CN104546857B - The antibacterial application of compound naphthoylenequinazolone - Google Patents
The antibacterial application of compound naphthoylenequinazolone Download PDFInfo
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- 230000000844 anti-bacterial effect Effects 0.000 title abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 20
- 241000191967 Staphylococcus aureus Species 0.000 claims abstract description 12
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- 239000000126 substance Substances 0.000 claims abstract description 9
- 125000005605 benzo group Chemical group 0.000 claims abstract description 5
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- 238000006555 catalytic reaction Methods 0.000 description 1
- UCKZMPLVLCKKMO-LHLIQPBNSA-N cephamycin Chemical class S1CC(C)=C(C(O)=O)N2C(=O)[C@@H](C)[C@]21OC UCKZMPLVLCKKMO-LHLIQPBNSA-N 0.000 description 1
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- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses the antibacterial application of a kind of micromolecular compound, the antibacterial application of a kind of beta-lactam.This micromolecular compound is naphthoylenequinazolone, chemical combination name: benzo [lmn] diquinazolino [2,1 b:1', 2'j] [3,8] phenanthroline 6,9,15,20 tetra one.The present invention is that mechanism of action based on beta-lactam class antibiotic finds new micromolecular compound.It was found that above-mentioned micromolecular compound has suppression and bactericidal action to the staphylococcus aureus of ampicillin-resistant, the disease that staphylococcus aureus causes can be treated, can be used for the sterilization of hospital environment.Medicine can be made the various dosage forms adapting to various routes of administration in the industrial implementation of the present invention by this micromolecular compound.
Description
Technical field
The present invention relates to chemicals screening field, be specifically related to the antibacterial application of a kind of micromolecular compound.
Background technology
At present, the method preventing and treating bacterial disease pathogenic microorganism infection associated diseases is to use vaccine immunity and/or throw to anti-
Raw element.The vaccine used at present needs certain time just can play immunization after entering body, and has numerous disease extremely
The present does not also have operational vaccine；Antibiotic preventing and treating bacterial disease is used to there is the problem such as Drug resistance and drug residue.
Naphthoylenequinazolone is the little molecularization being first synthesized by I.I.Ponomarev etc.
Compound, this little molecule has cis and trans totally two kinds of stereochemical structures isomer (Ponomarev, I.I.;Vinogradova,
S.V.;Rusanov,A.L.;Skuratova,N.A.;Barashkov,N.N.;(1990);Synthesis and spectra
of naphthoylenequinazolones.Izvestiya Akademii Nauk SSSR,Seriya
Khimicheskaya11:2609-12.).This product is that the research is main in order to develop a kind of dyestuff and luminescent substance originally
Report the synthetic method of this little molecule, measure the Absorption and fluorescence spectrum of this little molecule simultaneously.This little molecule is pressing down
Application in terms of bacterium has no report.
Bacteria cell wall main component is Peptidoglycan (peptidoglycan), also known as mucopeptide (mucopetide).Cell wall
Mechanical strength depend on the existence of Peptidoglycan.Synthetic peptide polysaccharide is the distinctive ability of prokaryote.Peptidoglycan is by n-acetyl
Glucamine and n-acetyl born of the same parents two kinds of amino sugars of acid connect the polysaccharide support being spaced formation through β-1.4 glycosidic bond.In n-second
Connect tetrapeptide side chain on acyl 3-O-.alpha.-carboxyethyl-D-glucosamine. molecule, connected by peptide bridge or peptide chain again between peptide chain, form a mechanicalness the strongest
Network structure.The Peptidoglycan support of various bacteria cell walls is the most identical, in the composition of tetrapeptide side chain and connected mode thereof with bacterium
Kind and different.
Summary of the invention
It is an object of the invention to provide the antibacterial application of a kind of micromolecular compound, in order to solve existence in prior art
Problem.
For achieving the above object, the present invention provides the anti-Staphylococcus aureus purposes of a kind of micromolecular compound, and it is special
Levying and be, described micromolecular compound is naphthoylenequinazolone.
The structure of this micromolecular compound is as shown in Figure 1.
The present invention is directed to some antibacterial with drug resistance and have notable killing action, experiment display is involved in the present invention
Micromolecular compound naphthoylenequinazolone has the multiple golden yellow Portugal of toleration to antibiotic such as ampicillin etc.
