CN105566149B - Chalcone cationic antimicrobial peptide simulant with antimicrobial activity and preparation method thereof - Google Patents

Chalcone cationic antimicrobial peptide simulant with antimicrobial activity and preparation method thereof Download PDF

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CN105566149B
CN105566149B CN201610126211.9A CN201610126211A CN105566149B CN 105566149 B CN105566149 B CN 105566149B CN 201610126211 A CN201610126211 A CN 201610126211A CN 105566149 B CN105566149 B CN 105566149B
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chalcone
preparation
solvent
antimicrobial peptide
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CN105566149A (en
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张恩
秦上尚
徐帅民
王铭铭
赵娣
白鹏燕
周萌萌
王平
王上
王亚娜
崔得运
化永刚
刘宏民
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Zhengzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—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
    • 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
    • C07C45/68—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 by increase in the number of carbon atoms
    • C07C45/72—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 by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/74—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 by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to the field of medicinal chemistry, and discloses a chalcone cationic antimicrobial peptide simulant with antimicrobial activity and a preparation method thereof. A target product is obtained simply and quickly through four steps of reaction, and the main structure is shown as formula I. An in vitro antimicrobial activity test proves that most of the series of compounds show good antibacterial effects on staphylococcus aureus and escherichia coli, and part of compounds also show excellent antimicrobial activity on superbacteria including methicillin-resistant staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and carbapenemases enterobacteriaceae (CRE). An in vitro erythrocyte toxicity test also shows that the series of compounds have less erythrocyte toxicity, and therefore, the series of compounds are expected to be used as a novel candidate antimicrobial drug. The formula I is shown in the description.

Description

Chalcone cationic antimicrobial peptide mimics with antibacterial activity and preparation method thereof
Technical field
The invention belongs to field of pharmaceutical chemistry technology, the chalcone cationic antibacterial peptide simulation with antibacterial activity is disclosed Thing and preparation method thereof.
Background technology
Antibacterial peptide is the class peptide material being widely present in nature biotechnology, used as the 1st road defence line of living organism Antiviral infringement can be supported, antibacterial peptide has the multiple biological activities such as antibacterium, fungi, virus, cancer inhibitting and killing cell, and not It is also easy to produce the resistance to the action of a drug.With the appearance of increasing antibiotics resistance microorganism so that antibacterial peptide is in pharmaceuticals industry and food There is good application prospect in the fields such as additive, and these characteristics make antibacterial peptide most be hopeful to replace conventional antibiotic.Therefore, synthesize Do not allow the antibacterial peptide compounds for being also easy to produce drug resistance extremely urgent again with preferable antibacterial activity.
Antibacterial peptide is different from its particular mechanism of conventional antibiotic, it is not likely to produce drug resistance, is a great latent class The peptide antibiotics of power.The antibacterial activity of natural antibacterial peptide is fine, but with hemolytic, to solve this shortcoming, medicine Scholar has synthesized a series of antibacterial peptide mimics, and the antibacterial activity of these analogies is fine, to mammalian cell hemolytic It is smaller.Bacterial drug resistance is continuously increased, therefore, synthesize the antibacterial for acting on bacterial cell of the selectivity in mammalian cell Medicine is particularly significant.Because the cell membrane of bacterium is negatively charged, as the target of antimicrobial, design synthesize a series of sun from Sub- antibacterial peptide mimics, is proved to preferable antibacterial activity.Wherein, antibacterial peptide mimics polymeric coatings can be used to anti-thin Bacterium and fungi, make bacterium and fungi almost complete deactivation.In the most common cationic antimicrobial medicine for using, with quaternary ammonium group Cationic polymer have preferable application prospect in terms of antibiotic paint.
According to the literature, chalcone has antibacterial activity, the α in its structure, the parent in beta-unsaturated carbonyl and bacterium Sulfydryl in core group, such as protein carries out conjugate addition and causes bacterial death.Tomar et al. has synthesized with piperazine and 2, The chalcone analog of two series of 5- dichloro-thiophene cores, their MIC to all of strain subject50Value is in 2.22-100 μ In the range of g/mL (bibliography Bioorganic＆Medicinal Chemistry Letters 2007,17,5321-5324). Kromann et al. has synthesized a series of chalcone derivative that side chains are amido, and its MIC to MRSA is 2 μM of (bibliography Journal of Medicinal Chemistry 2005,48,2667-2677).The antibacterial activity of these chalcone derivatives Cause the concern of author, the antibacterial activity almost all of data display these compounds is stronger than the control group property of medicine.This also indicates that this Analog derivative is likely to turn into new antibacterials substitute.
The content of the invention
It is an object of the invention to provide a series of new chalcone cationic antibacterial peptide simulation of has a broad antifungal spectrum, small toxicity Thing, is conducive to new antimicrobial agent to research and develop.Another object is to provide its preparation method.
