CN109111396B - Quinoline aromatic vinyl derivative and preparation method and application thereof - Google Patents
Quinoline aromatic vinyl derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN109111396B CN109111396B CN201810989477.5A CN201810989477A CN109111396B CN 109111396 B CN109111396 B CN 109111396B CN 201810989477 A CN201810989477 A CN 201810989477A CN 109111396 B CN109111396 B CN 109111396B
- Authority
- CN
- China
- Prior art keywords
- phenyl
- aromatic vinyl
- iodoquinoline
- quinoline
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
-
- 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
Landscapes
- 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of chemistry and compound medicines, and discloses a quinoline aromatic vinyl derivative and a preparation method and application thereof. The chemical structural general formula of the quinoline aromatic vinyl derivative is as follows:
wherein R is:
R1and R2Is methyl, methylthio, hydroxyl, dimethylamino, diphenylamino, diethylamino, methoxy, imidazol-1-yl, hydrogen, C1-6 alkyl, C3-6 cycloalkyl, piperidinyl, morpholinyl, or piperazinyl; x is Cl, Br, I or benzenesulfonic acid group. HA is sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid or sulfonic acid. The quinoline is obtained by condensation reaction of quinoline analogue and aromatic aldehyde, the method is simple, and the raw materials are easy to obtain. The compound has good bacteriostatic and bactericidal activity on escherichia coli, staphylococcus aureus and bacillus subtilis.
Description
Technical Field
The invention belongs to the technical field of chemistry and compound medicines, and particularly relates to a quinoline aromatic vinyl derivative and a preparation method and application thereof.
Background
In recent years, various antibiotics are continuously developed and applied to the market and clinic, and particularly, under the requirement of rapidly eliminating infected patients by some medical institutions and medical personnel and patients, large-dose and excessive abnormal use of the antibiotics is increasingly serious. The phenomena lead the drug-resistant bacteria aiming at the antibacterial preparation to be rapidly developed and evolved, and the appearance of escherichia coli, staphylococcus aureus, bacillus subtilis and the like brings new troubles to clinical antibacterial and anti-infection treatment. However, infection by pathogenic microorganisms such as bacteria is always one of the important diseases threatening human health. Due to the wide antibacterial spectrum, strong antibacterial activity and wide clinical application of fluoroquinolone medicaments, in recent years, the medicament resistance phenomenon of bacteria to fluoroquinolone medicaments is increasingly serious, and the propagation of medicament resistant bacteria, the research of medical researchers and medical staff are forced to urgently develop and apply novel medicaments to overcome the problem of severe medicament resistance in the day.
Due to the emergence of the above-mentioned drug-resistant bacteria, conventional infectious diseases that have been controlled to some extent have become increasingly serious, and have attracted serious attention from clinical and microbiologists. The development of new drugs is slow at present, and the existing drugs can not treat drug-resistant bacteria, so that the problems are further aggravated. The development of drug molecules against drug-resistant bacteria with novel structures is a breakthrough to solve this problem.
Disclosure of Invention
In order to solve the above-mentioned disadvantages and drawbacks of the prior art, the present invention aims to provide a quinoline arylethene derivative. The compounds and salts thereof have good bacteriostatic and bactericidal activity on escherichia coli, staphylococcus aureus and bacillus subtilis.
The invention also aims to provide a preparation method of the quinoline aromatic vinyl derivative.
The invention also aims to provide application of the quinoline aromatic vinyl derivative.
The purpose of the invention is realized by the following technical scheme:
a quinoline aromatic vinyl derivative has a chemical structure general formula as follows:
wherein R is:
R1and R2Is methyl, methylthio, hydroxyl, dimethylamino, diphenylamino, diethylamino, methoxy, imidazol-1-yl, hydrogen, C1-6 alkyl, C3-6 cycloalkyl, piperidinyl, morpholinyl, or piperazinyl; x is Cl, Br, I or benzenesulfonic acid group. HA is inorganic acid or organic acid, the inorganic acid is sulfuric acid, phosphoric acid, hydrochloric acid or hydrobromic acid, and the organic acid is sulfonic acid.
Preferably, said R is1And R2Respectively is ortho-position, meta-position or para-position of the benzene ring; the X is I; the HA is hydrochloric acid.
