CN105859537A - Ring opening myrtle ketone analogue as well as preparation method and application thereof to antibacterial medicines - Google Patents
Ring opening myrtle ketone analogue as well as preparation method and application thereof to antibacterial medicines Download PDFInfo
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- CN105859537A CN105859537A CN201610270114.7A CN201610270114A CN105859537A CN 105859537 A CN105859537 A CN 105859537A CN 201610270114 A CN201610270114 A CN 201610270114A CN 105859537 A CN105859537 A CN 105859537A
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- 0 CCCCCCCC(c(c(O)c1)c(*C(C(C)(C)C(C2(C)C)=O)=C([C@]3CC(C)C)C2=O)c3c1O)=O Chemical compound CCCCCCCC(c(c(O)c1)c(*C(C(C)(C)C(C2(C)C)=O)=C([C@]3CC(C)C)C2=O)c3c1O)=O 0.000 description 12
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/757—Unsaturated compounds containing a keto groups being part of a ring containing —CHO groups
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- 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
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Abstract
The invention discloses a ring opening myrtle ketone analogue as well as a preparation method and application thereof to antibacterial medicines. The structure of the ring opening myrtle ketone analogue is shown in a formula (1) in the specification, wherein in the formula (1), R is H, a C1-C15 straight chain or branched chain or naphthenic base or an aromatic group. The ring opening myrtle ketone analogue has obvious activity of resisting Methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, Bacillus cereus, B.subtilis, B.thuringiensis or Escherichia coli, so the ring opening myrtle ketone analogue can be used for preparing bacterial infection resistant medicines and is especially applied to preventing and treating clinically common MRSA infectious diseases.
Description
Technical field:
The invention belongs to synthetic pharmacochemistry field, be specifically related to open loop Fructus Rhodomyrti keto analog and preparation method thereof and
Application in antibacterials.
Background technology:
Methicillin-resistant staphylococcus aureus (Methicillin-resistant Staphylococcus aureus,
MRSA), since Britain Jevons in 1961 finds first, ratio shared in infection of staphylococcus aureus is increasingly
Height, is rapidly increased to current 60%-70% by the 1%-5% of 20th century the mid-80, and gradient of infection more comes
The most serious, it has also become one of important pathogen of hospital and Nosocomial Infections.Current MRSA is to antibiotic conventional clinically in succession
Drug resistance occur, it has also become the multi-drug resistant pathogen of serious threat human health, its infection is the most all over the world, and can be
Domestic animal and person-to-person propagation, the bacteremia mortality rate caused after infection is up to 50%-80%.At present, MRSA infects with B-mode
Hepatitis, acquired immune deficiency syndrome (AIDS) are listed as the world today three the most scabrous big infectious disease.
MRSA has multi-drug resistant, and nearly all clinical common antibiotics such as beta-lactam are shown drug resistance.Ten thousand
Ancient mycin (Vancomycin) had been considered as the most once the first-selected antibiotic that treatment MRSA infects, but this antibiotic toxic and side effects
Greatly, long-term, high-dose uses serious to kidney damage, easily causes deafness, is therefore not intended as first-line drug and uses.Except through the ages
Outside mycin, the minority medicine such as Linezolid, daptomycin and tigecycline is ratified through U.S. FDA, although can be used for clinic and controls
Treat MRSA to infect, but the Resistant strain of said medicine is the most constantly found in recent years, and probability is gradually increased,
Cause the extensive concern of medical circle.In view of there is presently no well-content anti-MRSA infection medicine, therefore develop novel anti-
MRSA infection medicine seems particularly urgent, has great scientific meaning, wide market prospect and potential economic valency simultaneously
Value.
Semimyrtucommulone (2) and callistenone C (3) is to separate from Myrtus plant
, they are all to be polymerized through Michael additive reaction, for Fructus Rhodomyrti by a β-triketone and acyl phloroglucinol unit
Characteristic component in platymiscium.The activity experiment research of forefathers shows, they have good antibacterial activity (to golden yellow Fructus Vitis viniferae
The MIC of coccus Staphylococcus aureus is 8.0 μ g/mL).Due to the phloroglucinol fragment in molecule and β-triketone
Fragment does not occur dehydration to form cyclization, thus has the structure of polyhydroxy opened loop.Due to the construction features of its uniqueness, thus
Make the complete synthesis by a relatively simple of them.Based on they aforesaid features, thus the present invention will be right using them as research
As carrying out structure activity study, to find the lead drug molecule with the most anti-the most antibacterial MRSA activity, have important
Scientific meaning and potential economic worth.
Summary of the invention:
First purpose of the present invention is to provide to have and significantly suppresses Methicillin-resistant
Staphylococcus aureus(MRSA)、Staphylococcus aureus、Bacillus cereus、B.subtilis、
The open loop Fructus Rhodomyrti keto analog of B.thuringiensis or Escherichia coli growth.
The open loop Fructus Rhodomyrti keto analog of the present invention, shown in its structure such as formula (1):
Wherein R is H or C1-C15Straight chain, side chain and cycloalkyl or containing the isostructural aromatic group of phenyl ring.
Described open loop Fructus Rhodomyrti keto analog is preferably the arbitrary compound in formula (2):
Further preferably, described open loop Fructus Rhodomyrti keto analog is the arbitrary compound in formula (3):
Second object of the present invention is to provide the preparation method of a kind of above-mentioned open loop Fructus Rhodomyrti keto analog, and its feature exists
In, its building-up process is as follows:
Shown in synthesis flow such as formula (4):
With phloroglucinol and alkyl acyl chloride under the catalysis of methanesulfonic acid or aluminum chloride, obtain through friedel-crafts acylation
Precursor compound 6 in formula (4)；Another precursor compound 10 is by making raw material, in alkalescence with acetyl group phloroglucinol 6b
Under the conditions of carry out C-and methylate and obtain compound 7, then compound 7 again through Protic Acid Catalyzed inverse Claisen condensation and
Knoevenagel is condensed to yield；Precursor compound 6 and compound 10 (α, alpha, beta-unsaturated ketone) in the basic conditions, occur
Michael additive reaction, i.e. can get target product 11, and wherein R is H, C1-C15Straight chain, side chain and cycloalkyl or containing benzene
The isostructural aromatic group of ring.
. the above-mentioned open loop Fructus Rhodomyrti keto analog of the present invention has the activity of the resisting gram-positive bacteria of highly significant, its
The antibacterial activity of middle compound 11i-11n is than antimicrobial drug " last one barrier " good 2-4 times of vancomycin.
Therefore, the arbitrary compound during third object of the present invention is to provide above-mentioned open loop Fructus Rhodomyrti keto analog is in system
Application in standby antibacterials.