To realize the object of the invention, technical scheme is as follows：
The compound has following general structure I or II：
R is C6-14 alkyl.It is preferred that C6-14 alkyls.Specifically select following compound：
(1)6a：R=n-hexanes；
(2)6b：R=normal heptanes；
(3)6c：R=normal octanes；
(4)6d：R=n -nonanes；
(5)6e：R=positive flow silanes；
(6)6f：R=n-undecanes；
(7)6g：R=n-dodecanes
(8)6h：R=n-tetradecanes；
X be halogen, nitro, methoxyl group or hydroxyl, it is monosubstituted or disubstituted on phenyl ring.Specifically select following compound：
(9)6i：X=2-Br
(10)6j：X=3-Br
(11)6k：X=4-Br
(12)6l：X=3-NO2
(13)6m：X=4-NO2
(14)6n：X=3-OH
(15)6o：X=4-F
(16)6p：X=4-OCH3
(17)6q：X=4-Cl
(18)6r：X=3,4-Cl
Further relate to following compound：
Synthesis subject cationic antibacterial peptide mimics (6a-6t) route is as follows：
(a)：NaOH/EtOH, RT. (b)：RNH2, NaBH (OAc)3In1,2-Dichloroethane over nkight, RT.(c)：Boc-Lys (Boc)-OH, DIPEA, HBTU in DMF/CHCl3(5: 2), RT, 24h (d)：CH3COCl in CH3OH, 0 DEG C of-RT, 24h
Realized especially by following steps：
A in (), solvent there is aldol reaction and obtain compound in compound 1 and compound 2 under the catalytic action of alkali 3；Alkali used is NaOH, potassium hydroxide, the one kind in lithium hydroxide, potassium carbonate, saleratus, sodium phosphate, dibastic sodium phosphate； Solvent for use is one of methyl alcohol, ethanol, acetone, N,N-dimethylformamide, acetonitrile, isopropyl alcohol and water or wherein any two Kind or three kinds of mixture；
B with C6-14 alkylamines in the presence of reducing agent, nitrogen protection is reduced compound 3 at room temperature in (), solvent Aminating reaction obtains compound 4；Reducing agent used is sodium triacetoxy borohydride, sodium borohydride, in sodium cyanoborohydride It is a kind of；Solvent for use is one kind or any two or three of mixture in dichloromethane, chloroform, 1,2- dichloroethanes；
C (), in mixed solvent, the lysine that compound 4 is protected with double Boc reacts generation under catalysts conditions Compound 5；Used catalyst is O- BTAs-tetramethylurea hexafluorophosphoric acid ester (HBTU), dicyclohexylcarbodiimide (DCC), methane sulfonyl chloride (MSCl), paratoluensulfonyl chloride (TsCl), 4-Nitrobenzenesulfonyl chloride (NsCl), diisopropyl carbon two are sub- One kind or any two or three of mixing in amine (DIC), 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides (EDCI) Thing；Mixed solvent used is N,N-dimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane, chloroform, 1,2, and-dichloromethane is appointed Two kinds of mixed solvents of meaning；
D in (), solvent, compound 5 sloughs Boc protection groups under catalyst action and obtains target compound, catalysis used Agent is the one kind in chloroacetic chloride, dry hydrogen chloride its gas, and solvent for use is methyl alcohol, ethanol, propyl alcohol, isopropanol, n-butanol It is a kind of.
The present invention simply, quickly obtains target product, gained novel cation antibacterial peptide mimics pair by four-step reaction Gram-positive staphylococcus aureus type strain ATCC 29213 and enterococcus faecalis ATCC29212 and gram-negative The bacteriostasis that EHEC type strain ATCC 25922 and pseudomonas aeruginosa type strain ATCC 27853 do very well, greatly The minimum inhibitory concentration (minimum inhibitory concentration, MIC) of part of compounds can reach 1~8 μ g/ ML, and majority of compounds is simultaneously to the CRE performances of MRSA, VRE and product NDM-1 types metalloenzyme and KPC type serinases Go out and the equal even better fungistatic effect of sensitive strain.Fungistatic effect and positive control medicine of the majority of compounds to positive bacteria Linezolid is quite or more preferably；Compound 6c~6f, 6i~6j, 6o~6r is to staphylococcus aureus type strain ATCC 29213 show the fungistatic effect (1~2 μ g/mL) equal with positive control drug vancomycin, and compound 6d, 6e, 6o couple Gram-negative bacteria Escherichia coli (25922) show the fungistatic effect (2 μ g/mL) equal with positive control drug polymyxins, Compound 6c~6f, 6i~6q, 6s (4~8 μ g/mL) shows and positive control drug Meropenem (8 μ to pseudomonas aeruginosa G/mL) equal even preferably fungistatic effect.Erythrocyte in vitro toxicity test HC50Result shows that the series compound is presented to red The less toxicity of cell.A series of chalcone cation simulating peptide simulation of has a broad antifungal spectrum, hypotoxicity that therefore the present invention is provided Thing, is expected to carry out in-depth study as new antibacterial drug candidate, and it is increasingly serious to face drug-fast bacteria to the current whole world of solution Problem it is significant.
Specific embodiment
With reference to specific embodiment, the present invention is expanded on further.These embodiments be merely to illustrate the present invention and without In limitation the scope of protection of present invention.
The instrument that synthesis characterization of compound is used：H NMR spectroscopy uses Sweden's Bruker DPX-400 type NMR spectrometer with superconducting magnet Determine, TMS is internal standard；High resolution mass spectrum is determined using Waters-Micromass companies Q-Tof mass spectrographs.
The preparation of the compound 6a of embodiment 1
(1) double Boc protect the preparation of 1B：
Take 1B (5g, 34.2mmol) and NaOH (4.1g, 102.61mmol) added in 250mL single port bottles, 100mL water is added, is stirred under ice-water bath, system is clarified into sundown；By di-tert-butyl dicarbonate (Boc2O) (17.92g, 82.09mmol) it is dissolved in 50mL tetrahydrofuran solutions, (1d/s) is then added dropwise and enters reaction system；After completion of dropping, system is turned To enter continue at room temperature and react 24 hours.Stop reaction after the reaction time, vacuum rotary steam removes system tetrahydrofuran, then system Organic impurities in (50ml × 2) removing system is washed with ether；Then 1M sulfuric acid solution regulation system pH to 4 are used, dichloro is then used Methane extracts (50mL × 3), merges organic phase, and saturated sodium-chloride washes (50mL × 1), finally with anhydrous sodium sulfate drying, suction filtration, Concentration, vacuum drying obtain yellow foamy solid 7.5g, yield 63%.
(2) preparation of compound 6a
NaOH (832mg, 20.8mmol) is taken in 500mL single necked round bottom flask, adds 100mL hydroecium temperature magnetic force to stir Mix lower dissolving；Then by compound 1 (acetophenone) (2.00g, 16.6mmol) and compound 2 (terephthalaldehyde) (2.28g, 17.0mmol) add in 250mL conical flasks, add 100mL EtOH Sonicates to the system to clarify substantially, then by the settled solution Constant pressure dropping (1d/s) is arrived in the single port bottle of above-mentioned agitated sodium hydroxide solution, continues to react at room temperature after completion of dropping, Now system milky is muddy.After about 6h, TLC detections (PE：EA=1:1) display reaction is complete.Stop reaction, by reaction system Pour into about 50mL frozen water, a large amount of yellow solids are separated out immediately, suction filtration, filter cake is washed to neutrality, be vacuum dried, obtain yellow and consolidate Body compound 3 (3.59g), yield is 91%.
