,114.5,107.4,105.6,103.7,54.9,53.2,52.3,48.7,38.2,27.8,27.0,26.9,26.2,25.4,25.1,24.3,22.9,22.8,22.8,22.8,22.5,22.4.13C NMR(126MHz,CDCl3)δ212.3,208.0,207.7,204.1,178.2,170.9,169.1,166.5,114.5,107.6,105.4,104.1,54.1,53.2,52.4,49.1,39.0,29.7,29.5,27.1,25.7,25.7,25.2,24.8,24.4,22.9,22.8,22.8,22.8,22.5,22.4。
Example 7:
4- (1- (3,5-Dihexanoyl-2,4,6-trihydroxyphenyl) -3-methylbutanyl) -5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione, i.e. I7The preparation of (1):
compound VI (100mmol) and methanesulfonic acid (300mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, heptanoyl chloride (300mmol) was slowly added dropwise to the reaction system. The reaction system was stirred for 10 minutes while continuing to maintain the temperature after the dropwise addition, cooled to room temperature after the reaction proceeded sufficiently, and the reaction mixture was poured into 150mL of ice water and extracted 3 times with n-hexane (150mL), and the organic phases were combined, washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then washed once with saturated brine. Drying the organic phase with anhydrous sodium sulfate, filtering, and spin-drying the filtrate under reduced pressure to obtain compound VII7，R1＝n-C6H13，R2＝n-C6H13The yield was 80%.
Sodium hydride (30mmol) was slowly added to the dissolved VII7To a solution (250mL) of intermediate V (20mmol) in tetrahydrofuran was added a solution (50mL) of intermediate V (20mmol), and the mixture was stirred at room temperature for half an hour. The reaction was checked by TCL and 150mL of 1N aqueous hydrochloric acid was added. The organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (150mL), washed with saturated brine (150mL), dried over anhydrous sodium sulfate, and concentratedObtaining a crude product. Recrystallizing the crude product with methanol to obtain pure light yellow powder (I)7)，R1＝n-C5H11，R2＝n-C5H11To obtain light yellow powder with yield of 60%.
1H NMR(400MHz,CDCl3):δ12.89(s,1H,major),12.01(s,1H,minor),11.25(s,1H,minor),10.39(s,1H,major),4.38(m,1H),3.29-3.11(m,4H),2.16-1.95(m,1H),1.82-1.63(m,5H),1.55-1.48(m,3H),1.45-1.30(m,22H),0.99-0.91(m,6H),0.91-0.84(m,6H)；13C NMR(125MHz,CDCl3)δ211.8,208.3,208.1,203.8,177.4,170.8,167.8,167.1,114.6,107.3,105.4,103.5,54.9,48.7,44.6,43.7,38.2,31.6,27.8,27.0,26.9,26.2,24.6,24.3,24.2,22.6,22.6,22.5,22.5,22.3,14.0,14.0；minor:δ212.3,208.5,208.3,204.1,178.2,170.8,168.8,166.5,114.6,107.5,105.2,103.8,54.1,49.1,44.6,43.7,39.0,31.6,31.6,29.5,27.1,25.7,25.6,24.8,24.5,24.4,24.3,22.6,22.5,22.4,14.0,14.0。
Example 8:
4- (1- (3,5-Diheptanoyl-2,4,6-trihydroxyphenyl) -3-methylbutanyl) -5-hydroxy-2,2,6, 6-tetramethylcyclohexox-4-ene-1, 3-dione, i.e. I8The preparation of (1):
compound VI (100mmol) and methanesulfonic acid (300mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, octanoyl chloride (300mmol) was slowly added dropwise to the reaction system. The reaction system was stirred for 10 minutes while continuing to maintain the temperature after the dropwise addition, cooled to room temperature after the reaction proceeded sufficiently, and the reaction mixture was poured into 150mL of ice water and extracted 3 times with n-hexane (150mL), and the organic phases were combined, washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then washed once with saturated brine. Drying the organic phase with anhydrous sodium sulfate, filtering, and spin-drying the filtrate under reduced pressure to obtain compound VII8，R1＝n-C7H15，R2＝n-C7H15The yield was 81%.
Sodium hydride (30mmol) was slowly added to the dissolved VII8To a solution (250mL) of intermediate V (20mmol) in tetrahydrofuran was added a solution (50mL) of intermediate V (20mmol), and the mixture was stirred at room temperature for half an hour. The reaction was checked by TCL and 150mL of 1N aqueous hydrochloric acid was added. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate (150mL), washed with saturated brine (150mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure light yellow powder (I)8)，R1＝n-C7H15，R2＝n-C7H15To obtain a light yellow powder with a yield of 81%.