Described antibacterials are preferably anti-Methicillin-resistant Staphylococcus aureus
(MRSA), Staphylococcus aureus, Bacillus cereus, B.subtilis, B.thuringiensis or
The medicine of Escherichia coli antibacterial.Owing to above-mentioned antibacterial is had preferably by the open loop Fructus Rhodomyrti keto analog of the present invention
Bacteriostatic activity, therefore, it is possible to develop into the killing bacteria agent of wide spectrum.
Described antibacterials are bacterial-infection resisting agent or preventing and treating antibacterial infection medicine.
Fourth object of the present invention is to provide a kind of antibacterials of offer, it is characterised in that containing above-mentioned open loop Fructus Persicae gold
Arbitrary compound in ma's keto analog is as active ingredient, and pharmaceutically acceptable carrier.
Described antibacterials are preferably anti-Methicillin-resistant Staphylococcus aureus
(MRSA), Staphylococcus aureus, Bacillus cereus, B.subtilis, B.thuringiensis or
The medicine of Escherichia coli antibacterial.
Described antibacterials are bacterial-infection resisting agent or preventing and treating antibacterial infection medicine.
The present invention has synthesized a class and has had notable anti-Methicillin-resistant Staphylococcus aureus
(MRSA), Staphylococcus aureus, Bacillus cereus, B.subtilis, B.thuringiensis or
The open loop Fructus Rhodomyrti keto analog of Escherichia coli, their antibacterial activity is than antimicrobial drug " last one barrier " through the ages
Good 2-4 times of mycin, and provide a kind of short-cut method synthesizing above-claimed cpd.Due to the present invention open loop Fructus Rhodomyrti ketone seemingly
Thing have significant anti-Methicillin-resistant Staphylococcus aureus (MRSA),
Staphylococcus aureus, Bacillus cereus, B.subtilis, B.thuringiensis or Escherichia
Coli activity, therefore may be used for preparing bacterial-infection resisting class medicine, especially the most common in preventing and treating
Application on Methicillin-resistant Staphylococcus aureus (MRSA) infectious disease.
Detailed description of the invention:
Following example are to further illustrate the present invention rather than limitation of the present invention.
Embodiment 1: the preparation method of open loop Fructus Rhodomyrti keto analog:
The building-up process of the open loop Fructus Rhodomyrti keto analog of the present invention is as follows:
With phloroglucinol and alkyl acyl chloride under the catalysis of methanesulfonic acid or aluminum chloride, obtain through friedel-crafts acylation
Precursor compound 6 in formula (5), wherein R is H, C1-C15Straight chain, side chain and cycloalkyl or containing the isostructural virtue of phenyl ring
Perfume base group；Another precursor compound 10 then can carry out C-by making raw material with acetyl group phloroglucinol 6b in the basic conditions
Methylate, quickly obtain through Protic Acid Catalyzed inverse Claisen condensation and Knoevenagel condensation the most again；Before obtaining
After body compound 6 and compound 10 (α, alpha, beta-unsaturated ketone), the most in the basic conditions, them are promoted to occur Michael to add
Becoming reaction, can obtain target product 11 smoothly, wherein R is H, C1-C15Straight chain, side chain and cycloalkyl or containing the knot such as phenyl ring
The aromatic group of structure.
Specifically comprise the following steps that
The synthesis of compound 6b-6k
(1) phloroglucinol (315mg, 2.5mmol) and acyl chlorides (3.75mmol) are placed in the round-bottomed flask that 10mL is dried,
It is heated to 60-80 DEG C.After stirring 10 minutes, in reaction system, it is slowly added dropwise pyrovinic acid (25mmol, 1.6mL).Continue
Stirring reaction system 30 minutes at temperature are held in continuation of insurance, are then cooled to room temperature.Reactant mixture is poured in 25mL frozen water, and
Extract 3 times by ethyl acetate (25mL), merge organic facies, and respectively with 25mL saturated sodium bicarbonate and brine It.Organic
Filtering after drying through anhydrous sodium sulfate, gained filtrate is spin-dried in reduced pressure.Remaining oily mixture is through flash column
Analysis (normal hexane: ethyl acetate=5:1) separates, and obtains corresponding acyl phloroglucinol compound.
Described acyl chlorides
When R is H, gained compound is 6a；
When R is CH3Time, gained compound is the 6b in formula (5)；
When R is C2H5Time, gained compound is the 6c in formula (5)；
When R is C3H5Time, gained compound is the 6d in formula (5)；
When R is iPr, gained compound is the 6e in formula (5)；
When R is C4H9Time, gained compound is the 6f in formula (5)；
When R is iBu, gained compound is the 6g in formula (5)；
When R is C5H11Time, gained compound is the 6h in formula (5)；
When R is C6H13Time, gained compound is the 6i in formula (5)；
When R is C7H15Time, gained compound is the 6j in formula (5)；
When R is C8H17Time, gained compound is the 6k in formula (5)；
The synthesis of compound 6l-6u
(2) phloroglucinol (315mg, 2.5mmol) and acyl chlorides (3.75mmol) are placed in the round-bottomed flask that 10mL is dried,
It is heated to 60-80 DEG C.After stirring 10 minutes, in reaction system, it is slowly added to aluminum chloride (12.5mmol, 1.66g).
Stir reaction system 3 hours at a temperature of being continually maintained in, be then cooled to room temperature.Reactant mixture is poured into 25mL frozen water
In, and extract 3 times by ethyl acetate (25mL), merge organic facies, and respectively with 25mL saturated sodium bicarbonate and brine It.
Organic facies filters after drying through anhydrous sodium sulfate, and gained filtrate is spin-dried in reduced pressure.Remaining oily mixture is through quickly
Column chromatography (normal hexane: ethyl acetate=5:1) separates, and obtains corresponding acyl phloroglucinol compound.
Described acyl chlorides
Work as R2For C9H17Time, gained compound is the 6l in formula (5)；
Work as R2For C10H21Time, gained compound is the 6m in formula (5)；
Work as R2For C11H23Time, gained compound is the 6n in formula (5)；
Work as R2For C13H27Time, gained compound is the 6o in formula (5)；
Work as R2For C15H31Time, gained compound is the 6p in formula (5)；
Work as R2For c-C4H7Time, gained compound is the 6q in formula (5)；
Work as R2For c-C5H9Time, gained compound is the 6r in formula (5)；
Work as R2For c-C6H11Time, gained compound is the 6s in formula (5)；
Work as R2For CH2During Ph, gained compound is the 6t in formula (5)；
Work as R2For C2H4During Ph, gained compound is the 6u in formula (5)；
The synthesis of compound 7
Under condition of ice bath, acetyl group phloroglucinol (2.75g, 16.5mmol) is dissolved in the anhydrous methanol solution of 60mL
In, then it is slowly added Feldalat NM (7.2g, 133mmol).After uniform stirring 10 minutes, in reaction system, slowly drip iodine
Methane (14.2mL, 228mmol).Continue to stir 30 minutes under condition of ice bath, and then reactant mixture is put at room temperature
Stir 24 hours.The aqueous hydrochloric acid solution being subsequently adding 100mL 2N terminates reaction.Mixture ethyl acetate (100mL) extracts
4 times, merge organic facies.Obtained organic facies 50mL saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and filters.Residue
It is further purified through rapid column chromatography (normal hexane: ethyl acetate=5:1) and obtains 3.17g colorless oil compound (compound
7), productivity 86% light brown chip solid.1H NMR(500MHz,CDCl3):δ1.33(s,6H),1.42(s,6H),2.57(s,
3H)；13CNMR(125MHz,CDCl3):δ23.8,24.3,27.4,52.0,56.7,109.4,196.7,199.1,201.7,
210.0。
The synthesis of compound 8
Acetyl group β-triketone (compound 7,3.17g, 14.2mmol) is placed in the round-bottomed flask of 50mL, the most wherein
Add the aqueous hydrochloric acid solution 30mL of 6N.And then reaction system is placed in 110 DEG C of oil baths, is stirred vigorously and is heated to reflux 24
Hour.Question response system is gradually decreased to room temperature, then reactant mixture ethyl acetate (50mL) is extracted 8 times, merges organic
Phase.Obtained organic facies filters after drying through anhydrous sodium sulfate, after rotary evaporation removes solvent, obtains yellowish-brown grease.