Take above-claimed cpd 3 (250mg, 1.06mmol) and sodium triacetoxy borohydride (292mg, 1.38mmol) in In 25mL single necked round bottom flask；5mL1 is subsequently adding, 2- dichloroethanes is eventually adding n-hexylamine (182 μ l, 1.38mmol), nitrogen It is stirred at room temperature under gas shielded；After being stirred overnight, next day TLC (PE：EA=1:2) detect, display reaction is complete, saturated sodium bicarbonate It is quenched and reacts and adjust pH to 8~9.Then system dichloromethane extraction is washed (15mL × 3), merges organic phase, organic phase water Wash (15mL × 1), final saturation sodium chloride solution is washed (15mL × 1), final organic phase anhydrous sodium sulfate drying, suction filtration, Concentration.Column chromatography (PE：EA=3:1,0.5% triethylamine) purifying obtain midbody compound 4, yield is about 58%.
The 1B (202mg, 0.583mmol) for taking double Boc protections adds 25mL single port bottles, is subsequently adding 5mL DMF/ 2mLCHCl3(5:2) stirred under ice-water bath, then add DIPEA (244 μ L, 1.4mmol) and HBTU (221mg, 0.583mmol), compound 4 (150mg, 0.467mmol) is added after being stirred 5 minutes under the mixed system ice-water bath, Then proceed to stir under ice-water bath be transferred to after half an hour and react 24 hours at room temperature.After the reaction time, TLC (PE：PA=1: 1) monitoring reaction, display raw material does not exist.Then the chloroform in system is boiled off, 15mL ethyl acetate is added afterwards；The body System is washed (10mL × 3) with 0.5M potassium hydrogen sulfate solutions, merges organic phase, and washing (10mL × 3), saturated nacl aqueous solution are washed (10mL × 1), final organic phase anhydrous sodium sulfate drying, filtering, concentration.Column chromatography (PE：EA=3:1) purifying obtains centre Body oily compound 5, yield about 85%.
Compound 5 (200mg, 0.308mmol) is dissolved in 5mL methyl alcohol, is stirred under turned welt rubber stopper ice-water bath beyond the Great Wall, so Syringe finishes rear system and to be transferred to continue at room temperature and react 24 to chloroacetic chloride (132 μ L, 1.85mmol) is added in above-mentioned system afterwards Hour.After reaction time arrives, TLC (PE：EA=1:1) monitoring reaction, display compound 5 does not exist, and stops reaction, and concentration is evaporated Solvent in system.System is vacuumized and obtains yellow foamy solid by vacuum diaphragm pump, suitable to being added in the bottle equipped with solid Amount absolute ether, scrapes solid cleaning, suction filtration, vacuum drying and obtains yellow solid target compound 6a, yield 89%.
Product is yellow solid, and yield is 89%.
1H NMR(400MHz,D2O) δ 7.69 (dd, J=11.9,8.0Hz, 2H), 7.49-7.39 (m, 2H), 7.39-7.22 (m, 5H), 7.08 (dd, J=19.0,7.8Hz, 2H), 4.55-4.23 (m, 3H), 3.24-3.00 (m, 2H), 2.96-2.71 (m, 3H), 1.86-1.66 (m, 2H), 1.65-1.42 (m, 2H), 1.34 (dd, J=15.0,7.6Hz, 4H), 1.08-0.87 (m, 6H),0.67–0.52(m,3H).
13C NMR(101MHz,D2O)δ193.05,169.45,169.27,145.30,139.76,138.63,137.07, 133.68,133.48,129.23,128.98,128.80,128.53,128.07,127.59,121.77,91.65,50.79, 50.62,49.29,48.25,38.96,38.89,30.68,30.65,30.15,27.90,26.44,26.38,25.82, 25.53,21.92,21.85,21.20,21.02,13.37.
HR-MS(ESI)Calcd for C28H39N3O2[M+H]+:450.3121,found:450.3125.
The preparation of the compound 6b of embodiment 2
Amine used is positive heptyl amice in step 2, and preparation method is with embodiment 1.
Product is faint yellow solid, and yield is 87%.
1H NMR(400MHz,D2O) δ 7.68 (dd, J=12.7,8.1Hz, 2H), 7.47-7.17 (m, 7H), 7.12 (d, J =7.8Hz, 1H), 7.04 (d, J=7.5Hz, 1H), 4.39 (dd, J=22.6,12.6Hz, 3H), 3.26-2.76 (m, 5H), 1.79 (d, J=26.8Hz, 2H), 1.70-1.48 (m, 2H), 1.48-1.16 (m, 4H), 0.90 (d, J=43.6Hz, 9H), 0.47 (dd, J=18.5,6.9Hz, 3H)
13C NMR(101MHz,D2O)δ192.14,169.54,169.23,145.05,139.81,137.19,133.50, 129.18,128.94,128.71,128.46,128.19,127.85,121.60,50.68,49.42,48.21,38.98, 31.09,30.92,30.18,28.14,26.48,26.41,26.22,25.82,22.05,21.24,21.11,13.57.
HR-MS(ESI)Calcd for C29H41N3O2[M+H]+:464.3272,found:464.3208.
The preparation of the compound 6c of embodiment 3
Amine used is n-octyl amine in step 2, and preparation method is with embodiment 1.
Product is yellow solid, and yield is 85.3%.
1H NMR(400MHz,D2O) δ 7.49 (dd, J=11.3,7.9Hz, 2H), 7.27-7.10 (m, 2H), 7.06 (d, J =7.6Hz, 2H), 7.02-6.86 (m, 4H), 6.83 (d, J=8.0Hz, 1H), 4.40-4.04 (m, 3H), 3.05 (s, 1H), 2.80-2.59 (m, 4H), 1.73-1.52 (m, 2H), 1.49-1.32 (m, 2H), 1.21 (s, 2H), 0.94 (ddd, J=41.7, 12.4,5.2Hz, 2H), 0.69 (s, 1H), 0.49 (d, J=8.7Hz, 10H), 0.17 (dt, J=9.9,7.0Hz, 3H)
13C NMR(101MHz,D2O)δ191.11,190.38,169.78,169.30,144.53,139.91,138.62, 137.55,137.44,134.05,133.58,129.16,128.89,128.68,128.50,128.28,121.80,121.35, 50.99,49.50,48.08,46.64,42.71,42.63,39.09,39.04,31.45,30.35,30.19,28.84, 28.52,27.98,26.58,26.50,26.01,22.34,22.31,21.37,21.30,13.82,13.79.