1H NMR(500MHz,CDCl3)δ12.90(s,0.67H,major),12.01(s,0.33H,minor),11.25(s,0.33H,major),10.40(s,0.67H,major),4.38(m,1H),3.30-3.11(m,4H),2.16-1.25(m,54H),0.89(m,12H).13C NMR(125MHz,CDCl3):major:δ211.8,208.3,208.1,203.8,177.3,170.8,167.8,167.1,114.6,107.3,105.4,103.5,54.9,48.7,44.7,43.7,38.2,31.7,29.4,29.4,29.3,29.2,27.8,27.0,26.9,26.2,24.9,24.6,24.2,22.7,22.6,22.6,22.5,22.3；minor:δ212.3,208.5,208.3,204.1,178.1,170.8,168.8,166.5,114.6,107.5,105.2,103.8,54.1,49.1,44.6,43.7,39.1,31.8,29.5,29.4,29.3,29.2,27.1,25.7,25.7,24.8,24.8,24.6,24.4,22.7,22.6,22.5,22.4,14.1。
Example 9:
5-Hydroxy-2,2,6,6-tetramethyl-4- (3-methyl-1- (2,4,6-trihydroxy-3, 5-dinonylphenyl) butyl) cyclohex-4-ene-1,3-dione, i.e. I9The preparation of (1):
compound VI (100mmol) and methanesulfonic acid (300mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, nonanoyl chloride (300mmol) was slowly added dropwise to the reaction system. Continuously stirring the reaction system at the temperature for 10 minutes after dripping, cooling to room temperature after the reaction is fully carried out, and pouring the reaction mixture into a container 150The organic phase was combined, washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then washed once with saturated brine. Drying the organic phase with anhydrous sodium sulfate, filtering, and spin-drying the filtrate under reduced pressure to obtain compound VII9，R1＝n-C8H17，R2＝n-C8H17The yield was 86%.
Sodium hydride (30mmol) was slowly added to the dissolved VII9To a solution (250mL) of intermediate V (20mmol) in tetrahydrofuran was added a solution (50mL) of intermediate V (20mmol), and the mixture was stirred at room temperature for half an hour. The reaction was checked by TCL and 150mL of 1N aqueous hydrochloric acid was added. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate (150mL), washed with saturated brine (150mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure light yellow powder (I)9)，R1＝n-C8H17，R2＝n-C8H17To obtain light yellow powder with the yield of 90 percent.
1H NMR(400MHz,CDCl3):δ12.89(s,0.67H,major),12.01(s,0.33H,minor),11.25(s,0.33H,minor),10.40(s,0.67H,major),4.38(m,1H),3.29-3.11(m,4H),2.15-1.25(m,39H),0.89(m,12H)；13C NMR(100MHz,CDCl3):major:δ211.8,208.4,208.1,203.8,177.4,170.8,167.8,167.1,114.6,107.3,105.4,103.5,55.0,48.7,44.7,43.7,38.2,31.9,31.9,29.6,29.5,29.2,27.8,27.0,26.9,26.2,24.9,24.6,24.2,22.7,22.6,22.5,22.3,14.1,14.1.minor:δ212.3,208.5,208.3,204.1,178.2,170.7,168.8,166.5,114.6,107.5,105.2,103.9,54.1,49.1,44.6,43.8,39.0,31.9,31.9,29.6,29.5,29.4,27.1,25.7,25.7,24.8,24.7,24.6,24.4,22.7,22.5,22.4,14.1,14.1。
Example 10:
4-(1-(3-Heptanoyl-2,4,6-trihydroxyphenyl)-3-methylbutyl)-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene1,3-dione, i.e. I10The preparation of (1):
compound VI (100mmol) and methanesulfonic acid (300mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, decanoyl chloride (300mmol) was slowly added dropwise to the reaction system. The reaction system was stirred for 10 minutes while continuing to maintain the temperature after the dropwise addition, cooled to room temperature after the reaction proceeded sufficiently, and the reaction mixture was poured into 150mL of ice water and extracted 3 times with n-hexane (150mL), and the organic phases were combined, washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then washed once with saturated brine. Drying the organic phase with anhydrous sodium sulfate, filtering, and spin-drying the filtrate under reduced pressure to obtain compound VII10，R1＝n-C9H19，R2＝n-C9H19The yield was 81%.
Sodium hydride (30mmol) was slowly added to the dissolved VII9To a solution (250mL) of intermediate V (20mmol) in tetrahydrofuran was added a solution (50mL) of intermediate V (20mmol), and the mixture was stirred at room temperature for half an hour. The reaction was checked by TCL and 150mL of 1N aqueous hydrochloric acid was added. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate (150mL), washed with saturated brine (150mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure light yellow powder (I)10)，R1＝n-C9H19，R2＝n-C9H19To obtain light yellow powder with the yield of 76%.