This grease is further purified through rapid column chromatography (normal hexane: ethyl acetate=1:1) and obtains 2.17g light brown powder admittedly
Body compound syncapic acid (compound 8), productivity 80%.Syncapic acid: yellowish-brown pulverulent solids；Ketone/alkene
The mixture of alcohol isomery, ratio is about 2:1.1H NMR (500MHz, CDCl3): ketone: δ 1.31 (s, 12H), 3.61 (s, 2H)；Alkene
Alcohol: δ 1.40 (s, 12H), 5.74 (brd, J=2.3Hz, 1H), 8.00 (br s, 1H)；13C NMR (100MHz, CDCl3): ketone:
δ21.8,50.2,59.1,204.3,208.9；Enol: δ 24.5,51.2,59.1,101.7,191.9,204.3,212.6.
The synthesis of compound 10
Burn to the 20mL round bottom equipped with syncapic acid (182mg, 1.0mmol) and isovaleral (172mg, 2.0mmol)
Being added on anhydrous methylene chloride (10mL) in Ping, uniform stirring, after 5 minutes, the most disposably adds proline under room temperature
(11.5mg,0.1mmol).After continuing stirring reaction system half an hour, by the mixture after reaction completely through one section about 3 lis
The long silica gel column chromatography (dichloromethane is as eluant) of rice is purified, and will can obtain 250mg water white oil with the yield of equivalent
Shape compound (compound 10).I: colorless oil；1H NMR (500MHz, CDCl3): δ 0.95 (d, J=6.7Hz, 6H),
1.30 (s, 6H), 1.31 (s, 6H), 1.89 (m, J=6.7Hz, 1H), 2.59 (dd, J=3.0,3.0Hz, 2H), 7.51 (dd, J
=3.0Hz, 1H)；13C NMR(125MHz,CDCl3):δ21.9,22.3,22.6,28.7,38.9,57.9,58.6,133.1,
159.1,196.4,199.5,208.8。
The synthesis of compound 11
Sodium hydride (in 30.0mg, 0.75mmol, 60% mineral oil) is slowly added dissolved with acyl phloroglucinol compound
In the tetrahydrofuran solution (5mL) of (compound 6) (0.5mmol), it is subsequently adding dissolved with compound 10 (beta-unsaturated ketone)
The tetrahydrofuran solution (2mL) of (62.5mg, 0.25mmol).After mixture stirs half an hour at room temperature, add 5mL 1N
Aqueous hydrochloric acid solution.Separating organic facies, aqueous phase extracts 3 times through ethyl acetate (5mL), and saturated aqueous common salt (5mL) washs, anhydrous sulfur
Acid sodium is dried, and rotary evaporation goes out remaining organic solvent.Remaining crude product separates (normal hexane: acetic acid through silicagel column again
Ethyl ester=10:1-2:1), will can obtain required target product 11 with the productivity of 30-80%.
Described compound 11, as shown in formula (2):
When R is H, gained compound is the 11a in formula (2)；
When R is CH3Time, gained compound is the 11b in formula (2)；
When R is C2H5Time, gained compound is the 11c in formula (2)；
When R is C3H5Time, gained compound is the 11d in formula (2)；
When R is iPr, gained compound is the 11e in formula (2)；
When R is C4H9Time, gained compound is the 11f in formula (2)；
When R is iBu, gained compound is the 11g in formula (2)；
When R is C5H11Time, gained compound is the 11h in formula (2)；
When R is C6H13Time, gained compound is the 11i in formula (2)；
When R is C7H15Time, gained compound is the 11j in formula (2)；
When R is C8H17Time, gained compound is the 11k in formula (2)；
When R is C9H17Time, gained compound is the 11l in formula (2)；
When R is C10H21Time, gained compound is the 11m in formula (2)；
When R is C11H23Time, gained compound is the 11n in formula (2)；
When R is C13H27Time, gained compound is the 11o in formula (2)；
When R is C15H31Time, gained compound is the 11p in formula (2)；
When R is c-C4H7Time, gained compound is the 11q in formula (2)；
When R is c-C5H9Time, gained compound is the 11r in formula (2)；
When R is c-C6H11Time, gained compound is the 11s in formula (2)；
When R is CH2During Ph, gained compound is the 11t in formula (2)；
When R is C2H4During Ph, gained compound is the 11u in formula (2)；
Shown in concrete structure such as formula (2):
The sign data of compound 11a-11u are as follows:
1, compound 11a:2,4,6-trihydroxy-3-(1-(2-hydroxy-3,3,5,5-tetramethyl-4,6-
dioxocyclohex-1-en-1-yl)-3-methylbutyl)benzaldehyde(11a).1H NMR(500MHz,CD3OD):
δ=0.85 (d, J=6.7Hz, 3H), 0.86 (d, J=6.6Hz, 3H), 1.33 (m, 12H), 1.43 (m, 1H), 2.05 (m, 2H),
4.45 (t, J=7.5Hz, 3H), 5.75 (s, 1H)), 10.1 (s, 1H)；13C NMR(100MHz,CD3: δ=10.9,14.1, OD)
19.3,22.4,22.6,25.5,26.9,28.1,30.3,38.3,38.7,39.0,68.3,98.1,109.2,114.7,
128.9,152.3,210.9,212.4.HRMS(ESI):calcd for C22H29O7 +,[M+H+]405.1906,found
405.1913.