Grape coccus such as E6, E7 all have bacteriostasis.
Micromolecular compound naphthoylenequinazolone involved in the present invention passes through suitable administration, can
With preventing and treating human or animal disease caused by antibacterial infects, therefore this micromolecular compound can be used for preventing and treating animal due to antibacterial
Prepared by the medicine of property cause pathogeny imcrobe infection associated diseases.The micromolecular compound that the present invention relates to can be used for through suitable approach to
Medicine is killed the medicine of bacterial disease pathogenic microorganism and is prepared.
The present invention is that mechanism of action based on beta-lactam antibiotic finds new micromolecular compound.By suppression
Cell wall mucopeptide synzyme, i.e. penicillin-binding protein (penicillin binding proteins, PBPs), thus hinder thin
Cell wall mucopeptide synthesizes, and makes bacterial cell wall defect, and thalline expands cracking, thus reaches the purpose of bacteria growing inhibiting.
First the present inventor has downloaded three protein structure files from Protein structure databases (PDB database),
Including 1HVB.pdb, 1XX2.pdb, 3Q6X.pdb, then pass through structural analysis of protein, it is determined that pharmaceutically-active target
Point.For the possible target spot of medicine effect, the protein targeting micromolecular compound virtual screening at calculating center, Beijing is used to put down
Platform, the micromolecular compound filtering out optimum carries out biological activity test checking.
The result of experimental verification shows, the present invention has suppression and kills the staphylococcus aureus of ampicillin-resistant
Bacterium effect.
Drug-resistant S. aureus is the primary pathogen of whole world nosocomial infection.It is expected to by external, is administered orally or quiet
Arteries and veins injection is for treating septicemia caused by sensitive bacterial, urinary tract infection, pulmonary infection, biliary tract infection etc..
The present invention is different from the kernel of existing beta-lactam antibiotic, and the beta-lactam of the present invention is positioned at hexatomic ring
In.Kernel based on the present invention can be designed that new efficient antibiotic or broad ectrum antibiotic.
The micromolecular compound naphthoylenequinazolone that the present invention relates to is in purposes involved in the present invention
Can be made into any dosage form of non-injection dose.In biomedicine doctor's clinic, dosing way involved in the present invention can be digestive tract
It is administered, mainly includes being administered orally, directly throwing stomach or/and carry out the non-injection administrations such as harmonization of the stomach intestinal tube injection through external, it is also possible to outside being
Apply or intravenous injection.The micromolecular compound of the present invention can also be used for the spraying disinfection sterilizing of hospital environment.So this little molecule
Medicine can be made the various dosage forms adapting to above route of administration in the industrial implementation of the present invention by compound.
In sum, the micromolecular compound of the present invention, to the suppression of staphylococcus aureus and killing action, can be treated
The disease that staphylococcus aureus causes, can be used for the sterilization of hospital environment.The micromolecular compound of the present invention is suppression
With kill staphylococcus aureus, the staphylococcus aureus especially for drug resistance provides the newly selected.Specifically, the present invention
Micromolecular compound can be used for the infection that the staphylococcus aureus of drug resistance causes, either human or animal.
Accompanying drawing explanation
The structure chart of the micromolecular compound of Fig. 1 present invention.
Detailed description of the invention
Naphthoylenequinazolone, chemical combination name: benzo [lmn] diquinazolino [2,1-b:1', 2'-
J] [3,8] phenanthroline-6,9,15,20-tetra one, the structure of this micromolecular compound is as it is shown in figure 1, this is little
Molecular compound numbering in other data base is as follows:
Following example are used for illustrating the present invention, but are not limited to the scope of the present invention.
The screening of embodiment 1 micromolecular compound
Numbering 48564 for chemical combination name: benzo [lmn] diquinazolino [2,1-b:1', 2'-j] [3,8]
phenanthroline-6,9,15,20-tetra one。
E6, E7 are ampicillin-resistant staphylococcus aureus.
1, experimental design
(1) select suitable solvent dissolve five kinds of micromolecular compounds (numbering is respectively 48564,25068,38929,
44331,68244).