1H NMR(500MHz,CDCl3)δ12.90(s,0.67H,major),12.01(s,0.33H,minor),11.25(s,0.33H,minor),10.40(s,0.67H,major),4.38(m,1H),3.31-3.10(m,4H),2.16-1.21(m,43H),0.96-0.81(m,12H).13C NMR(125MHz,CDCl3):major:δ211.8,208.4,208.1,203.8,177.4,170.8,167.8,167.1,114.6,107.3,105.4,103.5,55.0,48.7,44.7,43.7,38.2,31.8,29.4,29.4,29.3,29.2,27.8,27.0,26.9,26.2,24.9,24.6,24.2,22.7,22.7,22.7,22.7,22.6,22.5,22.3,14.1,14.1.minor:δ212.3,208.5,208.3,204.2,178.2,170.8,168.7,166.5,114.6,107.5,105.3,103.8,54.1,49.1,44.6,43.8,39.0,31.8,29.5,29.4,29.3,29.3,29.2,27.1,25.7,25.7,24.8,24.8,24.6,24.4,22.7,22.6,22.5,22.4,14.1,14.1.
Example 11:
4- (1- (3, 5-didecanoyl-2, 4,6-trihydroxyphenyl) -3-methylbutanyl) -5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione, i.e. I11The preparation of (1):
compound VI (100mmol) and methanesulfonic acid (300mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, dodecanoyl chloride (300mmol) was slowly added dropwise to the reaction system. The reaction system was stirred for 10 minutes while continuing to maintain the temperature after the dropwise addition, cooled to room temperature after the reaction proceeded sufficiently, and the reaction mixture was poured into 150mL of ice water and extracted 3 times with n-hexane (150mL), and the organic phases were combined, washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then washed once with saturated brine. Drying the organic phase with anhydrous sodium sulfate, filtering, and spin-drying the filtrate under reduced pressure to obtain compound VII11，R1＝n-C11H23，R2＝n-C11H23Yield 83%.
Sodium hydride (30mmol) was slowly added to the dissolved VII11To a solution (250mL) of intermediate V (20mmol) in tetrahydrofuran was added a solution (50mL) of intermediate V (20mmol), and the mixture was stirred at room temperature for half an hour. The reaction was checked by TCL and 150mL of 1N aqueous hydrochloric acid was added. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate (150mL), washed with saturated brine (150mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure light yellow powder (I)11)，R1＝n-C11H23，R2＝n-C11H23To obtain a light yellow powder with the yield of 87 percent.
1H NMR(500MHz,CDCl3)δ12.90(s,0.67H,major),12.01(s,0.33H,minor),11.25(s,0.33H,minor),10.40(s,0.67H,major),4.38(m,1H),3.29-3.10(m,4H),2.15-1.20(m,51H),0.93-0.83(m,12H)；13C NMR(125MHz,CDCl3):major:δ211.8,208.3,208.1,203.8,177.3,170.8,167.8,167.1,114.6,107.3,105.4,103.5,54.9,48.7,44.7,43.7,38.2,31.9,31.9,29.6,29.6,29.6,29.4,27.8,27.0,26.9,26.2,24.9,24.6,24.2,22.7,22.6,22.5,22.3；minor:δ212.3,208.5,208.3,204.1,178.1,170.8,168.8,166.5,125.5,107.5,105.2,103.8,54.1,49.1,44.7,43.8,39.0,31.9,31.9,30.3,29.5,29.5,29.4,29.4,27.1,25.7,25.7,24.8,24.7,24.6,24.4,22.7,22.5,22.4。
Example 12:
4- (1- (3-Hexanoyl-2,4,6-trihydroxyphenyl) -3-methylbutanyl) -5-hydroxy-2,2,6, 6-tetramethylcyclohexox-4-ene-1, 3-dione, i.e. I12The preparation of (1):
compound VI (100mmol) and methanesulfonic acid (300mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, cyclobutylcarbamoyl chloride (300mmol) was slowly added dropwise to the reaction system. The reaction system was stirred for 10 minutes while continuing to maintain the temperature after the dropwise addition, cooled to room temperature after the reaction proceeded sufficiently, and the reaction mixture was poured into 150mL of ice water and extracted 3 times with n-hexane (150mL), and the organic phases were combined, washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then washed once with saturated brine. Drying the organic phase with anhydrous sodium sulfate, filtering, and spin-drying the filtrate under reduced pressure to obtain compound VII12，R1＝c-C4H7，R2＝c-C4H7Yield 78%.
Sodium hydride (30mmol) was slowly added to the dissolved VII12To a solution (250mL) of intermediate V (20mmol) in tetrahydrofuran was added a solution (50mL) of intermediate V (20mmol), and the mixture was stirred at room temperature for half an hour. The reaction was checked by TCL and 150mL of 1N aqueous hydrochloric acid was added. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate (150mL), washed with saturated brine (150mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product is purified by methanolCrystallizing to obtain pure light yellow powder (I)12)，R1＝c-C4H7，R2＝c-C4H7To obtain light yellow powder with a yield of 77%.