The preparation method of the quinoline aromatic vinyl derivative comprises the following specific steps:
s1, carrying out a Suzuki reaction on 6-bromo-2-methylquinoline, phenylboronic acid and potassium carbonate under the catalysis of [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, heating and stirring at 40-60 ℃ by taking a mixed solution of water and tetrahydrofuran as a solvent, distilling to remove redundant tetrahydrofuran after the reaction is finished, extracting by using an organic solvent, concentrating and collecting a solid, and purifying by using a silica gel column chromatography to generate 6-phenyl-2-methylquinoline;
s2, mixing 6-phenyl-2-methylquinoline and iodomethane in sulfolane, reacting at 55-60 ℃, cooling, adding ethyl acetate to obtain a precipitate solid, and filtering to obtain 6-phenyl-1, 2-dimethyl-1-iodoquinoline;
s3, mixing 6-phenyl-1, 2-dimethyl-1-iodoquinoline with a solvent A, adding an aromatic aldehyde analog R-CHO and a catalyst A, reacting at 30-60 ℃, cooling, adding excessive petroleum ether to precipitate solids, and filtering to obtain a quinoline aromatic ethylene derivative I, namely 6-phenyl-1-methyl-2- (substituted aromatic vinyl) -1-iodoquinoline;
s4, mixing phosphorus oxychloride and dry N, N-dimethylformamide under anhydrous and oxygen-free conditions, and stirring for 30min at 0-5 ℃ to generate a ViIsmeier reagent;
s5, dissolving 6-phenyl-1-methyl-2- (substituted aromatic vinyl) -1-iodoquinoline in anhydrous DMF, dropwise adding the solution into a ViIsmeier reagent, reacting at 60-80 ℃, adding ice water for quenching, adjusting the pH of a system to be more than 10 by using a NaOH solution, and finally filtering to obtain 6-phenyl-1-methyl-2- (substituted aromatic vinyl) -4-formyl-1-iodoquinoline;
s6, mixing 6-phenyl-1-methyl-2- (substituted aromatic vinyl) -4-formyl-1-iodoquinoline and 1, 3-diaminoguanidine salt in a dry anhydrous solvent B, dropwise adding a catalyst B for catalysis, reacting at 30-60 ℃, cooling, adding excessive ethyl acetate to precipitate solids, filtering to obtain a crude product, and recrystallizing by using anhydrous ethanol to obtain the 6-phenyl-1-methyl-2- (substituted aromatic vinyl) -4- (1, 3-diaminoguanidine) -1-iodoquinoline salt.
Preferably, the volume ratio of water to tetrahydrofuran in step S1 is 1: (1-1.5); the 6-phenyl-2-methylquinoline: phenylboronic acid: the molar ratio of potassium carbonate is 1: (1.2-1.5): (1.2-1.5); the stirring time is 4-6 h; the organic solvent is ethyl acetate or dichloromethane.
Preferably, the molar ratio of 6-phenyl-1, 2-dimethyl-1-iodoquinoline, iodomethane and sulfolane in step S2 is 1: (3-4): (10-15), wherein the total volume ratio of the ethyl acetate to the 6-phenyl-1, 2-dimethyl-1-iodoquinoline, the iodomethane and the sulfolane is (5-10): 1; the reaction time is 2-4 h.
Preferably, the molar ratio of 6-phenyl-1, 2-dimethyl-1-iodoquinoline, solvent A, aromatic aldehyde analog R-CHO and 4-methylpiperidine in step S3 is 1: (30-40): (0.7-1): (1.5-2); the solvent A is n-butyl alcohol DMF or DMSO, the catalyst A is 4-methylpiperidine or triethylamine, and the reaction time is 5-8 h.
Preferably, the molar ratio of the phosphorus oxychloride to the N, N-dimethylformamide in the step S4 is 1: (1-1.2).
Preferably, the molar ratio of 6-phenyl-1-methyl-2- (substituted aromatic vinyl) -1-iodoquinoline, DMF, ViIsmeier reagent in step S5 is 1: (20-30): (8-10); the reaction time is 4-6 h.
Preferably, the molar ratio of the 6-phenyl-1-methyl-2- (substituted aromatic vinyl) -4-formyl-1-iodoquinoline, the salt of 1, 3-diaminoguanidine and the solvent B in step S6 is 1: 1: (40-70), the catalyst B is concentrated hydrochloric acid or glacial acetic acid, and the solvent B is one or more of methanol, ethanol, acetonitrile or N, N-dimethylformamide; the reaction time is 1-2 h.
The application of the quinoline aromatic vinyl derivative in preparing the drug-resistant bacteria resistant drug.
Further, the drug-resistant bacteria drug comprises quinoline aromatic vinyl derivatives and pharmaceutically acceptable auxiliary agents.
Preferably, the drug-resistant bacteria drug is a drug resistant to staphylococcus aureus, a drug resistant to bacillus subtilis or a drug resistant to escherichia coli.
Preferably, the drug-resistant bacteria resistant drug is an injection, a tablet, a pill, a capsule, a suspension or an emulsion.
The general reaction formula of the invention is shown as the following formula:
compared with the prior art, the invention has the following beneficial effects:
1. the salt of the quinoline aromatic vinyl derivative 6-phenyl-1-methyl-2- (substituted aromatic vinyl) -4- (1, 3-diamino guanidino) -1-iodoquinoline has obvious inhibition effect on various drug-resistant bacteria, and particularly has strong inhibition effect on escherichia coli, staphylococcus aureus and bacillus subtilis;
2. the salt of the quinoline aromatic vinyl derivative 6-phenyl-1-methyl-2- (substituted aromatic vinyl) -4- (1, 3-diamino guanidino) -1-iodoquinoline has small toxicity to normal animal cells and high safety in the application of preparing antibiotic medicaments;
3. the salt of the quinoline aromatic vinyl derivative 6-phenyl-1-methyl-2- (substituted aromatic vinyl) -4- (1, 3-diamino guanidino) -1-iodoquinoline has the advantages of simple preparation method, low raw material price, preparation of the antibiotic, and large market space.