HR-MS(ESI)Calcd for C30H43N3O2[M+H]+:478.3434,found:478.3431.
The preparation of the compound 6d of embodiment 4
Amine used is positive nonyl amine in step 2, and preparation method is with embodiment 1.
Product is yellow solid, and yield is 75.3%.
1H NMR(400MHz,D2O) δ 7.49 (dd, J=12.9,7.8Hz, 2H), 7.30-6.89 (m, 8H), 6.83 (d, J =7.8Hz, 1H), 4.42-4.06 (m, 3H), 3.06-2.56 (m, 5H), 1.61 (dd, J=17.7,8.8Hz, 2H), 1.37 (dd, J=16.7,9.1Hz, 2H), 1.29-1.08 (m, 3H), 0.95 (d, J=15.9Hz, 3H), 0.57 (dd, J=77.6, 17.9Hz, 13H), 0.15 (dd, J=14.6,7.2Hz, 3H)
13C NMR(101MHz,D2O)δ190.61,169.64,169.25,144.63,139.85,137.31,133.98, 133.52,129.16,128.87,128.69,128.54,128.39,128.06,121.71,50.95,39.01,38.95, 31.55,30.22,29.16,28.99,28.77,28.58,26.55,26.44,25.94,22.34,21.28,13.76, 13.72.
HR-MS(ESI)Calcd for C31H45N3O2[M+H]+:492.3590,found:492.3592.
The preparation of the compound 6e of embodiment 5
Amine used is n-Decylamine in step 2, and preparation method is with embodiment 1.
Product is yellow solid, and yield is 91.6%.
1H NMR(400MHz,D2O) δ 7.49 (t, J=9.1Hz, 2H), 7.25-6.89 (m, 9H), 6.82 (d, J= 7.5Hz, 1H), 4.41-4.08 (m, 3H), 2.72 (ddd, J=55.9,46.6,25.2Hz, 5H), 1.58 (d, J=25.0Hz, 2H), (m, the 3H) of 1.48-1.27 (m, 2H), 1.28-0.80 (m, 6H), 0.60 (d, J=101.5Hz, 16H), 0.27-0.11
13C NMR(101MHz,D2O)δ169.67,169.33,137.47,134.23,128.51,125.01,39.00, 38.94,31.65,29.35,29.15,28.90,28.66,26.55,26.42,22.37,21.32,17.29,13.76, 13.72.
HR-MS(ESI)Calcd for C32H47N3O2[M+H]+:506.3747,found:506.3742.
The preparation of the compound 6f of embodiment 6
Amine used is positive undecylamine in step 2, and preparation method is with embodiment 1.
Product is yellow solid, and yield is 84%.
1H NMR(400MHz,D2O) δ 7.74 (t, J=7.5Hz, 2H), 7.49-7.15 (m, 8H), 7.06 (d, J= 7.6Hz, 1H), 4.66-4.28 (m, 3H), 3.33-2.76 (m, 5H), 1.82 (d, J=29.3Hz, 2H), 1.70-1.48 (m, 2H), (d, J=5.9Hz, the 3H) of 1.41 (d, J=7.0Hz, 5H), 0.73 (d, J=9.3Hz, 18H), 0.44
13C NMR(101MHz,D2O)δ191.22,169.66,169.35,144.59,143.58,139.80,138.65, 137.50,137.38,135.57,133.99,129.19,128.66,128.52,127.97,121.68,67.36,50.98, 49.94,39.01,38.94,31.70,30.21,29.57,29.52,29.32,29.26,28.97,28.76,27.87, 26.73,26.56,26.42,23.14,22.42,21.34,21.22,14.77,13.74,13.71.
HR-MS(ESI)Calcd for C33H49N3O2[M+H]+:520.3903,found:520.3901.
The preparation of the compound 6g of embodiment 7
Amine used is n-dodecylamine in step 2, and preparation method is with embodiment 1.
Product is yellow solid, and yield is 90.3%.
1H NMR(400MHz,D2O) δ 7.76 (d, J=7.4Hz, 2H), 7.49-7.40 (m, 2H), 7.39-7.12 (m, 6H), 7.06 (d, J=7.8Hz, 1H), 4.71 (s, 18H), 4.60-4.29 (m, 3H), 3.08 (d, J=14.3Hz, 1H), 2.88 (dt, J=21.0,7.4Hz, 2H), 1.81 (d, J=32.5Hz, 2H), 1.58 (d, J=27.1Hz, 2H), 1.41 (d, J= 7.2Hz, 3H), 1.16 (dd, J=16.3,6.9Hz, 1H), 0.83 (dd, J=51.2,45.0Hz, 18H), 0.59-0.44 (m, 3H).
13C NMR(101MHz,D2O)δ169.37,142.10,138.67,137.44,134.00,128.52,125.00, 51.00,38.97,31.80,29.69,29.33,26.43,22.48,21.37,13.79,13.74.
HR-MS(ESI)Calcd for C34H51N3O2[M+H]+:534.4060,found:534.4063.
The preparation of the compound 6h of embodiment 8
Amine used is positive tetradecy lamine in step 2, and preparation method is with embodiment 1.
Product is yellow solid, and yield is 88.7%.
1H NMR(400MHz,D2O) δ 7.75 (d, J=7.1Hz, 1H), 7.24 (ddd, J=61.6,44.6,30.4Hz, 5H), (d, J=64.7Hz, the 17H) of 3.18-2.66 (m, 3H), 1.85-1.23 (m, 5H), 0.67
13C NMR(101MHz,D2O)δ169.55,136.78,133.72,132.04,128.52,124.27,121.25, 50.95,38.95,31.85,29.76,29.39,26.41,22.52,13.74.
HR-MS(ESI)Calcd for C36H55N3O2[M+H]+:562.4373,found:562.4371.
The preparation of the compound 6i of embodiment 9
Compound 1 is 2- bromoacetophenones, and amine is positive nonyl amine in step 2, and preparation method is with embodiment 1.
Product is yellow solid, and yield is 89.5%.