1H NMR(500MHz,CDCl3)δ12.77(s,0.67H,major),11.86(s,0.33H,minor),11.27(s,0.33H,minor),10.42(s,0.67H,major),4.44-4.30(m,3H),2.45-1.80(m,14H),1.52(m,3H),1.45-1.26(m,10H),0.94-0.81(m,6H).13C NMR(126MHz,CDCl3)major:δ211.9,208.2,207.7,203.8,177.3,170.6,168.0,166.9,114.7,107.2,104.2,102.4,54.9,48.7,46.9,46.0,38.1,27.8,26.9,26.9,26.2,25.5,24.7,24.7,24.3,22.7,22.6,22.2,17.6,17.6；minor:δ212.3,208.2,208.2,204.1,178.2,170.5,169.0,166.2,114.7,107.4,104.1,102.8,54.0,49.1,46.8,46.0,38.9,29.3,27.1,25.6,25.4,24.8,24.8,24.5,22.6,22.6,22.2,17.6,17.6。
Example 13:
4- (1- (3,5-Di (cyclohexenone) -2,4, 6-trihydroxynyl) -3-methylbutanyl) -5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione, i.e. I13The preparation of (1):
compound VI (100mmol) and methanesulfonic acid (300mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, cyclohexylcarbonyl chloride (300mmol) was slowly added dropwise to the reaction system. The reaction system was stirred for 10 minutes while continuing to maintain the temperature after the dropwise addition, cooled to room temperature after the reaction proceeded sufficiently, and the reaction mixture was poured into 150mL of ice water and extracted 3 times with n-hexane (150mL), and the organic phases were combined, washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then washed once with saturated brine. Drying the organic phase with anhydrous sodium sulfate, filtering, and spin-drying the filtrate under reduced pressure to obtain compound VII13，R1＝c-C6H11，R2＝c-C6H11Yield 74%.
Sodium hydride (30mmol)) Slowly adding dissolved VII13To a solution (250mL) of intermediate V (20mmol) in tetrahydrofuran was added a solution (50mL) of intermediate V (20mmol), and the mixture was stirred at room temperature for half an hour. The reaction was checked by TCL and 150mL of 1N aqueous hydrochloric acid was added. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate (150mL), washed with saturated brine (150mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure light yellow powder (I)13)，R1＝c-C6H11，R2＝c-C6H11To obtain light yellow powder with 79 percent of yield.
1H NMR(500MHz,CDCl3):δ12.89(s,0.66H,major),12.01(s,0.33H,minor),11.35(s,0.33H,minor),10.51(s,1H,major),4.39(m,1H),3.87-3.71(m,2H),2.16-1.21(m,31H),0.96-0.81(m,10H)；13C NMR(126MHz,CDCl3)major:δ211.9,211.6,211.3,203.8,177.5,171.0,168.4,166.8,125.5,114.6,107.5,104.8,103.0,54.9,49.9,49.3,48.8,38.2,30.3,29.7,29.4,29.4,29.2,27.9,26.9,26.9,26.3,26.2,26.1,26.1,26.0,26.0,25.8,24.30 22.6,22.3；minor:13C NMR(125MHz,CDCl3):δ212.4,211.7,211.5,204.1,178.3,171.0,169.4,166.2,128.3,114.6,107.8,104.6,103.4,54.1,49.9,49.3,49.2,39.0,30.1,29.5,29.3,27.1,26.2,26.1,25.9,25.7,25.6,24.8,24.6,22.7,22.5。
Example 14:
5-Hydroxy-2,2,6,6-tetramethyl-4- (3-methyl-1- (2,4,6-trihydroxy-3,5-bis (2-phenyl) butyl) cyclohex-4-ene-1,3-dione, i.e. I14The preparation of (1):
compound VI (100mmol) and methanesulfonic acid (300mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, cyclophenylacetyl chloride (300mmol) was slowly added dropwise to the reaction system. The reaction was stirred for 10 minutes while continuing to maintain the temperature until the reaction was complete, cooled to room temperature, and the reaction mixture was poured into 150mLThe mixture was extracted 3 times with n-hexane (150mL) and the organic phases were combined, washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then washed once with saturated brine. Drying the organic phase with anhydrous sodium sulfate, filtering, and spin-drying the filtrate under reduced pressure to obtain compound VII14，R1＝CH2Ph，R2＝CH2Ph, yield 76%.
Sodium hydride (30mmol) was slowly added to the dissolved VII14To a solution (250mL) of intermediate V (20mmol) in tetrahydrofuran was added a solution (50mL) of intermediate V (20mmol), and the mixture was stirred at room temperature for half an hour. The reaction was checked by TCL and 150mL of 1N aqueous hydrochloric acid was added. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate (150mL), washed with saturated brine (150mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure light yellow powder (I)14)，R1＝CH2Ph，R2＝CH2Ph, gives a pale yellow powder in 71% yield.