Detailed Description
The following examples are presented to further illustrate the present invention and should not be construed as limiting the invention. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art. The reagents, methods and apparatus employed in the present invention are conventional in the art, except as otherwise indicated.
Example 16-phenyl-2-methylquinoline (b)
1. Preparation: under the protection of argon, 0.5g (2.26mmol) of 6-bromo-2-methylquinoline (a) is added into 3ml of THF and 3ml of water, then 0.465g (3.375mmol) of potassium carbonate, 0.367g (2.7mmol) of phenylboronic acid and 16.53mg (0.0226mmol) of [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride are sequentially added, and the reaction is stirred at 60 ℃ for 4 hours. After the reaction was completed, extraction was performed with ethyl acetate (100ml × 3 times), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain a crude product, which was subjected to column chromatography with an eluent of methanol/dichloromethane ═ 1:14(V: V) to obtain 0.41g of 6-phenyl-2-methylquinoline (b) as a gray solid in 83% yield.
2. The synthesis process is shown as formula (1):
3. and (3) performance testing: the 6-phenyl-2-methylquinoline (b) obtained in this example was analyzed by nuclear magnetic resonance, and the following nuclear magnetic resonance hydrogen spectrum results were obtained:1H NMR(400MHz,DMSO)δ8.31(d,J＝8.4Hz,1H),8.01(s,2H),7.83(s,1H),7.81(d,J＝5.2Hz,2H),7.43(dd,J＝17.3,J＝8.1Hz,3H),7.34(d,J＝7.3Hz,1H),2.68(s,3H)。
example 26-phenyl-1, 2-dimethyl-1-iodoquinoline (c)
1. Preparation: 0.50g (2.28mmol) of 6-phenyl-2-methylquinoline (b) was dissolved in 3ml of sulfolane, 0.42ml (6.84mmol) of methyl iodide was added dropwise thereto, and the mixture was stirred at 60 ℃ for 2 hours. After the reaction was completed, the reaction solution was poured into 20mL of ethyl acetate and allowed to stand, and a crude product was obtained by suction filtration under reduced pressure and washed with ethyl acetate to obtain 0.73g of 6-phenyl-1, 2-dimethyl-1-iodoquinoline (c) as a yellow solid in a yield of 89%.
2. The synthesis process is shown as formula (2):
3. and (3) performance testing: the 6-phenyl-1, 2-dimethyl-1-iodoquinoline obtained in this example was analyzed by nuclear magnetic resonance, and the results of nuclear magnetic resonance hydrogen spectrum were as follows:1H NMR(400MHz,DMSO)δ9.11(d,J＝8.6Hz,1H),8.74(d,J＝1.8Hz,1H),8.67(d,J＝9.3Hz,1H),8.57(dd,J＝9.3,1.9Hz,1H),8.15(t,J＝9.1Hz,1H),7.95(d,J＝7.4Hz,2H),7.61(t,J＝7.5Hz,2H),7.52(t,J＝7.3Hz,1H),4.49(s,3H),3.10(s,3H)。
example 36-phenyl-1-methyl-2- (4-dimethylaminostyryl) -1-iodoquinoline (I)1)
1. Preparation: the 6-phenyl-1, 2-dimethyl-1-iodoquinoline (c) obtained in example 2 and the aromatic aldehyde analog R-CHO dimethylaminobenzaldehyde were dissolved in n-butanol and reacted with the addition of a catalyst 4-methylpiperidine to give 0.62g of a violet black solid 6-phenyl-1-methyl-2- (4-dimethylaminostyryl) -1-iodoquinoline (I)1) The yield thereof was found to be 91%.
2.6-phenyl-1-methyl-2- (4-dimethylaminostyryl) -1-iodoquinoline (I)1) The chemical structure of (A) is shown as formula (3):
3. and (3) performance testing: 6-phenyl-1-methyl-2- (4-dimethylaminostyryl) -1-iodoquinoline (I) obtained in this example was subjected to nuclear magnetic resonance1) The results of the nuclear magnetic resonance hydrogen spectra obtained by the analysis were as follows:1H NMR(400MHz,DMSO)δ8.79(d,J＝9.2Hz,1H),8.59–8.44(m,3H),8.40(dd,J＝9.2,2.1Hz,1H),8.24(d,J＝15.4Hz,1H),7.93–7.88(m,2H),7.85(d,J＝9.0Hz,2H),7.61–7.46(m,4H),6.81(d,J＝9.0Hz,2H),4.46(s,3H),3.07(s,6H)。
example 46-phenyl-1-methyl-2- (4-dianilinostyryl) -1-iodoquinoline (I)2)
1. Preparation: using 6-phenyl-1, 2-dimethyl-1-iodoquinoline (c) obtained in example 2 and p-diphenylaminobenzaldehyde as starting materials, 0.73g of 6-phenyl-1-methyl-2- (4-diphenylaminostyryl) -1-iodoquinoline (I) as a black solid was obtained in the same manner as in example 32) The yield thereof was found to be 85%.