(2) beta-lactamase is divided into four classes by molecular biology: A fermentoid includes multiple plasmid-encoded penicillinase, lives
Property position is serine residue, and molecular weight is 29kDa；B fermentoid is metalloenzyme, and by chromosome or plasmid-encoded, enzymatic activity needs zinc
Ion participates in, and can be suppressed by ethylenediaminetetraacetic acid (EDTA)；The active site of C fermentoid is serine residue, and molecular weight is
39kDa, its generation is relevant with derivant, and C fermentoid refers mainly to the cephalosporinase (AmpC enzyme) of chromosome coding；D fermentoid also known as
For OXA type (hydrolysis oxazacillin) beta-lactamase.
(3) experiment bacterial strain uses therefor E6, E7 is from 307 hospitals, and escherichia coli (ndm-1) are Chinese People's Liberation Army military affairs doctor
The microorganism of subject institute is owned with epidemic research institute laboratory, and ATCC25922 is escherichia coli reference culture, public from ATCC
Department, W3110 is also escherichia coli reference culture.ATCC25922 and W3110 is purchased from ATCC company.
(4) for micromolecular compound may to produce metallo-β-lactamase antibacterial have independent inhibitory action or with
The antibiotic coordinate repression of beta-lactam, we select carbapenem antibiotics imipenem, utilize drug sensitive test paper
Method carries out the primary dcreening operation of the bacteriostatic activity of the micromolecular compound of antibacterial or Synergistic antimicrobial effect.
One, (Imipenem-EDTA paper disk method Synergism Testing, this is real to consult the test experience with reference to metallo-β-lactamase
Test principle be metal beta lactamase be a class active site be metal ion, and have to rely on the existence of divalent metal
And there is catalysis activity, EDTA can chelated metal ions (mainly Zn2+), EDTA makes metal beta lactamase inactivate, so that
Beta-lactam antibiotic plays bacteriostasis, can substantially expand near EDTA scraps of paper side inhibition zone).If little molecule chemical combination
Thing energy specificity suppression metallo-β-lactamase, synergy is similar with the result of Imipenem-EDTA paper disk method Synergism Testing.
If two micromolecular compounds have single bacteriostasis, then can be similar to antibiotic and produce antibacterial ring.
(5) other several beta-lactamases may be produced single inhibitory action or generation for micromolecular compound
With the collaborative bacteriostasis of antibiotic, we select penicillins and the antibiotic of cephamycin class, utilize paper disk method to carry out little
The primary dcreening operation of the bacteriostatic activity of molecular compound.
If a result class having collaborative bacteriostasis, synergy and Imipenem-EDTA paper disk method Synergism Testing
Seemingly.
If two micromolecular compounds have single bacteriostasis, then can be similar to antibiotic and produce antibacterial ring.
2, experimental procedure
(1) using double-deck agar plate to cultivate antibacterial, 50 DEG C melt LB semisolid culturemedium, take 5ML in sterile test tube
In, adding the antibacterial 500 μ L of incubated overnight, mix gently, it is the training of LB solid that the semisolid culturemedium mixed is layered on bottom
Support in the culture dish of base.
(2) in Biohazard Safety Equipment, in ten minutes, drug sensitive test paper is attached in the culture dish solidified, independent bacteriostatic experiment
Disk distance at more than 3cm, two disk distances of collaborative bacteriostatic experiment must be at about 1cm.In the most each drug sensitive test paper
The amount of contained antibiotic is all 10 μ g, the drug sensitive test paper content of compound 48564: 9.9 μ g, the drug sensitive test paper of compound 25068
Content: 8.2 μ g, the drug sensitive test paper content 10 μ g of compound 38929, the drug sensitive test paper content 12.5 μ g of compound 44331, chemical combination
The drug sensitive test paper content 10 μ g of thing 68244.Experiment compares the scraps of paper and is the solvent containing each compound same ratio.
(3) culture dish posting drug sensitive test paper is cultivated in the incubator of 37 DEG C 12h, observe fungistatic effect.
3, experimental result
Note: (1) IPM: imipenum, AMP: ampicillin, CEF: cefathiamidine；(2)-represent without bacteriostasis ,+represent
There is bacteriostasis；(3) in cooperative experiment, M represents micromolecular compound, owing to experimental result is without cooperative effect, therefore the most individually
Mark some compound.