1H NMR(500MHz,CDCl3):δ13.23(s,0.67H,major),12.35(s,0.33H,minor),10.99(s,0.33H,minor),10.16(s,0.67H,major),7.38-7.26(m,10H),4.65-4.43(m,4H),4.37(t,J＝6.8Hz,1H),2.14-1.28(m,15H),0.87(dd,J＝8.2,6.7Hz,6H)；13C NMR(125MHz,CDCl3):major:δ211.7,205.3,204.8,204.0,177.5,170.9,167.9,167.3,135.1,134.5,130.0,129.9,128.4,128.3,127.0,126.8,114.4,107.6,105.3,103.4,55.0,50.6,49.5,48.7,38.2,27.7,27.0,26.9,26.2,24.2,22.6,22.5,22.3；minor:13C NMR(125MHz,CDCl3)δ212.12,205.27,205.22,204.25,178.30,170.79,168.91,166.70,134.98,134.36,129.96,129.90,128.43,128.37,127.00,126.83,114.46,107.79,105.16,103.79,54.10,50.58,49.54,49.12,38.95,29.45,27.09,25.69,25.66,24.76,24.44,22.54,22.30。
Example 15:
5-Hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1- (2,4,6-trihydroxy-3,5-bis (3-phenylpropanoyl) phenyl) butyl) cyclohex-4-ene-1,3-dione, i.e., I15The preparation of (1):
compound VI (100mmol) and methanesulfonic acid (300mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, cyclopropanoyl chloride (300mmol) was slowly added dropwise to the reaction system. The reaction system was stirred for 10 minutes while continuing to maintain the temperature after the dropwise addition, cooled to room temperature after the reaction proceeded sufficiently, and the reaction mixture was poured into 150mL of ice water and extracted 3 times with n-hexane (150mL), and the organic phases were combined, washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then washed once with saturated brine. Drying the organic phase with anhydrous sodium sulfate, filtering, and spin-drying the filtrate under reduced pressure to obtain compound VII15，R1＝C2H4Ph，R2＝C2H4Ph, yield 75%.
Sodium hydride (30mmol) was slowly added to the dissolved VII15To a solution (250mL) of intermediate V (20mmol) in tetrahydrofuran was added a solution (50mL) of intermediate V (20mmol), and the mixture was stirred at room temperature for half an hour. The reaction was checked by TCL and 150mL of 1N aqueous hydrochloric acid was added. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate (150mL), washed with saturated brine (150mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure light yellow powder (I)15)，R1＝C2H4Ph，R2＝C2H4Ph, gives a pale yellow powder in 68% yield.
1H NMR(400MHz,CDCl3):δ＝1HNMR(500MHz,CDCl3)δ13.04(s,0.67H,major),12.16(s,0.33H,minor),11.11(s,0.33H,minor),10.27(s,0.67H,major),7.35-7.20(m,10H),4.39(t,J＝14.5Hz,1H),3.55(m,4H),3.05(d,J＝7.4Hz,4H),2.09-1.71(m,2H),1.55-1.25(m,13H),0.93-0.75(m,6H)；13C NMR(125MHz,CDCl3):major:δ211.7,206.8,206.5,203.9,177.4,170.7,167.6,167.2,141.5,141.2,128.7,128.5,128.5,128.4,126.1,126.0,114.5,107.5,105.5,103.5,55.0,48.7,46.3,45.4,38.2,30.7,30.5,27.72,27.02,26.93,26.24,25.75,24.21,22.56,22.42,22.34；minor:13C NMR(125MHz,CDCl3)δ212.2,207.0,206.7,204.2,178.1,170.6,168.6,166.6,141.4,141.1,128.6,128.5,128.4,128.4,126.1,126.0,114.5,107.6,105.3,103.9,54.1,49.1,46.2,45.4,39.0,30.6,30.5,29.7,29.5,27.1,26.2,25.8,24.7,24.3,22.5,22.4,22.3。
Example 16:
4- (1- (3-Acetyl-5-butyl-2, 4,6-trihydroxyphenyl) -3-methylbutanyl) -5-hydroxy-2,2,6, 6-tetramethylhydantoin-4-ene-1, 3-dione, i.e. I16The preparation of (1):
obtaining a compound VII according to the method disclosed in the prior art CN 105622379A16，R1＝CH3，R2＝n-C3H7The yield was 60%.
Sodium hydride (30mmol) was slowly added to the dissolved VII16To a solution (250mL) of intermediate V (20mmol) in tetrahydrofuran was added a solution (50mL) of intermediate V (20mmol), and the mixture was stirred at room temperature for half an hour. The reaction was checked by TCL and 150mL of 1N aqueous hydrochloric acid was added. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate (150mL), washed with saturated brine (150mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure light yellow powder (I)16)，R1＝CH3，R2＝n-C3H7To obtain light yellow powder with 79 percent of yield.