2.6-phenyl-1-methyl-2- (4-diphenylanilino-styryl) -1-iodoquinoline (I)2) The chemical structure of (A) is shown as formula (4):
3. and (3) performance testing: 6-phenyl-1-methyl-2- (4-dianilinostyryl) -1-iodoquinoline (I) obtained in example 14 was subjected to nuclear magnetic resonance2) The results of the nuclear magnetic resonance hydrogen spectra obtained by the analysis were as follows:1H NMR(400MHz,DMSO)δ8.96(d,1H),8.71–8.50(m,4H),8.23(d,J＝15.0Hz,1H),8.02–7.80(m,7H),7.61(t,J＝7.6Hz,2H),7.55–7.45(m,3H),7.38–7.19(m,6H),7.13(d,J＝8.6Hz,2H),4.59(s,3H)。
example 56-phenyl-1-methyl-2- (4-dimethylaminostyrene)Yl) -4-formyl-1-iodoquinoline (d)1)
1. Preparation: under the protection of nitrogen, phosphorus oxychloride (POCl) is slowly dropped into 1ml of ultra-dry DMF3)1mL (10.72mmo1), and cooled to 0 ℃ to prepare a ViIsmeier reagent. After 30min of reaction, 6-phenyl-1-methyl-2- (4-dimethylaminostyryl) -1-iodoquinoline (I) obtained in example 3 is added1)0.50g (1.01mmol) was dissolved in 3mL of ultra-dry DMF, added dropwise to ViIsmeier reagent, and reacted at 80 ℃ for 5 hours. Cooling the reaction solution to 0 ℃, adding 30mL of water for quenching reaction, adjusting the pH of the reaction solution to 10 by using 2mol/L NaOH aqueous solution, continuing stirring for 30min, performing suction filtration under reduced pressure, and washing a filter cake by using water and methanol respectively to obtain 0.27g of red solid 6-phenyl-1-methyl-2- (4-dimethylamino styryl) -4-formyl-1-iodoquinoline (d)1) The yield thereof was found to be 51%.
2. The synthesis process is shown as the formula (5):
3. and (3) performance testing: the 6-phenyl-1-methyl-2- (4-dimethylaminostyryl) -4-formyl-1-iodoquinoline (d) obtained in this example was subjected to nuclear magnetic resonance1) The results of the nuclear magnetic resonance hydrogen spectra obtained by the analysis were as follows:1H NMR(400MHz,DMSO)δ9.93(s，1H)，8.79(s,J＝9.2Hz,1H),8.59–8.44(m,3H),8.40(dd,J＝9.2,2.1Hz,1H),8.24(d,J＝15.4Hz,1H),7.93–7.88(m,2H),7.85(d,J＝9.0Hz,2H),7.61–7.46(m,3H),6.81(d,J＝9.0Hz,2H),4.46(s,3H),3.07(s,6H)。
example 66-phenyl-1-methyl-2- (4-dianilinostyryl) -4-formyl-1-iodoquinoline (d)2)
1. Preparation: using 6-phenyl-1-methyl-2- (4-diphenylanilino-styryl) -1-iodoquinoline (I) obtained in example 42) With phosphorus oxychloride (POCl)3) The ViIsmeier-Hack reaction was carried out in dry N, N-dimethylformamide as in example 5 to give 0.23g of 6-phenyl-1-methyl-2- (4-dianilinostyryl) -4-formyl-1-iodoquinoline (d)2) The yield thereof was found to be 44%.
2. The synthesis process is shown as the formula (6):
3. and (3) performance testing: the 6-phenyl-1-methyl-2- (4-diphenylanilino-styryl) -4-formyl-1-iodoquinoline (d) obtained in this example was subjected to nuclear magnetic resonance2) The results of the nuclear magnetic resonance hydrogen spectra obtained by the analysis were as follows:1H NMR(400MHz,DMSO)δ9.87(s,1H),9.06(s,1H),8.71–8.50(m,4H),8.23(d,J＝15.0Hz,1H),8.02–7.80(m,7H),7.61(t,J＝7.6Hz,2H),7.55–7.45(m,3H),7.38–7.19(m,5H),7.13(d,J＝8.6Hz,2H),4.59(s,3H)。
example 76-phenyl-1-methyl-2- (4-dimethylaminostyryl) -4- (1, 3-diaminoguanidino) -1-iodoquinoline hydrochloride (II)1)
1. Preparation: the 6-phenyl-1-methyl-2- (4-dimethylaminostyryl) -4-formyl-1-iodoquinoline (d) obtained in example 5 is added1)0.50g (0.961mmol) was added to 3mL of anhydrous methanol, followed by addition of 0.12g (0.961mmol) of 1, 3-diaminoguanidine hydrochloride, dropwise addition of 1-2 drops of concentrated hydrochloric acid for catalysis, and reaction at room temperature for 1 hour. And after the reaction is finished, adding ethyl acetate into the reaction liquid, standing to separate out a solid, and performing vacuum filtration to obtain a red crude product. Recrystallization from anhydrous ethanol gave 0.35g of 6-phenyl-1-methyl-2- (4-dimethylaminostyryl) -4- (1, 3-diaminoguanidino) -1-iodoquinoline hydrochloride (II) as a red solid1) The yield thereof was found to be 58%.