2, compound 11b:4-(1-(3-acetyl-2,4,6-trihydroxyphenyl)-3-methylbutyl)-5-
hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(11b).1H NMR(400MHz,CDCl3):
δ=0.86 (m, 6H), 1.15-2.25 (m, 15H), 2.72 (s, 3H), 4.38 (t, J=7.8Hz, 1H)；further peaks
show keto-enol tautomerism in a ratio of 4:6；Enol tautomer: δ=5.97 (s, 1H), 7.07
(brs,1H),10.3(brs,1H),11.7(brs,1H)；Keto tautomer: δ=6.03 (s, 1H), 7.07 (brs, 1H)
10.6(brs,1H),11.2(brs,1H)；13C NMR(100MHz,CDCl3): δ=21.8,22.3,22.6,24.2,25.4,
26.2,26.9,27.0,27.0,27.9,32.2,38.2,48.7,55.1,97.9,104.1,108.7,114.8,159.5,
162.5,164.3,176.6,203.3,204.0,212.5.HRMS(ESI):calcd for C23H31O7 +,[M+H+]
419.2083,found 419.2070.
3, compound 11c:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-
trihydroxy-3-propionylphenyl)butyl)cyclohex-4-ene-1,3-dione(11c).1H NMR
(400MHz,CDCl3): δ=0.85 (d, J=6.5Hz, 3H), 0.86 (d, J=6.5Hz, 3H), 1.20 (t, J=7.2Hz,
3H), 1.27-1.45 (m, 10H), 1.50 (s, 3H), 1.75 (m, 1H), 2.12 (m, 1H), 3.15 (q, J=7.2Hz, 2H),
4.38 (t, J=7.7Hz, 1H)；further peaks show keto-enol tautomerism in a ratio of 3:
7；Enol tautomer: δ=5.95 (s, 1H), 6.54 (brs, 1H), 10.3 (brs, 1H), 11.6 (brs, 1H)；keto
Tautomer: δ=6.00 (s, 1H), 6.54 (brs, 1H) 10.6 (brs, 1H), 11.2 (brs, 1H)；13C NMR(100MHz,
CDCl3): δ=8.6,22.3,22.4,22.6,24.2,26.1,26.8,27.0,27.9,36.9,38.2,48 .6,55.1,
97.9,103.3,108.9,114.8,159.1,162.5,163.8,176.6,203.2,207.3,212.5.HRMS(ESI):
calcd for C24H33O7 +,[M+H+]433.2226,found 433.2258.
4, compound 11d:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-
trihydroxy-3-butyrylphenyl)butyl)cyclohex-4-ene-1,3-dione(11d).1H NMR(400MHz,
CDCl3): δ=0.85 (d, J=6.5Hz, 3H), 0.86 (d, J=6.5Hz, 3H), 1.01 (t, J=7.5Hz, 3H), 1.29-
1.45 (m, 10H), 1.50 (s, 3H), 1.75 (m, 3H), 2.13 (m, 1H), 3.08 (t, J=7.2Hz, 2H), 4.37 (t, J=
7.7Hz,1H)；further peaks show keto-enol tautomerism in a ratio of 3:7；enol
Tautomer: δ=5.93 (s, 1H), 6.31 (brs, 1H), 10.3 (brs, 1H), 11.6 (brs, 1H)；keto tautomer:δ
=5.98 (s, 1H), 6.31 (brs, 1H) 10.6 (brs, 1H), 11.2 (brs, 1H)；13C NMR(100MHz,CDCl3): δ=
14.0,18.1,22.3,22.6,22.8,24.3,26.1,26.8,26.9,27.9,29.0,29.3,29.4,38.2,45.5,
48.6,55.1,98.0,103.6,109.0,114.8,114.9,158.8,162.8,164.3,176.6,203.2,206.6,
212.5.HRMS(ESI):calcd for C25H35O7 +,[M+H+]447.2383,found 447.2380.
5, compound 11e:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-
trihydroxy-3-isobutyrylphenyl)butyl)cyclohex-4-ene-1,3-dione(11e).1H NMR
(400MHz,CDCl3): δ=0.85 (d, J=6.5Hz, 3H), 0.87 (d, J=6.5Hz, 3H), 1.23 (d, J=6.1Hz,
6H), 1.22 (d, J=6.1Hz, 3H), 1.30-1.55 (m, 13H), 1.55-1.86 (m, 3H), 2.14 (m, 1H), 3.95 (m,
1H), 4.39 (t, J=7.7Hz, 1H)；further peaks show keto-enol tautomerism in a ratio
of 3:7；Enol tautomer: δ=5.92 (s, 1H), 6.05 (brs, 1H), 10.4 (brs, 1H), 11.6 (brs, 1H)；
Keto tautomer: δ=5.98 (s, 1H), 6.05 (brs, 1H) 10.6 (brs, 1H), 11.2 (brs, 1H)；13C NMR
(100MHz,CDCl3): δ=14.2,19.2,19.3,22.9,22.9,26.9,28.0,28.8,29.0,29.1,30.1,
30.5,38.3,38.7,39.0,48.6,98.1,109.4,114.7,176.6,204.2,210.9,212.4.HRMS(ESI):
calcd for C25H35O7 +,[M+H+]447.2383,found 447.2389.
6, compound 11f:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-
trihydroxy-3-pentanoylphenyl)butyl)cyclohex-4-ene-1,3-dione(11f).1H NMR
(400MHz,CDCl3): δ=0.86 (m, 6H), 0.95 (t, J=7.3Hz, 3H), 1.25-1.45 (m, 13H), 1.61-1.80
(m, 5H), 2.12 (m, 1H), 3.10 (t, J=7.5Hz, 2H), 4.37 (t, J=7.5Hz, 1H)；further peaks show
keto-enol tautomerism in a ratio of 3:7；Enol tautomer: δ=5.91 (s, 1H), 6.02 (brs,
1H),10.3(brs,1H),11.6(brs,1H)；Keto tautomer: δ=5.97 (s, 1H), 6.02 (brs, 1H) 10.6
(brs,1H),11.2(brs,1H)；13C NMR(100MHz,CDCl3): δ=11.4,14.0,14.1,18.8,22.3,22.6,
22.7,22.8,24.3,26.2,26.9,26.9,27.0,27.9,29.1,29.4,31.6,34.7,36.1,38.2,38.7,
48.7,55.1,98.0,103.9,109.1,114.8,158.6,162.8,164.1,176.6,203.2,206.8,
212.4.HRMS(ESI):calcd for C26H37O7 +,[M+H+]461.2539,found 461.2536.