1H NMR(500MHz,CDCl3)δ12.92(d,0.67H,major),12.04(d,0.33H,minor),11.18(d,0.33H,minor),10.33(d,0.67H,major),4.37(m,1H),3.28-3.06(m,2H),2.76(s,3H),2.20-1.30(m,17H),1.09-0.96(t,J＝7.4Hz,3H),0.94-0.82(m,6H)；13C NMR(100MHz,CDCl3):the pairs of major regio-isomers:δ211.8,211.7,208.1,207.9,205.4,205.1,203.9,203.8,177.3,171.0,170.8,168.1,167.4,167.4,167.2,114.5,114.5,107.4,107.2,105.7,105.5,103.8,103.4,55.0,48.7,46.5,45.6,38.2,38.2,33.5,32.4,27.7,27.1,27.0,26.9,26.2,25.7,24.7,24.2,24.2,22.6,22.5,22.4,22.4,22.4,22.3,18.1,18.0,14.0,13.9；the pairs of minor regio-isomers:13C NMR(126MHz,CDCl3)δ212.2,212.2,208.3,208.0,205.5,205.4,204.2,204.2,178.1,178.1,170.9,170.7,169.1,168.5,167.4,166.8,166.7,114.5,114.5,107.7,107.4,105.4,105.3,104.2,103.7,54.1,49.1,46.5,45.6,39.0,39.0,33.4,32.4,29.5,29.4,27.7,27.1,27.1,26.9,26.2,25.8,24.7,24.3,24.3,22.5,22.5,22.4,22.4,22.3,22.3,18.0,17.9,14.0,13.9.Note:This compound existed as a pair of atropisomers and regio-isomers。
Example 17:
4- (1- (3-Acetyl-5-hexanoyl-2,4,6-trihydroxyphenyl) -3-methylbutanyl) -5-hydroxy-2,2,6, 6-tetramethylhydantoin-4-ene-1, 3-dione, i.e. I17The preparation of (1):
obtaining a compound VII according to the method disclosed in the prior art CN 105622379A17，R1＝CH3，R2＝n-C5H11The yield was 65%.
Sodium hydride (30mmol) was slowly added to the dissolved VII17To a solution (250mL) of intermediate V (20mmol) in tetrahydrofuran was added a solution (50mL) of intermediate V (20mmol), and the mixture was stirred at room temperature for half an hour. The reaction was checked by TCL and 150mL of 1N aqueous hydrochloric acid was added. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate (150mL), washed with saturated brine (150mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure light yellow powder (I)17)，R1＝CH3，R2＝n-C5H11To obtain light yellow powder with yield of 71%.
1H NMR(400MHz,CDCl3):1H NMR(500MHz,CDCl3)δ12.92(d,0.67H,major),12.04(d,0.33H,minor),11.18(d,0.33H,minor),10.33(d,0.66H,major),4.37(m,1H),3.28-3.06(m,2H),2.76(m,3H),2.22-1.30(m,21H),1.09-0.96(m,3H),0.94-0.82(m,6H)；13C NMR(125MHz,CDCl3):the pairs of major regio-isomers:δ211.8,211.7,208.3,208.1,205.4,205.1,204.2,203.9,203.8,177.3,177.2,171.0,170.8,168.1,167.5,167.3,167.2,114.6,114.5,107.4,107.2,105.7,105.4,103.8,103.4,54.9,48.7,44.7,43.7,38.2,38.1,33.5,32.4,31.6,27.7,27.1,27.0,26.9,26.2,25.7,24.7,24.5,24.3,24.2,22.6,22.6,22.5,22.4,22.4,22.3,22.3,14.0,13.9；the pairs of minor regio-isomers:13C NMR(125MHz,CDCl3):δ212.3,212.2,208.5,208.2,205.5,205.4,204.2,204.1,178.1,178.0,170.9,170.7,169.2,168.5,166.74,166.65,114.55,114.50,107.52,107.38,105.44,105.26,103.80,103.72,54.12,49.14,44.59,43.68,39.07,38.99,33.44,32.38,31.58,29.49,29.45,27.10,27.08,26.22,25.82,24.44,24.34,24.26,24.20,22.62,22.54,22.48,22.32,14.01,13.99.Note:This compound existed as a pair of atropisomers and regio-isomers。
Example 18:
4- (1- (3-decanoyl-2, 4,6-trihydroxyphenyl) -3-methylbutanyl) -5-hydroxy-2,2,6, 6-tetramethylhydroxy-4-ene-1, 3-dione, i.e. I18The preparation of (1):
obtaining a compound VII according to the method disclosed in the prior art CN 105622379A18，R1＝CH3，R2＝n-C7H15The yield was 62%.
Sodium hydride (30mmol) was slowly added to the dissolved VII18To a solution (250mL) of intermediate V (20mmol) in tetrahydrofuran was added a solution (50mL) of intermediate V (20mmol), and the mixture was stirred at room temperature for half an hour. The reaction was checked by TCL and 150mL of 1N aqueous hydrochloric acid was added. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate (150mL), washed with saturated brine (150mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure light yellow powder (I)18)，R1＝CH3，R2＝n-C7H15To obtain light yellow powder with the yield of 66 percent.