2. The synthesis process is shown as the formula (7):
3. and (3) performance testing: 6-phenyl-1-methyl-2- (4-dimethylaminostyryl) -4- (1, 3-diaminoguanidino) -1-iodoquinoline hydrochloride (II) obtained in this example was subjected to nuclear magnetic resonance1) The results of the nuclear magnetic resonance hydrogen spectra obtained by the analysis were as follows:1H NMR(400MHz,DMSO)δ10.93(s,1H),8.90(s,J＝6.2Hz,1H),8.79(s,J＝9.2Hz,1H),8.65(s,J＝9.1Hz,2H),8.59–8.44(m,4H),8.40(dd,J＝9.2,2.1Hz,1H),8.24(d,J＝15.4Hz,1H),7.93–7.88(m,3H),7.85(d,J＝9.0Hz,2H),7.61–7.46(m,3H),6.81(d,J＝9.0Hz,2H),4.46(s,3H),3.07(s,6H)。
example 86-phenyl-1-methyl-2- (4-dianilinostyryl) -4- (1, 3-diaminoguanidino) -1-iodoquinoline hydrochloride (II)2)
1. Preparation: using 6-phenyl-1-methyl-2- (4-dianilinostyryl) -4-formyl-1-iodoquinoline (d) obtained in example 62) And 1, 3-Diaminoguanidine hydrochloride as starting materials in the same manner as in example 7 to give 0.33g of 6-phenyl-1-methyl-2- (4-dianilinostyryl) -4- (1, 3-diaminoguanidino) -1-iodoquinoline hydrochloride (II) as a black solid2) The yield thereof was found to be 56%.
2.6-phenyl-1-methyl-2- (4-dianilinostyryl) -4- (1, 3-diaminoguanidino) -1-iodoquinoline hydrochloride (II)2) The chemical structure of (A) is shown as formula (8):
3. and (3) performance testing: 6-phenyl-1-methyl-2- (4-dianilinostyryl) -4- (1, 3-diaminoguanidino) -1-iodoquinoline hydrochloride (II) obtained in this example was subjected to nuclear magnetic resonance2) The results of the nuclear magnetic resonance hydrogen spectra obtained by the analysis were as follows:1H NMR(400MHz,DMSO)δ12.32(s,1H),9.02(d,J＝9.1Hz,1H),8.68(d,J＝1.7Hz,1H),8.61(d,J＝9.1Hz,2H),8.55–8.33(m,4H),8.25(d,J＝15.7Hz,1H),7.93(t,J＝9.1Hz,6H),7.82(d,J＝15.7Hz,2H),7.61(t,J＝7.6Hz,2H),7.55–7.42(m,3H),7.32–7.01(m,8H),4.57(s,3H)。
example 9 antimicrobial Activity screening
1. The minimum inhibitory concentration MIC (μ g/mL) values for each test compound were determined using the broth microdilution method described in the Clinical and Laboratory Standards Institute (CLSI) guidelines, and the test compounds are represented by the structural formula shown in table 1:
TABLE 1 Quinolinoarylethylene derivatives (II)1-II2) Structural formula (I)
(1) Preparing an antibacterial agent and a culture medium: the test compound is dissolved in DMSO to prepare a stock solution with the concentration of 1.6mg/mL, and the stock solution is filtered and sterilized for later use. Sterilizing the prepared MH broth culture medium for 30min by high pressure steam, and cooling for later use.
(2) Plate preparation: the bacteria concentration is measured by a bacteria suspension microplate reader at 600nm, and MH broth is diluted to a concentration equivalent to 0.5 McLeod turbiditube (bacteria content 0.5 × 10)8CFU/mL), adding 100 mu L of the bacterial liquid into each hole of a 96-hole plate for later use.
(3) Columns 1 and 12 of the 96-well plate were not dosed, and were blank controls. To the 2 nd well was added sequentially 8. mu.L of Compound II prepared in step 21～II2And respectively supplementing 100 mu L of bacteria liquid into the antibacterial drug stock solution, fully mixing the bacteria liquid, sucking 100 mu L of mixed liquid from the row 2 to the corresponding row 3 hole, fully mixing the bacteria liquid again, sucking 100 mu L of mixed liquid to the row 4, repeating the process until the row 8, sucking 100 mu L of mixed liquid and discarding, namely adding medicines by adopting a half-time dilution method to ensure that the concentrations of the medicines in each hole from the row 2 to the row 11 are respectively 64 mu g/mL, 32 mu g/mL, 16 mu g/mL, 8 mu g/mL, 4 mu g/mL, 2 mu g/mL, 1 mu g/mL, 0.5 mu g/mL, 0.25 mu g/mL and 0.125 mu g/mL. DMSO was used as a solvent control group, and penicillin was used as a positive control group.