7, compound 11g:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-
trihydroxy-3-(3-methylbutanoyl)phenyl)butyl)cyclohex-4-ene-1,3-dione(11g).1H
NMR(400MHz,CDCl3): δ=0.85 (d, J=6.5Hz, 3H), 0.86 (d, J=6.5Hz, 3H), 1.01 (d, J=6.6Hz,
6H), 1.29-1.45 (m, 10H), 1.50 (s, 3H), 1.78 (m, 1H), 2.11 (m, 1H), 2.99 (d, J=6.7Hz, 2H),
4.37 (t, J=7.8Hz, 1H)；further peaks show keto-enol tautomerism in a ratio of 3:
7；Enol tautomer: δ=5.94 (s, 1H), 6.79 (brs, 1H), 10.4 (brs, 1H), 11.6 (brs, 1H)；keto
Tautomer: δ=6.00 (s, 1H), 6.79 (brs, 1H) 10.6 (brs, 1H), 11.2 (brs, 1H)；13C NMR(100MHz,
CDCl3): δ=14.1,17.6,20.6,22.3,22.5,22.6,22.8,24.2,25.3,26.1,26.8,2 6.9,27.0,
27.9,29.0,29.4,31.0,31.6,38.2,48.7,52.2,55.1,98.0,103.3,109.0,114.8,114.9,
159.1,162.9,164.3,176.7,203.2,206.4,208.0,212.6.HRMS(ESI):calcd for C26H37O7 +,
[M+H+]461.2539,found 461.2541.
8, compound 11h:4-(1-(3-hexanoyl-2,4,6-trihydroxyphenyl)-3-methylbutyl)-
5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(11h).1H NMR(400MHz,
CDCl3): δ=0.86 (m, 6H), 0.92 (t, J=7.1Hz, 3H), 1.16-1.45 (m, 15H), 1.61-1.80 (m, 5H),
2.12 (m, 1H), 3.09 (t, J=7.6Hz, 2H), 4.37 (t, J=7.8Hz, 1H)；further peaks show keto-
enol tautomerism in a ratio of 3:7；Enol tautomer: δ=5.91 (s, 1H), 5.98 (brs, 1H),
10.3(brs,1H),11.6(brs,1H)；Keto tautomer: δ=5.97 (s, 1H), 5.98 (brs, 1H) 10.6 (brs,
1H),11.2(brs,1H)；13C NMR(100MHz,CDCl3): δ=14.0,22.3,22.6,22.6,24.2,24.4,26.2,
26.9,26.9,27.0,27.9,31.7,38.2,43.6,48.7,55.1,98.0,103.6,108.9,114.8,158.7,
163.0,164.3,176.6,203.1,207.1,212.4.HRMS(ESI):calcd for C27H39O7 +,[M+H+]
475.2696,found 475.2682.
9, compound 11i:4-(1-(3-heptanoyl-2,4,6-trihydroxyphenyl)-3-methylbutyl)-
5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(11i).1H NMR(400MHz,
CDCl3): δ=0.86 (m, 9H), 1.16-1.45 (m, 16H), 1.61-1.80 (m, 3H), 2.10 (m, 1H), 3.10 (t, J=
7.4Hz, 2H), 4.39 (t, J=7.8Hz, 1H)；further peaks show keto-enol tautomerism in a
ratio of 3:7；Enol tautomer: δ=5.96 (s, 1H), 6.68 (brs, 1H), 10.4 (brs, 1H), 11.6 (brs,
1H)；Keto tautomer: δ=6.02 (s, 1H), 6.68 (brs, 1H) 10.6 (brs, 1H), 11.3 (brs, 1H)；13C NMR
(100MHz,CDCl3): δ=14.1,22.3,22.6,24.3,24.7,25.6,26.2,26.9,27.0,28.0,29.2,
30.3,31.4,31.7,38.3,38.7,43.6,48.7,55.1,98.0,103.5,109.0,114.8,115.0,158.8,
162.7,164.0,176.7,203.2,206.9,212.5.HRMS(ESI):calcd for C28H41O7 +,[M+H+]
489.2852,found 489.2855.
10, compound 11j:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-
trihydroxy-3-octanoylphenyl)butyl)cyclohex-4-ene-1,3-dione(11j).1H NMR
(400MHz,CDCl3): δ=0.88 (m, 9H), 1.16-1.45 (m, 18H), 1.50 (s, 3H), 1.61-1.80 (m, 3H), 2.10
(m, 1H), 3.11 (t, J=7.4Hz, 2H), 4.39 (t, J=7.8Hz, 1H)；further peaks show keto-enol
tautomerism in a ratio of 3:7；Enol tautomer: δ=5.97 (s, 1H), 6.78 (brs, 1H), 10.4
(brs,1H),11.6(brs,1H)；Keto tautomer: δ=6.02 (s, 1H), 6.89 (brs, 1H) 10.6 (brs, 1H),
11.3(brs,1H)；13C NMR(100MHz,CDCl3): δ=14.1,22.3,22.6,22.7,24.3,24.8,26.9,27.0,
29.2,29.5,31.8,38.3,43.6,48.7,55.1,98.0,103.5,108.9,114.8,115.0,159.1,162.7,
163.9,176.7,203.2,207.0,212.6.HRMS(ESI):calcd for C29H43O7 +,[M+H+]503.3009,
found 503.2999.
11, compound 11k:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-
trihydroxy-3-nonanoylphenyl)butyl)cyclohex-4-ene-1,3-dione(11k).1H NMR
(400MHz,CDCl3): δ=0.88 (m, 9H), 1.16-1.45 (m, 20H), 1.50 (s, 3H), 1.61-1.80 (m, 3H), 2.13
(m, 1H), 3.11 (t, J=7.4Hz, 2H), 4.39 (t, J=7.8Hz, 1H)；further peaks show keto-enol
tautomerism in aratio of 3:7；Enol tautomer: δ=5.96 (s, 1H), 6.66 (brs, 1H), 10.4
(brs,1H),11.6(brs,1H)；Keto tautomer: δ=6.01 (s, 1H), 6.67 (brs, 1H) 10.6 (brs, 1H),
11.3(brs,1H)；13C NMR(100MHz,CDCl3): δ=14.1,22.3,22.6,22.7,24.3,24.8,26.9,27.0,
29.2,29.5,31.9,38.2,43.6,48.7,55.1,98.0,103.6,109.0,114.8,115.0,159.0,162.7,
164.0,176.7,203.2,206.9,212.5.HRMS(ESI):calcd for C30H45O7 +,[M+H+]517.3165,
found 517.3160.
12, compound 11l:4-(1-(3-decanoyl-2,4,6-trihydroxyphenyl)-3-methylbutyl)-
5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(11l).1H NMR(400MHz,
CDCl3): δ=0.87 (m, 9H), 1.16-1.45 (m, 22H), 1.50 (s, 3H), 1.61-1.80 (m, 3H), 2.10 (m, 1H),
3.09 (t, J=7.5Hz, 2H), 4.37 (t, J=7.8Hz, 1H)；further peaks show keto-enol
tautomerism in a ratio of 3:7；Enol tautomer: δ=5.92 (s, 1H), 6.32 (brs, 1H), 10.3
(brs,1H),11.6(brs,1H)；Keto tautomer: δ=5.98 (s, 1H), 6.32 (brs, 1H), 10.6 (brs, 1H),
11.2(brs,1H)；13C NMR(100MHz,CDCl3): δ=14.1,22.3,22.4,22.6,22.7,24.3,24.8,25.6,
26.2,26.9,27.0,27.9,29.1,29.3,29.5,29.5,31.9,38.2,43.6,48.7,55.1,98.0,103.6,
109.1,114.8,158.8,162.7,164.0,176.6,203.2,206.9,212.4.HRMS(ESI):calcd for
C31H47O7 +,[M+H+]531.3322,found 531.3341.