1H NMR(400MHz,D2O)δ7.35–7.23(m,3H),7.24–7.00(m,7H),6.91–6.73(m,1H), 4.60-4.30 (m, 3H), 3.32-2.67 (m, 5H), 1.92-1.67 (m, 2H), 1.66-1.49 (m, 3H), 1.21 (dd, J= 64.8,43.0Hz, 6H), 0.82 (d, J=31.8Hz, 14H), 0.49 (t, J=6.9Hz, 3H)
13C NMR(101MHz,D2O)δ195.82,169.66,146.10,140.42,133.05,118.97,50.78, 39.00,38.93,31.64,30.23,29.02,28.65,26.53,22.47,21.26,13.99.
HR-MS(ESI)Calcd for C31H44BrN3O2[M+H]+:570.2695,found:570.2692.
The preparation of the compound 6j of embodiment 10
Compound 1 is 3- bromoacetophenones, and amine is positive nonyl amine in step 2, and preparation method is with embodiment 1.
Product is yellow solid, and yield is 89.2%.
1H NMR(400MHz,D2O) δ 7.30 (t, J=7.6Hz, 2H), 7.13 (d, J=8.2Hz, 2H), 7.08-6.87 (m, 5H), 6.80 (d, J=6.3Hz, 1H), 4.42-3.93 (m, 3H), 2.62 (dt, J=15.0,7.0Hz, 4H), 1.57 (s, 2H),1.44–1.22(m,2H),1.14(s,2H),0.97(s,2H),0.72–0.31(m,13H),0.25–0.08(m,3H).
13C NMR(101MHz,D2O)δ188.74,169.63,169.10,144.83,140.09,131.70,129.95, 125.00,50.71,38.94,31.60,29.09,28.80,28.59,26.50,22.47,21.18,13.94.
HR-MS(ESI)Calcd for C31H44BrN3O2[M+H]+:570.2695,found:570.2697.
The preparation of the compound 6k of embodiment 11
Compound 1 is 4- bromoacetophenones, and amine is positive nonyl amine in step 2, and preparation method is with embodiment 1.
Product is yellow solid, and yield is 90.8%,
1H NMR(400MHz,D2O) δ 7.51 (d, J=7.5Hz, 1H), 7.43 (s, 1H), 7.22-6.93 (m, 5H), 6.93-6.74 (m, 3H), 4.22 (d, J=30.4Hz, 3H), 3.05-2.33 (m, 5H), 1.55 (s, 2H), 1.42-1.23 (m, 2H),1.13(s,2H),0.97(s,2H),0.71–0.33(m,13H),0.16(s,3H).
13C NMR(101MHz,D2O)δ169.59,169.02,157.94,140.07,139.30,138.78,135.31, 133.09,129.00,122.60,80.38,50.69,38.93,38.87,31.57,29.04,28.56,26.49,25.91, 22.46,21.26,13.95.
HR-MS(ESI)Calcd for C31H44BrN3O2[M+H]+:570.2695,found:570.2697.
The preparation of the compound 6l of embodiment 12
Compound 1 is 3- nitro-acetophenones, and amine is positive nonyl amine in step 2, and preparation method is with embodiment 1.
Product is yellow solid, and yield is 85.4%.
1H NMR(400MHz,D2O) δ 7.94 (d, J=113.1Hz, 3H), 7.50-6.60 (m, 6H), 4.25 (s, 2H), 3.57-3.36 (m, 1H), 3.25 (ddd, J=18.2,11.7,5.4Hz, 1H), 2.73 (d, J=72.4Hz, 3H), 1.46 (d, J =84.3Hz, 4H), 1.17-0.79 (m, 8H), 0.45 (s, 10H), 0.09 (s, 3H)
13C NMR(101MHz,D2O)δ216.52,184.81,175.12,140.10,128.02,122.22,72.02, 70.27,62.44,43.14,28.96,27.96,22.30,19.11,13.64,6.32.
HR-MS(ESI)Calcd for C31H44N4O4[M+H]+:537.3441,found:537.3444.
The preparation of the compound 6m of embodiment 13
Compound 1 is 4- nitro-acetophenones, and amine is positive nonyl amine in step 2, and preparation method is with embodiment 1.
Product is yellow solid, and yield is 87.7%.
1H NMR(400MHz,D2O) δ 7.86 (d, J=22.0Hz, 4H), 7.26 (dd, J=97.0,41.2Hz, 6H), 4.53(s,3H),3.42–2.72(m,4H),2.12–0.91(m,11H),0.66(s,11H),0.29(s,3H).
13C NMR(101MHz,D2O)δ149.52,149.21,129.49,127.34,123.51,109.53,39.06, 31.53,28.98,27.91,26.45,25.20,22.31,21.31,13.62.
HR-MS(ESI)Calcd for C31H44N4O4[M+H]+:537.3441,found:537.3445.
The preparation of the compound 6n of embodiment 14
Compound 1 is 3- hydroxy acetophenones, and amine is positive nonyl amine in step 2, and preparation method is with embodiment 1.
Product is yellow solid, and yield is 86%.
1H NMR(400MHz,D2O) δ 7.28 (dd, J=40.2,21.3Hz, 5H), 7.16-6.83 (m, 4H), 4.41 (d, J =46.0Hz, 3H), 4.22-3.95 (m, 2H), 3.25-2.72 (m, 8H), 1.89 (dtd, J=20.5,14.3,7.4Hz, 4H), 1.65–1.05(m,18H),0.72(s,13H),0.49–0.25(m,3H).
13C NMR(101MHz,D2O)δ170.51,53.53,52.57,38.95,31.58,29.20,27.64,26.22, 22.35,21.42,13.73.
HR-MS(ESI)Calcd for C31H45N3O3[M+H]+:508.3539,found:508.3537.
The preparation of the compound 6o of embodiment 15
Compound 1 is 4- fluoro acetophenones, and amine is positive nonyl amine in step 2, and preparation method is with embodiment 1.
Product is yellow solid, and yield is 84%.