4, interpretation
As can be seen from the above table:
(1) compound is to producing the escherichia coli of metallo-β-lactamase without bacteriostasis, and presses down without collaborative with imipenum
Bacterium effect；
(2) compound and other beta-lactam antibiotics are without collaborative bacteriostasis；
(3) 25068,48564 couples of ampicillin-resistants staphylococcus aureus E6, E7 of compound have bacteriostasis.These are two years old
Ampicillin is all tolerated by bacterium in strain, so may produce the beta-lactamase of penicillins from this two strains bacterium of interpretation of result.Can with this
Infer that 25068,48564 have inhibitory action to the simple antibacterial producing this fermentoid with preliminary；
(4) ATCC25922 is sensitive strain, the most sensitive to imipenum, ampicillin, cefathiamidine, but compound
25068,48564 it is not produced inhibitory action.This result can be used to the analysis of compounds mechanism to the bacteriostasis of E6, E7；
(5) reference culture W3110 can be seen that imipenum, ampicillin, cefathiamidine sensitivity from experimental result, same
Sample 25068,48564 does not produce inhibitory action to it.
Embodiment 2 antibacterial sensitivity experiments to micromolecular compound
Antibacterial to micromolecular compound chemical combination name: benzo [lmn] diquinazolino [2,1-b:1', 2'-j] [3,
8] sensitivity experiments of phenanthroline-6,9,15,20-tetra one determines by measuring IC50:
E6, E7 are ampicillin-resistant staphylococcus aureus.
| Packet | Blank1 | Blank2 | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| A | 1.27 | 0.076 | 0.169 | 0.246 | 0.359 | 0.688 | 1.137 | 1.205 | 1.073 |
| B | 1.367 | 0.063 | 0.137 | 0.279 | 0.573 | 0.713 | 1.18 | 1.274 | 1.247 |
| E | 1.36 | 0.066 | 0.242 | 0.301 | 0.178 | 0.494 | 0.808 | 1.01 | 1.177 |
| F | 1.415 | 0.064 | 0.263 | 0.297 | 0.385 | 0.511 | 0.836 | 1.091 | 1.195 |
Note: wherein A, B are E6, E, F are E7.Blank1 for being not added with drug control, Blank2 for being not added with bacterial controls, medicine
Diluting for twice, unit is mg/L.Drug level: 1:195,2:97.5,3:48.75,4:24.38,5:12.19,6:6.1,7:
3.05。
Minimal inhibitory concentration (minimal inhibitory concentration, MIC) is visual results gained,
The mensuration of the IC50 of E6, E7 is respectively repeated twice:
E6:MIC:97.5mg/L；IC50:7.865225mg/L.
E7:MIC:97.5mg/L；IC50:7.352853mg/L.
Although, the present invention is described in detail to have used general explanation and specific embodiment, but at this
On the basis of invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore,
These modifications or improvements without departing from theon the basis of the spirit of the present invention, belong to the scope of protection of present invention.
Claims (2)
1. the micromolecular compound purposes in preparing anti-Staphylococcus aureus medicine, it is characterised in that described little point
Sub-compound is naphthoylenequinazolone, chemical combination name: benzo [lmn] diquinazolino [2,1-b:1',
2'-j] [3,8] phenanthroline-6,9,15,20-tetraone, its structural formula is as follows:
Purposes the most according to claim 1, it is characterised in that described anti-Staphylococcus aureus is anti-to antibiotic ammonia benzyl
There is the staphylococcus aureus of toleration in XiLin.
Priority Applications (1)
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH11149984A (en) * | 1997-11-18 | 1999-06-02 | Mitsui Chem Inc | Organic electroluminescent element |
| CN1307565A (en) * | 1998-04-29 | 2001-08-08 | 史密丝克莱恩比彻姆有限公司 | Quinolones used as MRS inhibitor and bactericides |
| CN1468210A (en) * | 2000-10-02 | 2004-01-14 | ŦԼ������ѧ�о������ | Naphthylsalicylanilides as antimicrobial and antiinflammatory agents |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH11149984A (en) * | 1997-11-18 | 1999-06-02 | Mitsui Chem Inc | Organic electroluminescent element |
| CN1307565A (en) * | 1998-04-29 | 2001-08-08 | 史密丝克莱恩比彻姆有限公司 | Quinolones used as MRS inhibitor and bactericides |
| CN1468210A (en) * | 2000-10-02 | 2004-01-14 | ŦԼ������ѧ�о������ | Naphthylsalicylanilides as antimicrobial and antiinflammatory agents |
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