13, compound 11m:4-(1-(3-decanoyl-2,4,6-trihydroxyphenyl)-3-methylbutyl)-
5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(11m).1H NMR(400MHz,
CDCl3): δ=0.86 (m, 9H), 1.16-1.45 (m, 24H), 1.50 (s, 3H), 1.61-1.80 (m, 3H), 2.11 (m, 1H),
3.09 (t, J=7.4Hz, 2H), 4.37 (t, J=7.8Hz, 1H)；further peaks show keto-enol
tautomerism in a ratio of 3:7；Enol tautomer: δ=5.92 (s, 1H), 6.29 (brs, 1H), 10.3
(brs,1H),11.6(brs,1H)；Keto tautomer: δ=5.98 (s, 1H), 6.34 (brs, 1H), 10.6 (brs, 1H),
11.2(brs,1H)；13C NMR(100MHz,CDCl3): δ=14.1,22.3,22.4,22.6,22.7,24.8,26.2,26.9,
27.0,29.3,29.5,29.5,29.6,29.6,31.9,38.2,43.6,48.7,49.0,55.1,98.0,103.7,109.1,
114.8,115.0,158.8,162.8,164.1,176.6,203.2,206.9,212.5.HRMS(ESI):calcd for
C32H49O7 +,[M+H+]545.3478,found 545.3476.
14, compound 11n:4-(1-(3-dodecanoyl-2,4,6-trihydroxyphenyl)-3-
methylbutyl)-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(11n).1H
NMR(400MHz,CDCl3): δ=0.86 (m, 9H), 1.16-1.45 (m, 26H), 1.50 (s, 3H), 1.61-1.80 (m, 3H),
2.11 (m, 1H), 3.09 (t, J=7.4Hz, 2H), 4.37 (t, J=7.8Hz, 1H)；further peaks show keto-
enol tautomerism in a ratio of 3:7；Enol tautomer: δ=5.94 (s, 1H), 6.59 (brs, 1H),
10.3(brs,1H),11.6(brs,1H)；Keto tautomer: δ=6.00 (s, 1H), 6.66 (brs, 1H), 10.6 (brs,
1H),11.2(brs,1H)；13C NMR(100MHz,CDCl3): δ=14.1,22.3,22.4,22.6,22.7,24.3,24.8,
26.9,29.4,29.5,29.6,29.6,29.7,29.7,31.9,38.2,43.6,48.7,55.1,97.8,103.5,109.1,
114.8,159.0,162.6,163.9,176.6,203.2,206.9,212.5.HRMS(ESI):calcd for C33H51O7 +,
[M+H+]559.3635,found 559.3630.
15, compound 11o:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-
trihydroxy-3-tetradecanoylphenyl)butyl)cyclohex-4-ene-1,3-dione(11o).1H NMR
(400MHz,CDCl3): δ=0.86 (m, 9H), 1.16-1.45 (m, 30H), 1.50 (s, 3H), 1.61-1.80 (m, 3H),
2.12 (m, 1H), 3.09 (t, J=7.5Hz, 2H), 4.37 (t, J=7.8Hz, 1H)；further peaks show keto-
enol tautomerism in a ratio of 3:7；Enol tautomer: δ=5.91 (s, 1H), 6.23 (brs, 1H),
10.3(brs,1H),11.6(brs,1H)；Keto tautomer: δ=5.97 (s, 1H), 6.22 (brs, 1H) 10.6 (brs,
1H),11.2(brs,1H)；13C NMR(100MHz,CDCl3): δ=14.1,22.3,22.6,22.7,24.2,24.3,26.2,
26.9,27.0,27.9,29.4,29.5,29.6,29.6,29.7,29.7,38.2,38.7,43.6,48.8,55.1,98.0,
109.1,114.8,162.6,164.3,202.9,207.1,212.7.HRMS(ESI):calcd for C35H55O7 +,[M+H+]
587.3948,found 587.3798.
16, compound 11p:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-
trihydroxy-3-palmitoylphenyl)butyl)cyclohex-4-ene-1,3-dione(11p).1H NMR
(400MHz,CDCl3): δ=0.86 (m, 9H), 1.16-1.45 (m, 34H), 1.49 (s, 3H), 1.61-1.80 (m, 3H), 2.10
(m, 1H), 3.09 (t, J=7.5Hz, 2H), 4.37 (t, J=7.8Hz, 1H)；further peaks show keto-enol
tautomerism in a ratio of 3:7；Enol tautomer: δ=5.93 (s, 1H), 6.60 (brs, 1H), 10.4
(brs,1H),11.6(brs,1H)；Keto tautomer: δ=6.00 (s, 1H), 6.50 (brs, 1H) 10.6 (brs, 1H),
11.3(brs,1H)；13C NMR(100MHz,CDCl3): δ=14.1,22.3,22.4,22.6,22.7,24.3,24.8,25.6,
25.7,26.2,26.9,27.0,27.0,27.9,29.4,29.5,29.6,29.6,29.7,29.7,31.9,38.2,38.7,
43.6,48.7,55.1,98.0,109.2,162.8,164.0,176.6,203.2,206.6,212.5.HRMS(ESI):calcd
for C37H59O7 +,[M+H+]615.4261,found 615.4226.
17, compound 11q:4-(1-(3-(cyclobutanecarbonyl)-2,4,6-trihydroxyphenyl)-3-
methylbutyl)-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(11q).1H
NMR(400MHz,CDCl3+CD3OD): δ=0.86 (m, 6H), 1.25-1.45 (m, 13H), 1.60-2.50 (m, 8H), 4.40 (m,
2H), δ=5.82 (s, 1H)；13C NMR(100MHz,CDCl3+CD3: δ=17.5,22.4,22.6,24.6,24.8, OD)
25.3,25.5,27.1,28.9,30.0,31.6,38.4,38.8,46.3,46.5,52.0,54.1,69.7,96.4,111.7,
112.7,157.0,163.2,178.7,207.6,208.0,211.4.HRMS(ESI):calcd for C26H35O7 +,[M+H+]
459.2383,found 459.2393.