1H NMR(500MHz,CDCl3):δ12.93(d,0.67H,major),12.04(d,0.33H,minor),11.19(d,0.33H,minor),10.33(d,0.66H,major),4.44-4.33(m,1H),3.28-3.12(m,2H),2.78(s,3H),2.18-1.19(m,25H),0.95-0.84(m,9H)；13C NMR(125MHz,CDCl3):δ211.8,211.7,208.3,208.1,205.4,205.1,204.2,203.8,177.3,177.3,171.0,170.8,168.1,167.4,167.3,167.2,166.7,165.3,114.6,114.5,107.4,107.3,105.7,105.5,103.4,100.0,55.0,48.7,44.7,43.7,38.2,33.5,32.4,31.7,29.4,29.3,29.2,27.7,27.1,26.9,26.2,25.7,24.9,24.6,24.2,22.7,22.6,22.5,22.4.Note:This compound existed as a pair of atropisomers and regio-isomers。
Example 19: in vitro anti-MRSA Activity assay of Compounds of the invention
In this example, the Minimum Inhibitory Concentration (MIC) of the anti-MRSA activity of a sample is determined by Resazurin development. The assay will use a 96-well plate dilution titer technique, with the Minimum Inhibitory Concentration (MIC) of the various substances being determined simultaneously. Firstly, 7.5mL of indicator solution (100 mu g/mL of resazurin aqueous solution) and 5mL of bacteria solution to be tested (10)8CFU/mL) and 100 μ L of the mixed bacteria solution was added to each of all the test wells of columns 1 to 8. Then 100 mu L of sample I to be tested1-I18The DMSO solution (2. mu.g/mL) was added to each well in the first row, mixed well and 100. mu.L of the solution was transferred to the corresponding well in the second row and diluted in duplicate to row 8 in the same manner. Finally, the well plate with the added sample is placed into a constant temperature incubator and cultured for 10-12h at 37 ℃. The bacteria liquid turns red into no bacteriostatic activity, blue is bacteriostatic activity, and the lowest dilution concentration of the bacteria liquid maintaining blue is considered as the lowest bacteriostatic concentration of the compound to be detected.
The results are shown in table 1 and show that: in the test of Compound I1-I18The activity of most of the compounds is obviously excellentVancomycin in the last barrier of clinical antibacterial drugs. In particular compounds I6-I9The compounds have remarkable MRSA resisting activity, the MIC value of the compounds for resisting MRSA bacteria is as low as 0.02-0.08 mu g/mL, and the compounds are 12.5-50 times stronger than vancomycin (1.00 mu g/mL) which is a final barrier of clinical antibacterial drugs, and are one of MRSA resisting lead drug molecules with a new structure and strongest activity reported at home and abroad at present.
TABLE 1 Compound I1-I18anti-MRSA activity at cellular level
Example 20: evaluation of anti-SA Activity of Compounds of the present invention
In this example, the Minimum Inhibitory Concentration (MIC) of the anti-SA activity of the sample is determined by Resazurin color development. The assay will use a 96-well plate dilution titer technique, with the Minimum Inhibitory Concentration (MIC) of the various substances being determined simultaneously. Firstly, 7.5mL of indicator solution (100 mu g/mL of resazurin aqueous solution) and 5mL of bacteria solution to be tested (10)8CFU/mL) and 100 μ L of the mixed bacteria solution was added to each of all the test wells of columns 1 to 8. Then 100 mu L of sample I to be tested6-I9The DMSO solution (0.2. mu.g/mL) was sequentially added to each well of the first row, and after uniform mixing, 100. mu.L of the solution was transferred to the corresponding well of the second row and diluted to 8 th row by doubling in the same manner. Finally, the well plate with the added sample is placed into a constant temperature incubator and cultured for 10-12h at 37 ℃. The bacteria liquid turns red into no bacteriostatic activity, blue is bacteriostatic activity, and the lowest dilution concentration of the bacteria liquid maintaining blue is considered as the lowest bacteriostatic concentration of the compound to be detected.
The results show that: compound I6-I9All have very significant anti-SA activity, and the MIC values of the tested strains are obviously lower than those of vancomycin. Especially compounds I7The MIC value of most strains is as low as 0.01-0.04 mug/mL, which is 30-100 times better than the last barrier vancomycin (1.25 mug/mL) of the antibacterial drug.