(4) And (3) incubation: the 96-well plate was incubated in a 37 ℃ incubator for 24 h.
(5) And (5) judging a result: the lowest drug concentration that completely inhibited bacterial growth in the wells was the MIC. The test is only meaningful when bacteria grow significantly in blank control wells (i.e., no antibiotics).
(6) The bacteria used in the broth dilution method include bacteria used in the broth dilution method including Escherichia coli E.coli ATCC 25922, drug-resistant Escherichia coli E.coli ATCC BAA-2469, Staphylococcus aureus S.aureus ATCC BAA-41, enterococcus faecium E.faecalis ATCC 700221, enterococcus faecalis E.faecalis ATCC 29212, Bacillus subtilis 168, Acinetobacter baumannii ATCC 19606.
(7) The above method was used for the antibacterial test, and the minimum inhibitory concentration of the compound was expressed as MIC, and the results are shown in Table 2.
TABLE 2 Quinolinylaromatic derivatives (II)1-II2) MIC value of (u g/mL)
2. According to the MIC value of the minimum inhibitory concentration of the compound measured in the table 2, the MBC value of the minimum bactericidal concentration of the compound is measured.
(1) According to the minimum inhibitory concentration MIC value of the compound, respectively sucking 10 mu l of all the bacteria liquid with the concentration larger than MIC in the test tube.
(2) Coating a plate: and (3) dropwise adding the bacterial liquid onto the solid culture medium by using a liquid transfer gun, and uniformly smearing the bacterial liquid by using a coating rod.
(3) And (3) incubation: the solid medium is placed in a constant temperature incubator at 37 ℃ for 24 h.
(4) And (5) judging a result: the lowest drug concentration that completely killed the bacteria in the solid medium was the MBC value.
(5) The antibacterial test was carried out by the above method, and the minimum inhibitory concentration of the compound was represented by MBC, and the results are shown in Table 3. The results show that the quinoline aromatic vinyl derivative can inhibit and kill various drug-resistant bacteria in vitro, and can be used for preparing antibiotic drugs for resisting the drug-resistant bacteria.
TABLE 3 Quinolinoarylethylene derivatives (II)1-II2) MBC value of (mu g/mL)
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations and simplifications are intended to be included in the scope of the present invention.
Claims (9)
1. The quinoline aromatic vinyl derivative is characterized in that the chemical structural general formula of the quinoline aromatic vinyl derivative is as follows:
wherein R is:
2. The method for preparing quinoline aromatic vinyl derivatives according to claim 1, comprising the following steps:
s1, carrying out a Suzuki reaction on 6-bromo-2-methylquinoline, phenylboronic acid and potassium carbonate under the catalysis of [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, heating and stirring at 40-60 ℃ by taking a mixed solution of water and tetrahydrofuran as a solvent, distilling to remove redundant tetrahydrofuran after the reaction is finished, extracting by using an organic solvent, concentrating and collecting a solid, and purifying by using a silica gel column chromatography to generate 6-phenyl-2-methylquinoline;
s2, mixing 6-phenyl-2-methylquinoline and iodomethane in sulfolane, reacting at 55-60 ℃, cooling, adding ethyl acetate to obtain a precipitate solid, and filtering to obtain 6-phenyl-1, 2-dimethyl-1-iodoquinoline;
s3, mixing 6-phenyl-1, 2-dimethyl-1-iodoquinoline with a solvent A, adding an aromatic aldehyde analog R-CHO and a catalyst A, reacting at 30-60 ℃, cooling, adding excessive petroleum ether to precipitate solids, and filtering to obtain a quinoline aromatic ethylene derivative I, namely 6-phenyl-1-methyl-2- (substituted aromatic vinyl) -1-iodoquinoline; the catalyst A is 4-methylpiperidine;
s4, mixing phosphorus oxychloride and dry N, N-dimethylformamide under anhydrous and oxygen-free conditions, and stirring for 30min at 0-5 ℃ to generate a Vilsmeier reagent;
s5, dissolving 6-phenyl-1-methyl-2- (substituted aromatic vinyl) -1-iodoquinoline in anhydrous DMF, dropwise adding the solution into a Vilsmeier reagent, reacting at 60-80 ℃, adding ice water for quenching, adjusting the pH of a system to be more than 10 by using a NaOH solution, and finally filtering to obtain 6-phenyl-1-methyl-2- (substituted aromatic vinyl) -4-formyl-1-iodoquinoline;
s6, mixing 6-phenyl-1-methyl-2- (substituted aromatic vinyl) -4-formyl-1-iodoquinoline and 1, 3-diaminoguanidine salt in a dry anhydrous solvent B, dropping a catalyst B for catalysis, reacting at 30-60 ℃, cooling, adding excessive ethyl acetate to precipitate solids, filtering to obtain a crude product, and recrystallizing by using anhydrous ethanol to obtain 6-phenyl-1-methyl-2- (substituted aromatic vinyl) -4- (1, 3-diaminoguanidine) -1-iodoquinoline salt; the catalyst B is concentrated hydrochloric acid.