1H NMR(400MHz,D2O) δ 7.80-7.59 (m, 2H), 7.42-7.17 (m, 4H), 7.06 (dd, J=43.5, 7.3Hz, 2H), 6.77 (dt, J=29.3,8.0Hz, 2H), 4.63-4.15 (m, 3H), 3.33-2.46 (m, 5H), 1.76 (d, J =23.9Hz, 2H), 1.69-1.44 (m, 3H), 1.35 (s, 2H), 1.26-0.99 (m, 4H), 0.73 (d, J=100.0Hz, 13H), 0.29 (d, J=4.9Hz, 3H)
13C NMR(101MHz,D2O)δ189.33,170.88,169.62,169.19,168.07,163.99,155.20, 144.66,133.87,131.00,129.13,125.00,115.40,50.86,38.93,38.86,31.49,30.15, 28.96,28.74,28.55,27.83,26.48,26.36,22.28,21.21,13.62,13.57.
HR-MS(ESI)Calcd for C31H44FN3O2[M+H]+:510.3496,found:510.3495.
Implementation is grinned the preparation of 16 compound 6p
Compound 1 is 4- methoxyacetophenones, and amine is positive nonyl amine in step 2, and preparation method is with embodiment 1.
Product is yellow solid, and yield is 87.5%.
1H NMR(400MHz,D2O)δ7.86–7.49(m,2H),7.51–7.24(m,3H),7.21–6.96(m,2H), 6.67 (dd, J=20.8,8.4Hz, 2H), 4.42 (d, J=31.9Hz, 2H), 3.60-3.40 (m, 4H), 2.87 (dd, J= 16.9,9.0Hz, 4H), 1.84 (d, J=47.0Hz, 1H), 1.56 (d, J=7.1Hz, 2H), 1.51-1.01 (m, 10H), 0.73 (s, 12H), 0.42 (d, J=4.8Hz, 3H)
13C NMR(101MHz,D2O)δ72.03,62.44,55.36,39.00,31.61,29.02,27.93,26.54, 22.38,13.75.
HR-MS(ESI)Calcd for C31H47N3O3[M+H]+:522.3696,found:522.3698
The preparation of the compound 6q of embodiment 17
Compound 1 is 4- chloro-acetophenones, and amine is positive nonyl amine in step 2, and preparation method is with embodiment 1.
Product is yellow solid, and yield is 88%.
1H NMR(400MHz,CDCl3) δ 10.16 (dd, J=12.3,8.4Hz, 2H), 9.94 (t, J=13.6Hz, 2H), 9.81 (t, J=13.5Hz, 2H), 9.75-9.68 (m, 1H), 9.66-9.55 (m, 3H), 7.24 (s, 29H), 7.12-6.77 (m, 3H), 5.86-5.26 (m, 5H), 4.34 (d, J=16.7Hz, 2H), 4.12 (dd, J=15.0,7.3Hz, 2H), 3.93 (s, 2H), (t, J=6.8Hz, the 3H) of 3.67 (ddd, J=24.9,13.0,5.4Hz, 3H), 3.48-3.14 (m, 13H), 2.93
13C NMR(101MHz,CDCl3)δ138.34,135.84,132.45,132.42,132.39,131.75, 131.22,131.16,129.08,41.53,34.12,31.58,31.14,29.07,24.96,23.77,16.34.
HR-MS(ESI)Calcd for C31H44ClN3O2[M+H]+:526.3200,found:526.3195.
The preparation of the compound 6r of embodiment 18
Compound 1 is 3,4- dichloroacetophenones, and amine is positive nonyl amine in step 2, and preparation method is with embodiment 1.
Product is yellow solid, and yield is 90%.
1H NMR(400MHz,D2O)δ7.41(s,1H),7.29(s,1H),7.10(s,2H),7.06–6.83(m,4H), 6.76 (s, 1H), 4.39-3.87 (m, 3H), 2.98-2.38 (m, 4H), 1.54 (s, 2H), 1.29 (d, J=26.0Hz, 2H), (d, J=4.9Hz, the 3H) of 1.13 (s, 2H), 0.84 (t, J=28.5Hz, 3H), 0.71-0.26 (m, 12H), 0.15
13C NMR(101MHz,D2O)δ169.61,145.46,138.85,137.00,136.97,132.67,128.40, 38.87,31.57,29.05,28.58,26.49,22.44,21.15,13.85.
HR-MS(ESI)Calcd for C31H43Cl2N3O2[M+H]+:560.2811,found:560.2811.
The preparation of the compound 6s of embodiment 19
Compound 1 is 1- acetyl group naphthalenes, and amine is positive nonyl amine in step 2, and preparation method is with embodiment 1.
Product is yellow solid, and yield is 83%.
1H NMR(400MHz,D2O) δ 8.00 (dd, J=24.9,7.9Hz, 1H), 7.54-7.25 (m, 3H), 7.24-6.72 (m, 10H), 4.35 (t, J=46.3Hz, 3H), 3.13-2.55 (m, 5H), 1.76 (s, 2H), 1.53 (d, J=6.8Hz, 3H), 1.33 (d, J=17.0Hz, 2H), 1.19-0.96 (m, 5H), 0.65 (d, J=29.6Hz, 13H), 0.34 (d, J=6.2Hz, 3H).
13C NMR(101MHz,D2O)δ134.11,133.49,100.00,38.97,31.46,28.89,27.83, 26.41,22.33,21.24,13.82.
HR-MS(ESI)Calcd for C35H47N3O2[M+H]+:542.3747,found:542.3750.
The preparation of the compound 6t of embodiment 20
Compound 1 is 2 acetyl naphthalene, and amine is positive nonyl amine in step 2, and preparation method is with embodiment 1.
Product is yellow solid, and yield is 82.6%.
1H NMR(400MHz,D2O) δ 7.88 (d, J=9.8Hz, 1H), 7.37 (s, 1H), 7.28-6.59 (m, 11H), 4.13 (t, J=60.0Hz, 3H), 2.93-2.30 (m, 4H), 1.72-0.98 (m, 6H), 1.00-0.60 (m, 3H), 0.41 (d, J =100.9Hz, 13H), -0.01 (d, J=6.3Hz, 3H)
13C NMR(101MHz,D2O)δ144.15,134.71,132.05,128.46,128.32,127.62,125.00, 38.96,31.49,28.96,26.46,22.33,13.80,13.75.
HR-MS(ESI)Calcd for C35H47N3O2[M+H]+:542.3747,found:542.3751.