18, compound 11r:4-(1-(3-(cyclopentanecarbonyl)-2,4,6-trihydroxyphenyl)-
3-methylbutyl)-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(11r).1H
NMR(400MHz,CDCl3): δ=0.86 (m, 6H), 1.25-1.45 (m, 13H), 1.60-1.95 (m, 10H), 2.12 (m, 1H),
4.08 (m, 1H), 4.38 (t, J=7.5Hz, 1H)；further peaks show keto-enol tautomerism in a
ratio of 3:7；Enol tautomer: δ=5.91 (s, 1H), 6.29 (brs, 1H), 10.4 (brs, 1H), 11.6 (brs,
1H)；Keto tautomer: δ=5.96 (s, 1H), 6.29 (brs, 1H) 10.6 (brs, 1H), 11.3 (brs, 1H)；13C NMR
(100MHz,CDCl3): δ=22.4,22.6,24.3,26.2,26.2,26.9,26.9,29.2,30.2,48.9,50.1,
53.7,55.0,69.9,98.1,109.4,114.8,158.9,163.2,163.9,176.9,204.7,209.6,211.2,
212.4.HRMS(ESI):calcd for C27H37O7 +,[M+H+]473.2578,found 473.2566.
19, compound 11s:4-(1-(3-(cyclohexanecarbonyl)-2,4,6-trihydroxyphenyl)-3-
methylbutyl)-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(11s).1H
NMR(400MHz,CDCl3): δ=0.86 (m, 6H), 1.25-1.45 (m, 19H), 1.78 (m, 3H), 1.95 (m, 2H), 2.12
(m, 1H), 3.6 (m, 1H), 4.37 (t, J=7.5Hz, 1H)；further peaks show keto-enol tautomerism
in a ratio of 3:7；Enol tautomer: δ=5.92 (s, 1H), 6.43 (brs, 1H), 10.4 (brs, 1H), 11.6
(brs,1H)；Keto tautomer: δ=5.97 (s, 1H), 6.43 (brs, 1H) 10.6 (brs, 1H), 11.3 (brs, 1H)；13C
NMR(100MHz,CDCl3): δ=14.1,22.3,22.5,22.7,22.8,24.3,26.1,26.1,26.9,26.9,28.0,
29.2,29.5,29.6,31.6,31.7,38.3,38.7,48.7,49.3,53.6,55.1,98.1,109.2,114.8,
114.9,158.9,163.4,164.0,176.7,203.1,210.1,211.4,212.5.HRMS(ESI):calcd for
C28H39O7 +,[M+H+]487.2696,found 487.2722.
20, compound 11t:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-
trihydroxy-3-(2-phenylacetyl)phenyl)butyl)cyclohex-4-ene-1,3-dione(11t).1H
NMR(400MHz,CDCl3): δ=0.87 (m, 6H), 1.25-1.45 (m, 13H), 1.75 (m, 1H), 2.12 (m, 1H), 4.38
(t, J=7.5Hz, 1H), 4.46 (m, 2H), 7.20-7.50 (m, 5H),；further peaks show keto-enol
tautomerism in a ratio of 3:7；Enol tautomer: δ=5.95 (s, 1H), 6.24 (brs, 1H), 10.2
(brs,1H),11.7(brs,1H)；Keto tautomer: δ=6.00 (s, 1H), 6.24 (brs, 1H), 11.1 (brs, 1H)；13C NMR(100MHz,CDCl3): δ=14.2,22.3,22.8,26.1,26.7,28.0,38.6,40.8,48.8,49.4,
55.1,98.2,103.5,109.3,114.7,125.5,126.8,127.4,128.5,129.9,158.6,162.9,164.9,
176.1,176.8,203.3,203.7,212.4.HRMS(ESI):calcd for C29H35O7 +,[M+H+]495.2383,
found 495.2375.
21, compound 11u:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-
trihydroxy-3-(3-phenylpropanoyl)phenyl)butyl)cyclohex-4-ene-1,3-dione(11u).1H
NMR(400MHz,CDCl3): δ=0.87 (m, 6H), 1.25-1.55 (m, 13H), 1.77 (m, 1H), 2.12 (m, 1H), 3.05
(t, J=7.5Hz, 2H), 3.46 (t, J=7.5Hz, 2H), 4.39 (t, J=7.5Hz, 1H), 7.20-7.35 (m, 5H)；
further peaks show keto-enol tautomerism in a ratio of 3:7；Enol tautomer: δ=
5.94(s,1H),6.24(brs,1H),10.3(brs,1H),11.6(brs,1H)；Keto tautomer: δ=6.00 (s,
1H),6.25(brs,1H)11.1(brs,1H)；13C NMR(100MHz,CDCl3): δ=14.1,18.8,20.7,22.3,
22.6,22.8,24.2,25.3,25.7,26.2,26.9,27.0,27.9,29.1,29.2,29.4,30.6,31.6,34.7,
36.1,38.2,38.6,45.2,48.7,49.4,55.2,98.1,103.5,109.1,114.7,114.9,125.4,126.1,
128.2,128.5,128.5,129.0,141.4,158.7,162.5,164.3,176.6,177.5,203.3,205.3,
212.4.HRMS(ESI):calcd for C10H13O3 +,[M+H+]509.2539,found 509.2557.
Embodiment 2: the anti-MRSA activity rating of compound
The present embodiment will use the minimum inhibitory concentration (MIC) of "diazoresorcinol" determination of color sample anti-MRSA activity.Test
Middle by the 96 orifice plate dilution titer technology of use, measure the minimum inhibitory concentration (MIC) of many kinds of substance simultaneously.First by 7.5mL's
Indicator solution (the "diazoresorcinol" aqueous solutions of 100 μ g/mL) and the bacterium solution (10 to be measured of 5mL8CFU/mL) mixing, and to the 1st to
Each addition 100 μ L mixed bacteria liquids in all instrument connections of the 8th row.Then by the DMSO of 100 μ L testing sample compound 11a-11u
Solution (64 μ g/mL) is added sequentially in each plate hole of first row, and the solution uniformly taking out 100 μ L after mixing transfers to second
Arrange in corresponding plate hole, and be diluted to the 8th row with same method multiplication.Finally, the orifice plate having added sample is put into constant temperature
Incubator, cultivates 10-12h for 37 DEG C.The bacterium solution color that reddens is for without bacteriostatic activity, blue for there being bacteriostatic activity, bacterium solution maintenance blueness
Minimum diluted concentration is considered as the minimum inhibitory concentration of testing compound.
Result is as shown in table 1:
Table 1: the activity (MIC) of In Vitro Anti MRSA Yu SA of compound 11a-11u
Result shows: overwhelming majority compound all has significant anti-MRSA activity.Wherein compound 11i-11n has non-
The most significantly its antibacterial activity, the low 0.25-0.50 μ g/mL that reaches of their MIC value, more mould than antimicrobial drug " last one barrier "
Good 2-4 times of (Vancomycin) 1.0 μ g/mL of element.
Embodiment 3: the anti-SA activity rating of compound
The present embodiment will use the minimum inhibitory concentration (MIC) of "diazoresorcinol" determination of color sample anti-SA activity.In test
96 orifice plate dilution titer technology will be used, measure the minimum inhibitory concentration (MIC) of many kinds of substance simultaneously.First by the finger of 7.5mL
Show the bacterium solution (10 to be measured of agent solution (the "diazoresorcinol" aqueous solutions of 100 μ g/mL) and 5mL8CFU/mL) mixing, and to the 1st to the 8th
Each addition 100 μ L mixed bacteria liquids in all instrument connections of row.Then by DMSO solution (64 μ of 100 μ L testing sample 11a-11u
G/mL) being added sequentially in each plate hole of first row, uniformly taking out the solution of 100 μ L after mixing, to transfer to secondary series corresponding
In plate hole, and it is diluted to the 8th row with same method multiplication.Finally, the orifice plate having added sample is put into constant incubator, 37
DEG C cultivate 10-12h.The bacterium solution color that reddens is for without bacteriostatic activity, and blue for there being bacteriostatic activity, the minimum dilution of bacterium solution maintenance blueness is dense
Degree is considered as the minimum inhibitory concentration of testing compound.
Result is as shown in table 1, and result shows: overwhelming majority compound all has significant anti-SA activity.Compound 11i-
11n has its antibacterial activity of highly significant, and their MIC value is low reaches 0.25-0.50 μ g/mL, than antimicrobial drug " last screen together
Barrier " good 1-2 times of vancomycin (0.5 μ g/mL).
Embodiment 4: the activity rating of the anti-Bacillus cereus of compound
The present embodiment will use the minimum inhibitory concentration of "diazoresorcinol" determination of color sample anti-Bacillus cereus activity
(MIC).Test will use 96 orifice plate dilution titer technology, measure the minimum inhibitory concentration (MIC) of many kinds of substance simultaneously.First
Bacterium solution (10 to be measured by the indicator solution (the "diazoresorcinol" aqueous solutions of 100 μ g/mL) of 7.5mL Yu 5mL8CFU/mL) mixing,
And in all instrument connections of the 1st to the 8th row, respectively add 100 μ L mixed bacteria liquids.Then by 100 μ L testing sample 11i-11p's
DMSO solution (64 μ g/mL) is added sequentially in each plate hole of first row, and the solution uniformly taking out 100 μ L after mixing is transferred to
In the corresponding plate hole of secondary series, and it is diluted to the 8th row with same method multiplication.Finally, the orifice plate having added sample is put into
Constant incubator, cultivates 10-12h for 37 DEG C.The bacterium solution color that reddens is for without bacteriostatic activity, and blue for there being bacteriostatic activity, bacterium solution maintenance is blue
The minimum diluted concentration of color is considered as the minimum inhibitory concentration of testing compound.
Result is as shown in table 2:
The antibacterial activity in vitro (MIC) of table 2 compound 11i-11p
Result shows: compound 11i-11p has the anti-Bacillus cereus activity of highly significant, their MIC value
For 0.13-16 μ g/mL, with antimicrobial drug " last one barrier " vancomycin (0.5 μ g/mL) is suitable.
Embodiment 5: the activity of anti-B.subtilis, B.thuringiensis or Escherichia coli of compound
Evaluate
Anti-B.subtilis, B.thuringiensis or Escherichia coli bacterium activity of compound 11i-11p is commented
Valency method is similar with the anti-Bacillus cereus activity of embodiment 4 with operating process.Its result is as shown in table 2, all chemical combination
Thing demonstrates significant broad spectrum antibiotic activity.
Claims (10)
1. open loop Fructus Rhodomyrti keto analog, shown in its structure such as formula (1):
Wherein R is H, C1-C15Straight chain, side chain or cycloalkyl or aromatic group.
Open loop Fructus Rhodomyrti keto analog the most according to claim 1, it is characterised in that described open loop Fructus Rhodomyrti ketone is seemingly
Thing is the arbitrary compound in formula (2):
Open loop Fructus Rhodomyrti keto analog the most according to claim 2, it is characterised in that described open loop Fructus Rhodomyrti ketone is seemingly
Thing is the arbitrary compound in formula (3):
4. the preparation method of the open loop Fructus Rhodomyrti keto analog described in a claim 1, it is characterised in that its building-up process is such as
Under:
Shown in synthesis flow such as formula (4):
With phloroglucinol and alkyl acyl chloride under the catalysis of methanesulfonic acid or aluminum chloride, obtain formula through friedel-crafts acylation
(4) precursor compound 6 in；Another precursor compound 10 is by making raw material with acetyl group phloroglucinol 6b, in alkalescence condition
Under carry out C-and methylate and obtain compound 7, then compound 7 again through Protic Acid Catalyzed inverse Claisen condensation and
Knoevenagel is condensed to yield compound 10；In the basic conditions, there is Michael addition in precursor compound 6 and compound 10
Reaction, i.e. can get compound 11-open loop Fructus Rhodomyrti keto analog, and wherein R is H, C1-C15Straight chain, side chain or cycloalkyl or virtue
Perfume base group.
5. the arbitrary compound in the open loop Fructus Rhodomyrti keto analog described in claim 1,2 or 3 is in preparation antibacterials
Application.
Application the most according to claim 5, it is characterised in that described antibacterials are anti-Methicillin-
resistant Staphylococcus aureus、Staphylococcus aureus、Bacillus cereus、
The medicine of B.subtilis, B.thuringiensis or Escherichia coli antibacterial.
7. according to the application described in claim 5 or 6, it is characterised in that described antibacterials are bacterial-infection resisting agent or anti-
Control antibacterial infection medicine.
8. antibacterials, it is characterised in that containing in the open loop Fructus Rhodomyrti keto analog described in claim 1,2 or 3
Arbitrary compound is as active ingredient, and pharmaceutically acceptable carrier.
Antibacterials the most according to claim 8, it is characterised in that described antibacterials are anti-Methicillin-
resistant Staphylococcus aureus(MRSA)、Staphylococcus aureus、Bacillus cereus、
The medicine of B.subtilis, B.thuringiensis or Escherichia coli antibacterial.
Antibacterials the most according to claim 8 or claim 9, it is characterised in that described antibacterials are bacterial-infection resisting agent
Or preventing and treating antibacterial infection medicine.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107501287A (en) * | 2017-08-22 | 2017-12-22 | 中国科学院华南植物园 | Myrtuco mmulone J and Myrtucommuacetalone and the like preparation method |
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| CN110724043B (en) * | 2019-10-09 | 2023-09-05 | 中国科学院华南植物园 | Synthesis method of antimalarial drug watsonines A |
| CN110878015A (en) * | 2019-12-06 | 2020-03-13 | 云南师范大学 | Phloroglucinol analogue and preparation method and application thereof |
| CN110878015B (en) * | 2019-12-06 | 2023-07-07 | 云南师范大学 | Phloroglucinol analogue and preparation method and application thereof |
| CN113929570A (en) * | 2021-11-02 | 2022-01-14 | 湖南中嘉生物医药有限公司 | Myrtle ketone derivative and preparation method and application thereof |
| CN113929570B (en) * | 2021-11-02 | 2024-01-30 | 湖南中嘉生物医药有限公司 | Myrtle derivative and preparation method and application thereof |
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