3. The method for producing a quinoline aromatic vinyl derivative according to claim 2, wherein the volume ratio of water to tetrahydrofuran in step S1 is 1: (1-1.5); the 6-phenyl-2-methylquinoline: phenylboronic acid: the molar ratio of potassium carbonate is 1: (1.2-1.5): (1.2-1.5); the stirring time is 4-6 h; the organic solvent is ethyl acetate or dichloromethane; in step S2, the molar ratio of 6-phenyl-1, 2-dimethyl-1-iodoquinoline, iodomethane, and sulfolane is 1: (3-4): (10-15), wherein the total volume ratio of the ethyl acetate to the 6-phenyl-1, 2-dimethyl-1-iodoquinoline, the iodomethane and the sulfolane is (5-10): 1; the reaction time is 2-4 h; the molar ratio of 6-phenyl-1, 2-dimethyl-1-iodoquinoline, solvent a, aromatic aldehyde analog R-CHO and 4-methylpiperidine described in step S3 is 1: (30-40): (0.7-1): (1.5-2); the solvent A is n-butyl alcohol, DMF or DMSO, and the reaction time is 5-8 h.
4. The method for producing a quinoline aromatic vinyl derivative according to claim 2, wherein the molar ratio of phosphorus oxychloride to N, N-dimethylformamide in step S4 is 1: (1-1.2); the molar ratio of the 6-phenyl-1-methyl-2- (substituted aromatic vinyl) -1-iodoquinoline, DMF and Vilsmeier reagent in the step S5 is 1: (20-30): (8-10); the reaction time is 4-6 h.
5. The method for producing a quinoline arylethylene derivative according to claim 2, wherein the molar ratio of 6-phenyl-1-methyl-2- (substituted aromatic vinyl) -4-formyl-1-iodoquinoline, the salt of 1, 3-diaminoguanidine, and the solvent B in step S6 is 1: 1: (40-70), wherein the solvent B is one or more of methanol, ethanol, acetonitrile or N, N-dimethylformamide; the reaction time is 1-2 h.
6. The use of the quinoline arylethene derivatives as claimed in claim 1 for the manufacture of a medicament against drug-resistant bacteria.
7. The use of a quinoline aromatic vinyl derivative according to claim 6 in the manufacture of a drug-resistant medicament comprising the quinoline aromatic vinyl derivative of claim 1 and a pharmaceutically acceptable adjuvant.
8. The use of the quinoline aromatic vinyl derivative according to claim 7 for preparing a drug-resistant medicament, wherein the bacteria against which the drug-resistant medicament is directed are staphylococcus aureus, bacillus subtilis or escherichia coli.
9. The use of a quinoline arylethene derivative as claimed in claim 6, wherein said medicament is in the form of an injection, tablet, pill, capsule, suspension or emulsion.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810989477.5A CN109111396B (en) | 2018-08-28 | 2018-08-28 | Quinoline aromatic vinyl derivative and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810989477.5A CN109111396B (en) | 2018-08-28 | 2018-08-28 | Quinoline aromatic vinyl derivative and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109111396A CN109111396A (en) | 2019-01-01 |
| CN109111396B true CN109111396B (en) | 2021-09-03 |
Family
ID=64861064
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810989477.5A Active CN109111396B (en) | 2018-08-28 | 2018-08-28 | Quinoline aromatic vinyl derivative and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109111396B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110627715B (en) * | 2019-08-27 | 2022-11-22 | 广东工业大学 | Quinoline aromatic ethylene derivative and application thereof in preparation of fluorescent dye and fluorescent probe |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4006239A (en) * | 1974-04-11 | 1977-02-01 | Bayer Aktiengesellschaft | Benzoic acid amides for mycobacterium infections |
| CN1703412A (en) * | 2002-10-10 | 2005-11-30 | 莫弗凯姆联合化学股份公司 | Novel compounds with antibacterial activity |
| CN101277696A (en) * | 2005-08-03 | 2008-10-01 | 詹森药业有限公司 | Quinoline derivatives as antibacterial agents |
| WO2011156626A1 (en) * | 2010-06-09 | 2011-12-15 | Rutgers, The State University Of New Jersey | Antimicrobial agents |
| KR20180031591A (en) * | 2016-09-19 | 2018-03-28 | 아주대학교산학협력단 | Composition for alterative to antibiotics comprising quinolinium derivatives and composition for enhancing antibiotics sensitivity using the same |
| CN108309977A (en) * | 2018-05-15 | 2018-07-24 | 广东工业大学 | Application of the indoles ethylene substituted chinoline derivative in preparing drug-resistance bacteria medicine |
-
2018
- 2018-08-28 CN CN201810989477.5A patent/CN109111396B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4006239A (en) * | 1974-04-11 | 1977-02-01 | Bayer Aktiengesellschaft | Benzoic acid amides for mycobacterium infections |