The antibacterial activity in vitro of application examples 1 is tested：
1st, experimental technique
Micro broth dilution method：
(1) prepared by antibacterials storage liquid：The concentration for preparing antibacterials stock solution is 2560 μ g/mL, and solubility is low Antibacterials can be slightly less than above-mentioned concentration.Required antibacterials amount of solution or pulvis amount can formula calculated.What is prepared is anti- Bacterium medicine storage liquid should be stored in less than -20 DEG C environment, and storage life is no more than 6 months.
(2) preparation of bacterium to be measured：MH (B) is fallen within the single bacterium on MH (A) culture dish of oese picking incubated overnight to train Support in base, 0.5 Maxwell is calibrated to than turbid standard, containing about bacterium number 1 × 108CFU/mL, then dilutes 100 times, that is, obtain containing about bacterium Number 1 × 106The bacterium solution of CFU/mL, it is standby.
(3) antibacterials stock solution mother liquor (2560 μ g/mL) is diluted 10 times respectively, it is the anti-of 256 μ g/mL to obtain concentration Bacterium drug solution.96 aseptic orifice plates are taken, the first hole adds the antibacterials of 200 μ L, and the second to ten hole is separately added into 100 μ L's MH broth bouillons, draw 100 μ L and add the second hole from the first hole, mix, then draw 100 holes of μ L to the 3rd, the like, the Draw 100 μ L and discard in ten holes.Now each hole drug concentration is followed successively by：256th, 128,64,32,16,8,4,2,1,0.5 μ g/mL, the 11-holes add 200 μ L bacterium solutions (positive control), and the 12nd hole adds 200 μ LMH (B) culture mediums (negative control).
(4) bacterium solution got ready and then before 1 to 10 hole respectively adds 50 μ L, make the final bacterial concentration of every pipe be about 5 × 105CFU/mL, the 1st hole to the 11st hole drug concentration is respectively 128,64,32,16,8,4,2,1,05,0.25 μ g/mL.Will inoculation 96 good orifice plates are placed 37 DEG C of incubators and are cultivated, 24h observation bacterium solution growing states.Simultaneously Quality Control is done with type strain.
(5) result judges and explains：Before the MIC for reading and reporting institute's test strain, the thin of growth control pipe should be checked Whether bacteria growing situation is good, while should also check the Secondary Culture situation of inoculum to determine if pollution, Quality-control strains MIC value whether be in Quality Control scope.To visually observe, medicine least concentration pipe without bacterial growth person, as tested bacterium MIC。
The erythrocyte in vitro hemolytic of application examples 2 is tested
(1) experiment material：10mLEP is managed, 96 orifice plates, fresh degreasing sheep blood.
(2) PBS：500mL specifications, sodium chloride 4g, potassium chloride 100mg, two hypophosphite monohydrate sodium dihydrogen 1.49g, nothing Water potassium dihydrogen phosphate 100mg, deionized water is settled to 490mL, and between regulation PH7.2-7.4, sterilizing is surpassed with 10mL is sterilized After pure water dissolving 900mg glucose in addition PBS solution.
The preparation of (3) 5% red blood cell suspensions：In fresh de- fiber sheep blood freezing and refrigerator, the PBS bufferings for having configured It is instant to take in liquid placement and 37 DEG C of water-baths.
(4) two 10mL EP pipes are taken and is placed in rack for test tube, the fresh sheep blood that 37 DEG C of PBS are taken out water-bath and refrigerated is together Spray alcohol, is put into super-clean bench.Drawn respectively with liquid-transfering gun during 5700 microlitres of PBS add two EP pipes, then draw 300 microlitres respectively Sheep blood, is slowly added into PBS solution, lid lid, and slow reverse mixing, is put into centrifuge 1500 and leaves heart 10min up and down, takes Go out EP pipes, carefully draw supernatant, remove supernatant.It is separately added into 5~7mL PBS solutions again again, slow reverse mixing, puts up and down Enter centrifugation 1500 and leave heart 10min.So operate repeatedly, until centrifuged supernatant is no longer muddy.After last time is centrifuged, Supernatant is skimmed, red blood cell deposit indwelling is stand-by.
(5) several 10mL EP pipes are taken, on holding test tubes frame, the PBS (37 DEG C) of 5700 μ L is added in every EP pipe, so The red blood cell deposit of 300 μ L is sequentially added afterwards.Slow reverse mixing up and down, in this way, the just red cell suspension of configuration 5%.
(6) configuration of sample solution：(DMSO final concentrations can not be more than 0.5%) is dissolved with a small amount of DMSO, and uses phase The DMSO of same volume does negative control.DMSO after dissolving PBS dilute (for example, it is 1000 μ g/mL that the first hole concentration is ordered, that The content of medicine is exactly 2mg in the 50 μ L that first hole adds, and is configured to the solution of 2mg/50 μ L), now in this branch EP pipes Medicine is initial drug.Then it is parallel to take nine 1.5mL EP pipes and be placed in rack for test tube, it is separately added into the PBS (numberings 2 of 200 μ L Number, No. 3, No. 4 ... No. 10).The all such operation repetitive of all medicines.Finally, by drawing the medicine of 200 μ L in initial drug EP pipes Product solution is added in No. 2 EP pipes, is drawn after purging repeatedly in 200 μ L to No. 3 EP pipes, is purged repeatedly ... and is repeated, until No. 10 EP pipes.In this way, having diluted medicine.
(7) bed board：96 orifice plates are taken, experiment numbers, drug code, date is finished writing.Liquid-transfering gun is adjusted to 150 μ L, will be configured 5% good red cell suspension light and slow reverse mixing up and down, draws spread in 96 orifice plates (6 × 10) successively.Then will configure Medicine correspondence is added in 96 orifice plates, three multiple holes of a medicine.Placed after adding and 1h is incubated in 37 DEG C of insulating boxs.
