CN116574024A - Preparation method and antibacterial application of benzoic acid derivative based on 4-carboxyl-4' - (diphenylamino) biphenyl - Google Patents
Preparation method and antibacterial application of benzoic acid derivative based on 4-carboxyl-4' - (diphenylamino) biphenyl Download PDFInfo
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- diphenylamino
- biphenyl
- benzoic acid
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- DZJBDJVZXNGYDL-UHFFFAOYSA-N 4-[4-(n-phenylanilino)phenyl]benzoic acid Chemical group C1=CC(C(=O)O)=CC=C1C1=CC=C(N(C=2C=CC=CC=2)C=2C=CC=CC=2)C=C1 DZJBDJVZXNGYDL-UHFFFAOYSA-N 0.000 title claims abstract description 19
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 230000000844 anti-bacterial effect Effects 0.000 title abstract description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 10
- 239000012043 crude product Substances 0.000 claims description 10
- 239000012046 mixed solvent Substances 0.000 claims description 8
- 239000003242 anti bacterial agent Substances 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- PQCXFUXRTRESBD-UHFFFAOYSA-N (4-methoxycarbonylphenyl)boronic acid Chemical compound COC(=O)C1=CC=C(B(O)O)C=C1 PQCXFUXRTRESBD-UHFFFAOYSA-N 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- ZRXVCYGHAUGABY-UHFFFAOYSA-N 4-bromo-n,n-bis(4-bromophenyl)aniline Chemical compound C1=CC(Br)=CC=C1N(C=1C=CC(Br)=CC=1)C1=CC=C(Br)C=C1 ZRXVCYGHAUGABY-UHFFFAOYSA-N 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 239000000047 product Substances 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims 1
- 229920006395 saturated elastomer Polymers 0.000 claims 1
- 241000894006 Bacteria Species 0.000 abstract description 18
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 7
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- 102000004190 Enzymes Human genes 0.000 description 3
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 3
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- 241000588724 Escherichia coli Species 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
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- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 2
- 230000036542 oxidative stress Effects 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
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- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- DTGGJUIFYJXAJI-OBGWFSINSA-N (e)-2-cyano-3-[4-(n-phenylanilino)phenyl]prop-2-enoic acid Chemical compound C1=CC(/C=C(C(=O)O)\C#N)=CC=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 DTGGJUIFYJXAJI-OBGWFSINSA-N 0.000 description 1
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 1
- SQTLUXJWUCHKMT-UHFFFAOYSA-N 4-bromo-n,n-diphenylaniline Chemical compound C1=CC(Br)=CC=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 SQTLUXJWUCHKMT-UHFFFAOYSA-N 0.000 description 1
- KIGVOJUDEQXKII-UHFFFAOYSA-N 4-bromo-n-(4-bromophenyl)-n-phenylaniline Chemical compound C1=CC(Br)=CC=C1N(C=1C=CC(Br)=CC=1)C1=CC=CC=C1 KIGVOJUDEQXKII-UHFFFAOYSA-N 0.000 description 1
- 101100510326 Caenorhabditis elegans tpa-1 gene Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
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- 206010034133 Pathogen resistance Diseases 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
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- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
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- 239000003814 drug Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000009920 food preservation Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
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- 230000003834 intracellular effect Effects 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
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- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a preparation method and antibacterial application of a benzoic acid derivative based on 4-carboxyl-4' - (diphenylamino) biphenyl. The invention takes 4-carboxyl-4' - (diphenylamino) biphenyl as a molecular structure backbone, and realizes the purposes of regulating and controlling the interaction affinity and antibacterial activity of molecules and bacteria by introducing antibacterial active groups. The synthesized benzoic acid derivative of the 4-carboxyl-4' - (diphenylamino) biphenyl has low cytotoxicity, good antibacterial effect, can realize effective inhibition of in-vivo and in-vitro bacteria, and has the application prospect of antibacterial treatment.
Description
Technical Field
The invention belongs to the technical field of biological medicine, and particularly relates to a preparation method and antibacterial application of a benzoic acid derivative based on 4-carboxyl-4' - (diphenylamino) biphenyl.
Background
Bacterial infections have long been an important threat to human health, with bacterial resistance problems continually escalating due to irregular antibiotic use and abuse. Meanwhile, bacterial biofilms further increase the incidence and mortality of bacterial infections, bringing heavy pressure to the healthcare sector. In the biofilm state, bacterial pathogens are significantly resistant to external attack (e.g., antibiotics, chemicals, disinfectants, etc.), increasing the difficulty of effective drug delivery therapies. Aiming at the serious threat of bacterial infection, the development of an effective novel non-antibiotic antibacterial agent is an effective way for preventing and relieving the threat of bacterial infection and biofilm development.
Researchers have generated great interest in antimicrobial agents of natural origin. Benzoic acid is an organic acid of natural origin, which is commonly found in animals, plants and microorganisms. Benzoic acid has been demonstrated to have antibacterial activity and has been used in the fields of food preservation and daily chemicals. The benzoic acid derivative has excellent modification value, and can generate stronger antibacterial activity through reasonable structure regulation and structural modification. At present, the research on antibacterial application based on benzoic acid and derivatives thereof mostly lacks of exploration of mechanisms, biological safety evaluation and in-vivo antibacterial application, and the action mechanisms and in-vivo application prospects of the compounds are further needed to be deeply understood so as to promote development of novel non-antibiotic antibacterial agents similar to antibacterial mechanisms.
Disclosure of Invention
In order to overcome the problems of overuse and abuse of the antibacterial agent and effectively realize antibacterial application to bacteria and biological films, the invention provides a preparation method of a benzoic acid derivative based on 4-carboxyl-4' - (diphenylamino) biphenyl and an antibacterial application thereof. According to the invention, 4-carboxyl-4' - (diphenylamino) biphenyl is taken as a molecular structure backbone, and antibacterial active groups are introduced, so that the purposes of regulating and controlling the interaction affinity and antibacterial activity of molecules and bacteria are realized, the structure-activity relationship between the molecular structure and the antibacterial effect is obtained, and the potential antibacterial mechanism of the molecules is explored.
The structural formula of the benzoic acid derivative based on 4-carboxyl-4' - (diphenylamino) biphenyl is as follows:
the preparation method of the benzoic acid derivative based on 4-carboxyl-4' - (diphenylamino) biphenyl comprises the following steps:
step S1: dissolving tri (4-bromophenyl) amine, p-methoxycarbonyl phenylboronic acid, tetraphenylphosphine palladium and potassium carbonate in a mixed solvent of 1, 4-dioxane and water according to a molar ratio of 10-25:90-110:1:140-180, and carrying out reflux reaction for 8-12h at 85-95 ℃ under the protection of nitrogen or inert gas; after cooling to room temperature, extracting the reaction liquid by using dichloromethane and/or ethyl acetate to obtain a crude product, and purifying the crude product by using a silica gel column;
step S2: dissolving the product obtained in the step S1 in a mixed solvent of 1, 4-dioxane and water, and then adding a saturated potassium carbonate aqueous solution for reflux reaction at 90-98 ℃ for 44-48h; cooling to room temperature, and adding acid to adjust the pH value to 2-3; and (5) spin-drying to separate out solid.
The volume ratio of the 1, 4-dioxane to the water in the mixed solvent of the 1, 4-dioxane and the water is 18-22:1.
In the step S2, the volume ratio of the mixed solvent of the 1, 4-dioxane and water to the saturated potassium carbonate aqueous solution is 4-6:1.
Use of the above-mentioned benzoic acid derivatives based on 4-carboxy-4' - (diphenylamino) biphenyl for the preparation of an antibacterial agent.
The invention has the beneficial effects that:
(1) The preparation method of the benzoic acid derivative based on 4-carboxyl-4' - (diphenylamino) biphenyl provided by the invention has the advantages of simple synthetic route and strong applicability.
(2) According to the invention, 4-carboxyl-4' - (diphenylamino) biphenyl is selected as a molecular backbone, a benzoic acid group with antibacterial activity is modified, the number of substituents is regulated, the overall hydrophilicity and hydrophobicity and cytotoxicity of the compound are effectively balanced, the regulation and control of molecular physical and chemical properties are realized, the affinity of the compound to bacteria is effectively improved through hydrophobic interaction and hydrogen bond interaction, and meanwhile, the toxicity of the compound to mammalian cells and blood is reduced, so that the aim of exploring the structure-activity relationship of molecular structure and antibacterial performance is fulfilled. Provides a certain design thought for the development work of the follow-up non-antibiotic antibacterial agent.
(3) The benzoic acid derivative based on 4-carboxyl-4' - (diphenylamino) biphenyl provided by the research shows good capability of resisting gram-positive bacteria such as staphylococcus aureus, methicillin-resistant staphylococcus aureus, staphylococcus epidermidis and the like and biomembranes thereof, and particularly aims at S.aureus. Not only can kill and inhibit planktonic S.aureus and biological membranes thereof, but also can be effectively used for a mouse wound infection model, inhibit the further development of mouse wound bacterial infection, effectively promote wound healing, and respectively have a Minimum Inhibitory Concentration (MIC) and a Minimum Bactericidal Concentration (MBC) of 0.039 mug/mL and 0.156 mug/mL for staphylococcus aureus. Meanwhile, TPA-3CA also exhibits good clearance of S.aureus biofilm and is also effective in inhibiting wound infection in mice caused by S.aureus.
(4) The study is based on the good antibacterial effect of TPA-3CA, and the antibacterial mechanism which is internally involved is initially explored. Mainly comprises inhibiting the activity of important enzymes, inducing oxidative stress of bacteria, destroying the permeability of cytoplasmic membranes and the structural integrity of bacterial membranes, etc.
(5) The benzoic acid derivative based on 4-carboxyl-4' - (diphenylamino) biphenyl provided by the research has higher antibacterial activity and biocompatibility, low cytotoxicity and low hemolytic side effect, and has good biosafety.
Drawings
FIG. 1 is a schematic plate diagram of the minimum bactericidal concentration of TPA-3CA on S.aureus prepared in example 1;
FIG. 2 is a molecular docking simulation of TPA-3CA with dihydrofolate reductase (DHFR) prepared in example 1;
FIG. 3 is an effect of TPA-3CA prepared in example 1 on S.aureus cytoplasmic membrane permeability;
FIG. 4 is an effect of TPA-3CA prepared in example 1 on S.aureus reactive oxygen species levels;
FIG. 5 is a scanning electron microscope image of the effect of TPA-3CA prepared in example 1 on S.aureus microtopography;
FIG. 6 is a graph showing cytotoxicity of TPA-3CA on HeLa cells at various concentrations prepared in example 1;
FIG. 7 is a schematic representation of hemolysis of TPA-3CA prepared in example 1 at various concentrations;
FIG. 8 is a photograph showing the biological membrane Crystal Violet (CV) staining by TPA-3CA prepared in example 1 at various concentrations, and FIG. b is a quantitative characterization of FIG. a by a microplate reader;
FIG. 9 is a graph showing the effect of TPA-3CA prepared in example 1 on treatment of mice back full-thickness wound infection model, and FIG. (b) is a quantitative characterization of FIG. (a) by ImageJ.2.0;
FIG. 10 is a schematic representation of the inhibition of bacteria infection by the whole back wound of mice by TPA-3CA prepared in example 1.
Detailed Description
The above-described matters of the present invention will be described in further detail by way of examples, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples, and all techniques realized based on the above-described matters of the present invention are within the scope of the present invention.
Example 1
Synthesis of TPA-3 CA:
tris (4-bromophenyl) amine (5.00 g,10.37 mmol), p-methoxycarbonylphenylboronic acid (8.81 g,48.95 mmol), tetrakis triphenylphosphine palladium (0.60 g,0.52 mmol) and potassium carbonate (11.45 g,82.84 mmol) were weighed and dissolved thoroughly in 250mL of an aqueous solution of 1, 4-dioxane and refluxed at 90℃for 10h under nitrogen protection. After cooling to room temperature, the reaction mixture was extracted with dichloromethane to give the crude product. The crude product was purified using a silica gel column eluting with petroleum ether/dichloromethane=1:6 (v/v). Compound 1 was obtained as a pale yellow solid (2.31 g, yield: 46.20%). 1 H NMR(400MHz,Chloroform-d)δ8.12(d,J＝8.5Hz,6H),7.68(d,J＝8.5Hz,6H),7.60(d,J＝8.7Hz,6H),7.28(d,J＝8.7Hz,6H),3.97(s,9H).
Compound 1 (2.31 g,3.57 mmol) was dissolved well in 25mL of 1, 4-dioxane aqueous solution, 4.7mL of saturated potassium carbonate aqueous solution was added, and the mixture was refluxed at 95℃for 48h. After cooling to room temperature, an aqueous solution of dilute hydrochloric acid was added for acidification. The precipitated solid was spin-dried to give TPA-3CA as an orange-yellow solid (1.83 g, yield: 79.22%). 1 H NMR(400MHz,DMSO-d 6 )δ12.94(s,3H),8.01(d,J＝8.4Hz,6H),7.79(dd,J＝19.1,8.6Hz,12H),7.23(d,J＝8.7Hz,6H). 13 C NMR(101MHz,DMSO-d 6 )δ167.59,147.26,144.03,134.14,130.46,129.65,128.69,126.73,124.80.HRMS(ESI)m/z:calcd for C 39 H 27 NO 6 :604.176223,found 604.17622.
Comparative example 1
Synthesis of TPA-2 CA:
4,4' -Dibromotriphenylamine (1.00 g,2.48 mmol), p-methoxycarbonylphenylboronic acid (1.33 g,7.44 mmol), tetrakis triphenylphosphine palladium (0.28 g,0.25 mmol) and potassium carbonate (3.43 g,24.81 mmol) were weighed out and dissolved thoroughly in 25mL of 1, 4-dioxane aqueous solution and refluxed for 10h at 90℃under nitrogen protection. After cooling to room temperature, the reaction mixture was extracted with dichloromethane to give the crude product. The crude product was purified using a silica gel column eluting with petroleum ether/dichloromethane=1:4 (v/v). Compound 2 was obtained as a pale yellow solid (0.31 g, yield: 31.00%). 1 H NMR(400MHz,DMSO-d 6 )δ8.02(d,J＝8.5Hz,4H),7.82(d,J＝8.5Hz,4H),7.73(d,J＝8.7Hz,4H),7.42–7.36(m,2H),7.15(d,J＝8.5,6.1Hz,7H),3.88(s,6H)。
Compound 2 (1.00 g,2.07 mmol) was dissolved well in 25mL of 1, 4-dioxane aqueous solution, 5.01mL of saturated potassium carbonate aqueous solution was added, and the mixture was refluxed at 95℃for 24 hours. After cooling to room temperature, an aqueous solution of dilute hydrochloric acid was added for acidification. The precipitated solid was spin-dried to give TPA-2CA as a yellow solid (0.84 g, yield: 84.00%). 1 H NMR(400MHz,DMSO-d 6 )δ12.88(s,2H),8.00(d,J＝8.5Hz,4H),7.78(d,J＝8.5Hz,4H),7.71(d,J＝8.7Hz,4H),7.42–7.35(m,2H),7.18–7.11(m,7H). 13 C NMR(101MHz,DMSO-d 6 )δ167.61,147.59,147.00,144.09,133.54,130.44,130.29,129.55,128.53,126.63,125.54,124.08.HRMS(ESI)m/z:calcd for C 32 H 22 NO 4 :484.455432,found 484.155523.
Comparative example 2
Synthesis of TPA-1 CA:
4-Bromotriphenylamine (1.00 g,3.08 mmol), p-methoxycarbonylphenylboronic acid (1.11 g,6.17 mmol), tetraphenylphosphine palladium (0.36 g,0.31 mmol) and potassium carbonate (4.26 g,30.82 mmol) were weighed and dissolved in 25mL of 1, 4-dioxane aqueous solution and refluxed for 10 hours at 90℃under nitrogen protection. After cooling to room temperature, the reaction mixture was extracted with dichloromethane to give the crude product. The crude product was purified using a silica gel column eluting with petroleum ether/dichloromethane=1:3 (v/v). Compound 3 was obtained as a pale yellow solid (0.23 g, yield: 23.00%). 1 H NMR(400MHz,DMSO-d 6 )δ8.01(d,J＝8.5Hz,2H),7.79(d,J＝8.5Hz,2H),7.68(d,J＝8.7Hz,2H),7.35(dd,J＝8.4,7.3Hz,4H),7.12–7.02(m,8H),3.87(s,3H).
Compound 3 (0.23 g,0.61 mmol) was dissolved well in 10mL of 1, 4-dioxane aqueous solution, 1mL of saturated potassium carbonate aqueous solution was added, and the mixture was refluxed at 95℃for 12 hours. After cooling to room temperature, an aqueous solution of dilute hydrochloric acid was added for acidification. The precipitated solid was spin-dried to give TPA-1CA as a yellow solid (0.17 g, yield: 75.13%). 1 H NMR(400MHz,DMSO-d 6 )δ12.90(s,1H),7.99(d,J＝8.4Hz,2H),7.76(d,J＝8.3Hz,2H),7.67(d,J＝8.7Hz,2H),7.36(d,J＝7.9Hz,4H),7.13–7.03(m,8H). 13 C NMR(101MHz,DMSO-d 6 )δ167.61,148.02,147.31,144.17,132.82,130.43,130.12,129.42,128.38,126.52,124.95,124.02,123.18.HRMS(ESI)m/z:calcd for C 25 H 19 NO 2 :364.134302,found 364.13417.
Inhibition evaluation of planktonic bacteria:
inhibition of planktonic bacteria by the compounds was characterized by performing Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC). 4 bacteria were selected, S.aureus, methicillin-resistant Staphylococcus aureus (Methicillin resistant Staphylococcus aureus, MRSA), staphylococcus epidermidis (Staphylococcus epidermidis, S.epideris) and E.coli, respectively.
Diluting the bacterial liquid to 1X 10 4 CFU/mL, different concentrations of derivative were added and incubated at 37℃for 24h. And (3) determining the concentration of the lowest compound in which bacteria no longer grow by using an enzyme-labeled instrument, wherein the concentration is the minimum inhibitory concentration of the corresponding compound. The in vitro antibacterial activity of the polypeptide antibiotics Vancomycin (Van) is evaluated by taking the typical polypeptide antibiotics as a control group. The experimental results are shown in table 1 below.
TABLE 1 MIC of TPA-3CA for S.aureus, MRSA, S.epididis and E.coli (unit: μg/mL)
TPA-3CA with the concentration of 0, MIC, 2MIC, 4MIC and 8MIC is selected to be respectively incubated with S.aureus, bacteria are plated after incubation, bacterial colony counting is carried out after 24 hours, and the minimum compound concentration of the bacterial colony which can be reduced by 99.9 percent compared with a control group is the minimum sterilization concentration. As a result of the experiment, see FIG. 1, TPA-3CA was used at 0.156. Mu.g/mL for MBC of S.aureus.
Molecular docking simulation between TPA-3CA and dihydrofolate reductase (DHFR):
the binding pattern of TPA-3CA and dihydrofolate reductase (DHFR, PDB:3 DRC) was predicted by molecular docking simulation, which was performed between NTC and DHFR using AutoDock4.2.6 and visualized with PyMol. Referring to FIG. 2, TPA-3CA can interact with two amino acids of DHFR (ARG 57 and GLU 90) by hydrogen bonding at a distance ofAnd->The method provides a certain theoretical support for the good in-vitro antibacterial property of TPA-3 CA.
Effects of TPA-3CA on cytoplasmic membrane permeability:
experiments with PI uptake by s.aureusThe effect of TPA-3CA on cytoplasmic membrane permeability was evaluated. S. aureus suspension was washed with PBS and diluted to a final concentration of 1X 10 7 CFU/mL, 1, 2, 4, 6 and 8 XMIC of TPA-3CA solution was added, respectively, the control group was added with equal amounts of PBS, and the system was incubated at 37℃for 12h, respectively. After the incubation, bacterial precipitation was obtained by centrifugation. Each group of bacteria was stained with PI dye (10. Mu.L, 30. Mu.M) for 30min under light-protected conditions. Washing again to remove excess PI dye, finally re-spinning in PBS solution, and monitoring fluorescence intensity (lambda) of each group by using an enzyme-labeling instrument ex ＝535nm，λ em =617 nm). Referring to fig. 3, the fluorescence intensity of pi exhibited a significant dose dependence, with increasing incubation concentration, and the fluorescence intensity increased. When the TPA-3CA incubation concentration was increased to 8 XMIC, the fluorescence intensity could be increased to 15.5 times that of the control group. TPA-3CA can reduce the amount of biological film by about 21.68%, and has a considerable anti-biological film activity effect. Taken together, TPA-3CA is effective in increasing bacterial plasma membrane permeability.
Effects of TPA-3CA on intracellular reactive oxygen species levels:
the level of ROS in bacterial cells was determined using Reactive Oxygen Species (ROS) sensitive dye DCFH-DA. The fluorescence signal of DCFH-DA in bacteria incubated with TPA-3CA (1, 0.5, 1, 2, 3 and 4 XMIC) was detected using a fluorescence spectrophotometer using PBS as a control group. (lambda) ex ＝488nm，λ em =522 nm). Referring to FIG. 4, when the concentration of TPA-3CA increases from 0.5 XMIC to 4 XMIC, the fluorescence signal of DCFH-DA increases gradually, and after incubation with 4 XMIC of TPA-3CA, the fluorescence signal increases by 2.6 times compared with that of the control group, indicating that TPA-3CA is effective in inducing oxidative stress in bacteria.
Effects of TPA-3CA on bacterial microtopography:
centrifuging, washing and diluting S.aureus in logarithmic growth phase to 1.0X10 9 CFU/mL, bacterial suspensions were incubated with TPA-3CA for 12h at constant temperature of 0, 1, 2 and 4 XMIC. After the incubation, the cells were centrifuged at 8000rpm for 3min and the bacterial solution was washed with PBS several times. Bacteria were immobilized with 2.5% glutaraldehyde in water at 4℃for 12h, washed again with PBS, and then dehydrated with an aqueous gradient of ethanol. Subsequently, 10. Mu.L of dehydrated bacterial liquid was transferred and dropped onto a silicon wafer, dried and sprayed with gold, and scannedAnd observing the microscopic morphology of the bacteria under an electron microscope. Referring to fig. 5, the extent of bacterial membrane damage exhibited a significant dose dependence. After incubation with (4×MIC) TPA-3CA, bacterial density was significantly reduced and the membrane structure of most bacteria was pitted and broken. TPA-3CA can exert antibacterial activity by disrupting the cell membrane structure of S.aureus.
Cytotoxicity and hemolysis of TPA-3 CA:
cytotoxicity of TPA-3CA was determined using MTT assay. As shown in FIG. 6, cells still showed higher viability after varying concentrations of TPA-3CA were added to HeLa cells. Indicating that TPA-3CA has lower cytotoxicity.
Hemolysis refers to rupture of the red blood cell membrane or the appearance of small pores that allow hemoglobin to escape. The red cell free solution has increased transparency with hemolysis, and has deep red color and ultraviolet absorption at 540 nm. The biocompatibility of the material can be assessed by the rupture of cells after incubation of TPA-3CA with erythrocytes. As shown in FIG. 7, TPA-3CA did not cause red blood cell disruption at a concentration of 20. Mu.g/mL or less, and the supernatant was clear and transparent, and the hemolysis rate was as low as 5% or less. Indicating that TPA-3CA has good biocompatibility.
Anti-biofilm activity of TPA-3 CA:
anti-biofilm activity of TPA-3CA was assessed using CV staining. As shown in FIG. 8 (a), the CV dye color in the microwells changed significantly from dark purple to light purple as the TPA-3CA dosing concentration increased. Following quantification by means of an enzyme-labeled instrument, as shown in FIG. 8 (b), low concentrations of TPA-3CA showed little significant inhibition on the biofilm, but at an incubation concentration of 8 XMIC, the biofilm was reduced by about 21.68%. Indicating that TPA-3CA has certain anti-S.aureus biological membrane activity.
In vivo antibacterial use of TPA-3 CA:
the S.aureus induced bacterial back full-thickness wound infection model was used and the TPA-3CA, TPA-2CA and PBS components were used for treatment with a concentration of 0.156 μg/mL, twice daily and wound recovery and bacterial colonization were recorded. As shown in figure 9 (a), TPA-3CA can effectively accelerate the contraction process of wound area, relieve purulent secretion of wound tissues and effectively shorten the treatment period. FIG. 9 (b) shows the change in wound area treated with imageJ.2.0 software, showing that 100% epithelialization of the wound was achieved with TPA-3CA for 14 days. FIG. 10 is a graph showing bacterial colonization of wound tissue in mice of each group, and the bacterial colony count at the wound site was reduced to 9.06% of that of the control group after TPA-3CA administration, which is superior to that of the TPA-2CA administration group (36.4%). The TPA-3CA has good in-vivo antibacterial effect.
The foregoing is only a specific embodiment of the invention to enable those skilled in the art to understand or practice the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown and described herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (5)
1. A benzoic acid derivative based on 4-carboxy-4 '- (diphenylamino) biphenyl, characterized in that the benzoic acid derivative based on 4-carboxy-4' - (diphenylamino) biphenyl has the following structural formula:
2. the method for preparing the benzoic acid derivative based on 4-carboxyl-4' - (diphenylamino) biphenyl according to claim 1, wherein the preparation method comprises the following specific steps:
step S1: dissolving tri (4-bromophenyl) amine, p-methoxycarbonyl phenylboronic acid, tetraphenylphosphine palladium and potassium carbonate in a mixed solvent of 1, 4-dioxane and water according to a molar ratio of 10-25:90-110:1:140-180, and carrying out reflux reaction for 8-12h at 85-95 ℃ under the protection of nitrogen or inert gas; after cooling to room temperature, extracting the reaction liquid by using dichloromethane and/or ethyl acetate to obtain a crude product, and purifying the crude product by using a silica gel column;
step S2: dissolving the product obtained in the step S1 in a mixed solvent of 1, 4-dioxane and water, and then adding a saturated potassium carbonate aqueous solution for reflux reaction at 90-98 ℃ for 44-48h; cooling to room temperature, and adding acid to adjust the pH value to 2-3; and (5) spin-drying to separate out solid.
3. The preparation method according to claim 2, wherein the volume ratio of the 1, 4-dioxane to the water in the mixed solvent of the 1, 4-dioxane and the water is 18-22:1.
4. The preparation method according to claim 2, wherein the volume ratio of the mixed solvent of 1, 4-dioxane and water to the saturated aqueous potassium carbonate solution in the step S2 is 4-6:1.
5. Use of a benzoic acid derivative based on 4-carboxy-4' - (diphenylamino) biphenyl according to claim 1 in the preparation of an antibacterial agent.
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