TABLE 2 CompoundsI7Inhibitory Activity against different types of pathogenic bacteria
Example 21: evaluation of Activity of Compounds of the invention against Bacillus cereus
In this example, the Minimum Inhibitory Concentration (MIC) of the sample against Bacillus cereus activity was determined by Resazurin development. The assay will use a 96-well plate dilution titer technique, with the Minimum Inhibitory Concentration (MIC) of the various substances being determined simultaneously. Firstly, 7.5mL of indicator solution (100 mu g/mL of resazurin aqueous solution) and 5mL of bacteria solution to be tested (10)8CFU/mL) and 100 μ L of the mixed bacteria solution was added to each of all the test wells of columns 1 to 8. Then 100 mu L of sample I to be tested6-I9The DMSO solution (0.2. mu.g/mL) was sequentially added to each well of the first row, and after uniform mixing, 100. mu.L of the solution was transferred to the corresponding well of the second row and diluted to 8 th row by doubling in the same manner. Finally, the well plate with the added sample is placed into a constant temperature incubator and cultured for 10-12h at 37 ℃. The bacteria liquid turns red into no bacteriostatic activity, blue is bacteriostatic activity, and the lowest dilution concentration of the bacteria liquid maintaining blue is considered as the lowest bacteriostatic concentration of the compound to be detected.
The results show that: compound I6-I9Has very obvious anti-Bacillus cereus activity and obviously lower MIC value to tested strains than vancomycin. In particular I7The MIC value of the compound is 0.01-0.04 mu g/mL, which is 15-60 times stronger than that of vancomycin (0.62 mu g/mL) which is a clinical antibacterial drug and is a last barrier.
Example 22: evaluation of the Activity of Compounds against B.subtilis, B.Thiningensis or Escherichia coli
The method for evaluating the activity of the compound against B.subtilis, B.thuringiensis or Escherichia coli bacteria is similar to the operation process of the above-mentioned activity against Bacillus cereus. The results are shown in Table II above for Compound I6-I9Has very obvious anti-Bacillus cereus activity and obvious MIC value for tested strainsLower than vancomycin, and I7Shows the optimal broad-spectrum antibacterial activity.
While there have been shown and described what are at present considered the fundamental principles and essential features of the invention and its advantages, it will be apparent to those skilled in the art that the invention is not limited to the details of the foregoing exemplary embodiments, but is capable of other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.
Claims (10)
1. A myrtle ketone derivative is characterized in that the myrtle ketone derivative is a compound shown as a formula (I), an optical isomer, an enantiomer, a diastereoisomer, a racemate and pharmaceutically acceptable salts thereof,
wherein:
R1、R2independently selected from H, halogen, nitryl, hydroxyl, amino, C1-C12 straight chain, C1-C12 branched chain, C3-C12 naphthenic base, C3-C12 alkenyl, C3-C12 alkynyl, heterocyclic radical, aromatic ring, substituted aromatic ring, C2-C12 alkoxy or C2-C12 halogenated alkyl.
2. The method of claim 1Myrtle ketone derivative characterized in that R is1、R2Independently selected from C5-C10 straight chain, C5-C10 branched chain, C3-C6 naphthenic base, aromatic ring, substituted aromatic ring and C5-C10 halogenated alkyl.
3. A myrtle ketone derivative according to claim 1, wherein the substituted aromatic ring is a substituted benzene ring; preferably, the substituent of the substituted aromatic ring is selected from C1-C12 straight chain, C1-C12 branched chain, aromatic ring, halogen, nitro, hydroxyl and amino.
4. A myrtle ketone derivative according to claim 1, wherein R is1And R2Meanwhile, the substituted benzene ring is C5-C10 straight chain, C5-C10 branched chain, C3-C6 naphthenic base, C5-C10 halogenated alkyl, benzene ring or substituted benzene ring, wherein the substituent of the substituted benzene ring is selected from C1-C12 straight chain, C1-C12 branched chain, aromatic ring, halogen, nitro, hydroxyl and amino.
5. A myrtle ketone derivative according to claim 1, which is selected from the following compounds:
6. a myrtle ketone derivative according to claim 1, which is selected from the following compounds:
7. a process for preparing a myrtle ketone derivative according to claim 1, wherein the synthesis route is as follows:
wherein:
R1、R2independently selected from H, halogen, nitryl, hydroxyl, amino, C1-C12 straight chain, C1-C12 branched chain, C3-C12 naphthenic base, C3-C12 alkenyl, C3-C12 alkynyl, heterocyclic radical, aromatic ring, substituted aromatic ring, C2-C12 alkoxy or C2-C12 halogenated alkyl.
8. Use of a myrtle ketone derivative according to any one of claims 1 to 6 for the preparation of a medicament for the treatment or prevention of an infectious disease comprising MRSA, a gram-positive coccal infection or a gram-positive bacillal infection.
9. An antibacterial agent comprising any one of the compounds of the myrtle ketone derivatives according to any one of claims 1 to 6 as an active ingredient, and a pharmaceutically acceptable carrier.
10. The antibacterial agent according to claim 9, wherein the antibacterial agent is an agent against Methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, Bacillus cereus, p.acnes, e.faecalis, s.epididamides, e.coli, s.typhimurium or s.dysseniae bacteria.
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