(8) post-process：96 orifice plates are taken out from insulating box, centrifugation (3500rpm, 5min) in -4 DEG C of centrifuges is placed in. Centrifugation is finished, and every piece of plate correspondence all takes one piece of 96 new orifice plate.Plank control after mark and centrifugation.Then accordingly draw 100 μ L of supernatant liquid (hole hole correspondence).After absorption is finished, with ELIASA in measure OD values, analyze data obtains HC50。
Experimental result：
Table one：Target compound 6a~6t is red with external to Gram-negative and MIC (μ g/mL) results of positive criteria strain Cell hemolytic (HC50μ g/mL) result
Table two：Compound 6a~6t is to 10 plants without the MIC (μ g/ml) for repeating MRSA clinical strains
a：The staphylococcus aureus of methicillin-resistant
Table three：Compound 6a~6t produces NDM-1 enzyme clinical strains MIC (μ g/ml) to 10 plants without repetition
a:Produce the CRE of NDM-1
Table four：Compound 6a~6t produces KPC-2 enzyme clinical strains MIC (μ g/ml) result to 10 plants without repetition
a:Produce KPC-2 enzymes CRE
Table five：Compound 6a~6t is to 7 plants without MIC (μ g/ml) result for repeating VRE clinical strains
a:The enterococcus of vancomycin resistance
From table one, in synthesized compound 6a~6t, majority of compounds is for golden yellow to gram-positive bacteria Color staphylococcus type strain ATCC 29213 and large intestine enterococcus faecalis ATCC 29212, Gram-negative bacteria EHEC standard The MIC (μ g/mL) of strain ATCC 25922 and pseudomonas aeruginosa type strain ATCC 27853 shows this in below 16 μ g/mL Class compound has excellent broad spectrum antibiotic activity；Meanwhile, its erythrocyte in vitro hemolytic data display, with less poison Property.
More importantly such compound shows good for the CRE clinical strain bacterium of MRSA, VRE, product NDM-1 and KPC-2 enzymes Good antibacterial activity.Can be seen that such compound from above table (table one to table five) data has preferable patent medicine prospect.

Claims (7)

1. there is the chalcone cationic antimicrobial peptide mimics of antibacterial activity, it is characterised in that the structural formula of compound is as follows：
R is C6-14Alkyl.
2. there is the chalcone cationic antimicrobial peptide mimics of antibacterial activity as claimed in claim 1, it is characterised in that R is selected C6-14Alkyl.
3. there is the chalcone cationic antimicrobial peptide mimics of antibacterial activity as claimed in claim 2, it is characterised in that specific Select following compound：
(1)6a：R=n-hexanes；
(2)6b：R=normal heptanes；
(3)6c：R=normal octanes；
(4)6d：R=n -nonanes；
(5)6e：R=n-decanes；
(6)6f：R=n-undecanes；
(7)6g：R=n-dodecanes；
(8)6h：R=n-tetradecanes.
4. there is the chalcone cationic antimicrobial peptide mimics of antibacterial activity, it is characterised in that the structural formula of compound is as follows：
X be halogen, nitro, methoxyl group or hydroxyl, it is monosubstituted or disubstituted on phenyl ring.
5. there is the chalcone cationic antimicrobial peptide mimics of antibacterial activity as claimed in claim 4, it is characterised in that specific Select following compound：
(9)6i：X=2-Br
(10)6j：X=3-Br
(11)6k：X=4-Br
(12)6l：X=3-NO2
(13)6m：X=4-NO2
(14)6n：X=3-OH
(15)6o：X=4-F
(16)6p：X=4-OCH3
(17)6q：X=4-Cl
(18)6r：X=3,4-Cl.
6. there is the chalcone cationic antimicrobial peptide mimics of antibacterial activity, it is characterised in that be following compound：
(19)
Or
(20)
7. the method for preparing the chalcone cationic antimicrobial peptide mimics as described in claim 1 or 4 or 6, it is characterised in that logical Cross following manner realization：
R is C6‐14Alkyl；
Ar is
X be halogen, nitro, methoxyl group or hydroxyl, it is monosubstituted or disubstituted on phenyl ring；
A in (), solvent there is aldol reaction and obtain compound 3 in compound 1 and compound 2 under the catalytic action of alkali；Institute It is NaOH, potassium hydroxide, the one kind in lithium hydroxide, potassium carbonate, saleratus, sodium phosphate, dibastic sodium phosphate with alkali；It is used Solvent be one of methyl alcohol, ethanol, acetone, N,N-dimethylformamide, acetonitrile, isopropyl alcohol and water or it is wherein any two kinds or Three kinds of mixture；
B with C6-14 alkylamines in the presence of reducing agent, there is reduction amination in nitrogen protection to compound 3 at room temperature in (), solvent Reaction obtains compound 4；Reducing agent used is sodium triacetoxy borohydride, sodium borohydride, the one kind in sodium cyanoborohydride； Solvent for use is one kind or any two or three of mixture in dichloromethane, chloroform, 1,2- dichloroethanes；
C (), in mixed solvent, the lysine that compound 4 is protected with double Boc reacts generation chemical combination under catalysts conditions Thing 5；Used catalyst be O- BTAs-tetramethylurea hexafluorophosphoric acid ester (HBTU), dicyclohexylcarbodiimide (DCC), Methane sulfonyl chloride (MSCl), paratoluensulfonyl chloride (TsCl), 4-Nitrobenzenesulfonyl chloride (NsCl), DIC (DIC), the one kind in 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides (EDCI) or any two or three of mixing Thing；Mixed solvent used be N,N-dimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane, chloroform, 1,2- dichloromethane it is any Two kinds of mixed solvents；D in (), solvent, compound 5 sloughs Boc protection groups under catalyst action and obtains target compound, used Catalyst is the one kind in chloroacetic chloride, dry hydrogen chloride its gas, and solvent for use is methyl alcohol, ethanol, propyl alcohol, isopropanol, positive fourth One kind of alcohol.
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CN105130927A (en) * 2015-09-11 2015-12-09 郑州大学 Phenyl-nitrogen alkadienone derivative as well as preparation method and application thereof
CN105153259A (en) * 2015-09-11 2015-12-16 郑州大学 2/16-site-substituted chalcone derivative taking estrogen as mother nucleus and preparation method and application of derivative

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CN105130927A (en) * 2015-09-11 2015-12-09 郑州大学 Phenyl-nitrogen alkadienone derivative as well as preparation method and application thereof
CN105153259A (en) * 2015-09-11 2015-12-16 郑州大学 2/16-site-substituted chalcone derivative taking estrogen as mother nucleus and preparation method and application of derivative

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