| CN1703412A (en) * | 2002-10-10 | 2005-11-30 | 莫弗凯姆联合化学股份公司 | Novel compounds with antibacterial activity |
| CN101277696A (en) * | 2005-08-03 | 2008-10-01 | 詹森药业有限公司 | Quinoline derivatives as antibacterial agents |
| WO2011156626A1 (en) * | 2010-06-09 | 2011-12-15 | Rutgers, The State University Of New Jersey | Antimicrobial agents |
| KR20180031591A (en) * | 2016-09-19 | 2018-03-28 | 아주대학교산학협력단 | Composition for alterative to antibiotics comprising quinolinium derivatives and composition for enhancing antibiotics sensitivity using the same |
| CN108309977A (en) * | 2018-05-15 | 2018-07-24 | 广东工业大学 | Application of the indoles ethylene substituted chinoline derivative in preparing drug-resistance bacteria medicine |
Non-Patent Citations (4)
| Title |
|---|
| Inhibitors of RecA activity discovered by high-throughput screening: cell-permeable small molecules attenuate the SOS response in Escherichia coli;Tim J. Wigle等;《Journal of Biomolecular Screening》;20091231;第14卷(第9期);1092-1101 * |
| Synthesis and Antimicrobial Activity of Some Novel Thiazoles, 1,3,4-Thiadiazines, 1,3,4-Thiadiazoles Incorporating Coumarin Moiety;Anhar Abdel-Aziem;《Journal of Heterocyclic Chemistry》;20141229;第52卷(第1期);251-259 * |
| Synthesis and Evaluation of Quinazolines as Inhibitors of the Bacterial Cell Division Protein FtsZ;Gabriella M. Nepomuceno等;《ACS Medicinal Chemistry Letters》;20150207;第6卷(第3期);308-312 * |
| 基于3-MBA的FtsZ抑制剂的设计、合成及抗菌活性研究;胡忠平;《华中科技大学硕士学位论文》;20180115;1-44 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109111396A (en) | 2019-01-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Siddiqui et al. | Thermal solvent-free synthesis of novel pyrazolyl chalcones and pyrazolines as potential antimicrobial agents | |
| CN109111396B (en) | Quinoline aromatic vinyl derivative and preparation method and application thereof | |
| CN110526910B (en) | Thiazole orange benzyl quaternary ammonium salt derivative and preparation method and application thereof | |
| CN110551072A (en) | quinoxaline-N 1, N 4 -dioxide derivative with DNA topoisomerase activity inhibition function, preparation method and application | |
| CN108727329B (en) | N-hydroxyethyl formamido substituted dibenzoxanthene and application thereof | |
| CN109111397B (en) | Quinoline aromatic ethylene derivative and preparation method and application thereof | |
| CN112341402B (en) | Preparation method and application of pyrimidine compound capable of inhibiting bacteria in medical care process | |
| CN110938028B (en) | Preparation method of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole | |
| CN105859741B (en) | Plectranthin type ent- kaurene derivatives and its preparation method and application | |
| CN110372615B (en) | Pleuromutilin derivative with 2-aminobenzenethiol and 1,2, 3-triazole side chain as well as preparation and application thereof | |
| US5023261A (en) | Acylated benzofuro[3,2-c]quinoline compounds with utility as treatments for osteoporosis | |
| CN111646974A (en) | N-methyl gatifloxacin propenone derivative and preparation method and application thereof | |
| CN111646975B (en) | N-methyl lomefloxacin allyl ketone derivative and preparation method and application thereof | |
| CN111647004B (en) | Propenone derivative for removing N-methylofloxacin and preparation method and application thereof | |
| CN110172058B (en) | 7-azaspiro [5.6] dodecane-10-one compound and preparation method and application thereof | |
| CN106565657A (en) | Hesperetin cinnamate compound with anti-tumor activity and synthetic method thereof | |
| CN110590779B (en) | 3, 10 di-p-chlorophenyl 6, 12 diazatetracubane compound, and synthetic method, application and pharmaceutical composition thereof | |
| CN110437177A (en) | A kind of pleuromutilin derivative and its preparation method and application | |
| CN107955057B (en) | Fusidic acid chemical modifier and preparation method and application thereof | |
| CN107648217B (en) | Use of neogambogic acid or its derivative for preparing medicine for preventing and/or treating relevant diseases caused by bacteria | |
| CN107365274B (en) | Pyrimidine piperazine acidamide compound and its application | |
| Mohammed | Synthesis, characterization, and antibacterial activity of chalcones derivatives | |
| CN114957238B (en) | 3-hydroxy-pyrrole-2-ketone compound containing 1,3, 4-thiadiazole and synthetic method and application thereof | |
| CN112939860B (en) | Compound for treating drug-resistant gram-negative positive bacteria and preparation method thereof | |
| CN113045461B (en) | Stilbene type compound and synthesis method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |