CN115960039A - Aromatic ring substituted pyridine quaternary ammonium salt derivative and preparation method and application thereof - Google Patents
Aromatic ring substituted pyridine quaternary ammonium salt derivative and preparation method and application thereof Download PDFInfo
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- CN115960039A CN115960039A CN202310028252.4A CN202310028252A CN115960039A CN 115960039 A CN115960039 A CN 115960039A CN 202310028252 A CN202310028252 A CN 202310028252A CN 115960039 A CN115960039 A CN 115960039A
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- aromatic ring
- substituted
- compound
- hours
- dissolving
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- -1 pyridine quaternary ammonium salt Chemical class 0.000 title claims abstract description 40
- 125000003118 aryl group Chemical group 0.000 title claims abstract description 36
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 239000003814 drug Substances 0.000 claims abstract description 29
- 230000000844 anti-bacterial effect Effects 0.000 claims description 37
- 241000191967 Staphylococcus aureus Species 0.000 claims description 34
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 30
- 238000010438 heat treatment Methods 0.000 claims description 28
- YTAHJIFKAKIKAV-XNMGPUDCSA-N [(1R)-3-morpholin-4-yl-1-phenylpropyl] N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]carbamate Chemical compound O=C1[C@H](N=C(C2=C(N1)C=CC=C2)C1=CC=CC=C1)NC(O[C@H](CCN1CCOCC1)C1=CC=CC=C1)=O YTAHJIFKAKIKAV-XNMGPUDCSA-N 0.000 claims description 27
- 229940079593 drug Drugs 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 241000894006 Bacteria Species 0.000 claims description 21
- 230000035484 reaction time Effects 0.000 claims description 18
- 241000194031 Enterococcus faecium Species 0.000 claims description 17
- 241000193996 Streptococcus pyogenes Species 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- 241000194032 Enterococcus faecalis Species 0.000 claims description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical class C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims description 11
- 238000006555 catalytic reaction Methods 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- 241000588724 Escherichia coli Species 0.000 claims description 8
- 229940032049 enterococcus faecalis Drugs 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 241000194103 Bacillus pumilus Species 0.000 claims description 7
- 235000014469 Bacillus subtilis Nutrition 0.000 claims description 7
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
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- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000004428 fluoroalkoxy group Chemical group 0.000 claims description 4
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
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- 125000005504 styryl group Chemical group 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 4
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 claims description 3
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 3
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- YKYIFUROKBDHCY-ONEGZZNKSA-N (e)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one Chemical group CCO\C=C\C(=O)C(F)(F)F YKYIFUROKBDHCY-ONEGZZNKSA-N 0.000 claims description 2
- YAXWOADCWUUUNX-UHFFFAOYSA-N 1,2,2,3-tetramethylpiperidine Chemical compound CC1CCCN(C)C1(C)C YAXWOADCWUUUNX-UHFFFAOYSA-N 0.000 claims description 2
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 claims description 2
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 claims description 2
- 241000192125 Firmicutes Species 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
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- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 230000000977 initiatory effect Effects 0.000 claims 1
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Images
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- Pyridine Compounds (AREA)
Abstract
The invention belongs to the field of new medicine compounds, and particularly relates to an aromatic ring substituted pyridine quaternary ammonium salt derivative, and a preparation method and application thereof. The aromatic ring substituted pyridine quaternary ammonium salt derivative has completely different mother nucleus structures from the reported FtsZ inhibitor, and has different physicochemical properties.
Description
Technical Field
The invention belongs to the field of new medicine compounds, and particularly relates to an aromatic ring substituted pyridine quaternary ammonium salt derivative, and a preparation method and application thereof.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
With the widespread use and abuse of antibacterial drugs, bacterial infections have become one of the major problems that seriously threaten human life and health. The antibacterial drugs which are clinically used and developed by the traditional method at present are difficult to deal with the problem of drug resistance, so that the idea of changing the idea and adopting a completely new drug design concept is imperative. With the wide application of genome, proteome and cell biology technologies in bacterial research, finding new action targets and effective inhibitors thereof to overcome the problem of clinically intractable bacterial drug resistance is an important direction for the development of antibacterial drugs in future.
Filament temperature-sensitive protein (FtsZ) is an essential key protein in the process of prokaryotic cell division, has a novel action mechanism and is closely related to the whole process of bacterial cell division. FtsZ can be used as an antibacterial action target with development prospect mainly because of the following points. First, ubiquitous. FtsZ is widely present in about 850 bacteria, and includes a variety of clinically common pathogenic bacteria, such as ESKAPE pathogen, mycobacterium tuberculosis, mycoplasma pneumoniae, and the like. The FtsZ gene is contained even in halophilic bacteria (h.salinium) and thermophilic bacteria (p.woesei) of the archaea domain. This feature has contributed to the development of inhibitors with broad-spectrum antibacterial activity. Second, indispensable. FtsZ, as an initial regulatory protein of bacterial division, is involved in the whole process of bacterial cell division and is also the most important essential protein in the process. Once the compound inhibits dynamic polymerization of FtsZ or inhibits GTPase activity of FtsZ, the bacterium will fail to normally divide and eventually die. Third, it is highly conserved. The fact that FtsZ is the most conserved of the sixteen essential proteins for division and is not susceptible to variation in almost all pathogenic bacteria also determines that bacteria are not susceptible to FtsZ inhibitors. Fourth, specificity. Although FtsZ is a homologous analog of mammalian tubulin, it differs from nucleotide binding and catalytic modes in that the three-dimensional structure is very different, and the protein sequence homology is only about 10%. Typical tubulin inhibitors such as paclitaxel and nocodazole have not been reported in the literature to have significant inhibitory effects on FtsZ. This feature ensures good selectivity and low cytotoxicity of FtsZ towards eukaryotic cells and is also a prerequisite for the development of FtsZ inhibitors. Fifth, the inhibitor binds to the target more easily. FtsZ is widely distributed in the cytoplasm of bacteria and inhibitors can easily bind to the bacteria after penetrating the cell membrane. By analyzing the five characteristics of FtsZ protein, the inventor finds that a new drug with high antibacterial activity and relatively wide antibacterial spectrum can be developed by taking FtsZ as a target point.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide an aromatic ring substituted pyridine quaternary ammonium salt derivative, a preparation method and an application thereof, wherein the derivative has a completely different mother-core structure from the reported FtsZ inhibitor and has different physicochemical properties.
In order to achieve the purpose, the invention is realized by the following technical scheme:
in a first aspect, the present invention provides an aromatic ring-substituted quaternary pyridinium salt derivative, wherein the aromatic ring-substituted quaternary pyridinium salt derivative is selected from a compound represented by formula Ia, or a pharmaceutically acceptable salt, ester, solvate, tautomer, meso form, racemate, stereoisomer, metabolite, or prodrug thereof; the formula Ia is shown below:
wherein, R in Ia 1 The number of the substituent groups on the benzene ring can be one or more, and each substituent group is one of C1-C8 straight-chain or branched alkyl, alkoxy, alkylamino, halogen, nitro, fluoroalkyl, fluoroalkoxy and acetyl independently; x in Ia is halogen; r in Ia 2 Is an aromatic substituent including substituted phenyl, unsubstituted phenyl and naphthyl; r in Ia 3 Selected from methyl, or the site has no group.
In the compound shown in the formula Ia, when styryl is substituted at the 3-position, R 2 Is substituted by benzene ring, R 3 When the compound is positioned on hydrogen, the structure of the compound is shown as the following formula I:
wherein R is 1 One or more selected from C1-C8 straight chain or branched chain alkyl, alkoxy, halogen, nitro, fluoroalkyl and fluoroalkoxy, and R is 1 The substitution site is one or more of C-2, C-3, C-4 and C-5 positions; the X is I; further, said R 1 One of 4-methyl, 4-ethyl, 4-isopropyl, 4-tert-butyl, 4-chloro, 2-nitro, 4-cyano, 4-trifluoromethyl, 3,4-dichloro, 4-bromo, 3-bromo, 3,4,5-trimethoxy, 4-fluoro, 4-methoxy, 4-ethoxy, 4-propoxy, 4-butoxy, 4-pentoxy, 4-hexoxy, and 4-heptoxy is selected.
In the compound of formula Ia, when the styryl group is substituted at the 4-position, the compound has the structure shown in formula II below:
wherein R is 1 One or more selected from C1-C8 straight chain or branched chain alkyl, alkoxy, alkylamino, halogen, acetyl and hydroxyl, and the R is 1 The substitution site is one or two of C-3 and C-4; the X is I; further, said R 1 One of 4-tert-butyl, 4-hydroxy, 4-pentoxy, 4-hexoxy, 4-dimethylamino, 2-nitro, 4-fluoro, 4-amino, 3,4-dichloro, 4-isopropyl, 4-ethoxy, 4-isopropyl, 4-pyrrolidinyl, 4-piperidinylalkyl, 4-acetyl and 4-diacetamido; said R is 2 One selected from phenyl, 4-tert-butylphenyl and naphthyl; the R is 3 One selected from hydrogen and methyl.
In a second aspect, the present invention provides a method for preparing an aromatic ring-substituted quaternary pyridinium derivative represented by formula I, comprising the following steps:
the operation mode of the step a is as follows: dissolving Compound 1 in 1,4-dioxane H 2 O =10, 1, [1,1' -bis (diphenylphosphino) ferrocene]Under the condition of palladium dichloride catalysis, K is added 2 CO 3 And phenylboronic acid, heating and reacting to generate an intermediate 2; further, the heating temperature is 70-90 ℃, and the reaction time is 6-12 hours;
the operation of step b is as follows: dissolving Compound 2 in 1,4-dioxane H 2 In a mixed solvent of O =10 and 1, adding K under the catalysis of palladium tetratriphenylphosphine 2 CO 3 And phenylboronic acid, heating and reacting to generate an intermediate 3; further, the heating temperature is 70-90 ℃, and the reaction time is 8-16 hours;
the operation of step c is as follows: dissolving the intermediate 3 in carbon tetrachloride or chloroform, and adding N-bromosuccinimide to react under the condition initiated by azodiisobutyronitrile to generate an intermediate 4; further, the reaction temperature is 60-80 ℃, and the reaction time is 4-8 hours;
the operation of step d is as follows: dissolving the intermediate 4 in triethyl phosphite, and heating to react to generate an intermediate 5; further, the heating reaction time is 120-150 ℃, and the reaction time is 2-6 hours;
the procedure of step e is as follows: dissolving the intermediate 5 in tetrahydrofuran, and adding aldehydes to react in the presence of inorganic base to generate an intermediate 6; further, the reaction heating temperature is 25-40 ℃, and the reaction time is 8-12 hours;
the operation of step f is as follows: and dissolving the intermediate 6 in a polar aprotic solvent, adding excessive methyl iodide, and reacting at 42-80 ℃ for 15-24 hours to generate the compound shown in the formula I.
In a third aspect, the present invention provides a method for preparing an aromatic ring-substituted quaternary pyridinium derivative represented by formula II, comprising the following steps:
the operation of step g is as follows: dissolving compound 7 in 1,4-dioxane H 2 O =10, 1, [1,1' -bis (diphenylphosphino) ferrocene]Under the condition of palladium dichloride catalysis, K is added 2 CO 3 Reacting with phenylboronic acid by heating to generate an intermediate 8; further, the heating temperature is 70-90 ℃, and the reaction time is 6-12 hours;
the operation of step h is as follows: dissolving intermediate 8 in 1,4-dioxane H 2 In a mixed solvent of O =10 and 1, adding K under the catalysis of palladium tetratriphenylphosphine 2 CO 3 Reacting with phenylboronic acid by heating to generate an intermediate 9; further, the heating temperature is 70-90 ℃, and the reaction time is 8-16 hours;
the operation of step i is as follows: dissolving the intermediate 9 in a polar aprotic solvent, adding excessive methyl iodide, and reacting at 42-80 ℃ for 15-24 hours to generate an intermediate 10;
the operation of step j is as follows: dissolving the intermediate 10 in n-butanol, adding a benzaldehyde reagent under the condition of tetramethylpiperidine catalysis, and heating to react to generate a compound shown as a formula II; further, the heating temperature is 90-110 ℃, and the reaction time is 12-24 hours.
In a fourth aspect, the present invention provides a pharmaceutical composition, including the aromatic ring-substituted quaternary pyridinium derivative according to the first aspect and a carrier.
The "pharmaceutical composition" or "composition" according to the invention can be used for the treatment or prevention of the diseases according to the invention in a subject, in particular a mammal. In the pharmaceutical composition, the aromatic ring-substituted pyridinium quaternary derivative of the first aspect as an active ingredient should be in a synergistically effective dose, and the pharmaceutical dose belongs to the technical content which can be determined by conventional technical means in the field.
In addition, the active ingredients of the pharmaceutical composition may include other ingredients having antibacterial or auxiliary antibacterial effects in addition to the aromatic ring-substituted quaternary pyridinium derivative of the first aspect.
As used herein, the term "pharmaceutically acceptable" or "pharmaceutically acceptable" used interchangeably therewith, such as in the description of "pharmaceutically acceptable salts", means that the salts are not only physiologically acceptable to the subject, but also synthetic substances of value in pharmaceutical use, such as salts formed as intermediates in the performance of chiral separations, which salts, although not directly administered to the subject, may play a role in obtaining the final product of the invention.
Pharmaceutical compositions of the compounds of the invention may be administered by any of the following means: oral, aerosol inhalation, rectal, nasal, vaginal, topical, parenteral such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or infusion, or by means of an explanted reservoir, with oral, intramuscular, intraperitoneal or intravenous administration being preferred. In particular, the dosage form of the pharmaceutical composition can be a liquid dosage form and a solid dosage form. The liquid dosage forms can be true solutions, colloids, microparticles, emulsions, and suspensions. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, clathrate, landfill, patch, liniment, etc.
The pharmaceutical compositions of the present invention may also contain conventional carriers, including but not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins, such as human serum protein, buffer substances, such as phosphates, glycerol, sorbitol, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin and the like. The carrier may be present in the pharmaceutical composition in an amount of 1% to 98% by weight, typically about 80% by weight. For convenience, local anesthetics, preservatives, buffers, and the like can be dissolved directly in the vehicle.
In a fifth aspect, the present invention provides a pharmaceutical composition characterized by the aromatic ring-substituted quaternary pyridinium derivative according to the first aspect and/or the pharmaceutical composition according to the fourth aspect.
In a sixth aspect, the present invention provides an application of the aromatic ring-substituted quaternary pyridinium derivative of the first aspect and/or the pharmaceutical composition of the fourth aspect and/or the drug of the seventh aspect in preparing an antibacterial product.
The bacteria are sensitive bacteria and drug-resistant bacteria, the sensitive bacteria are one or more of bacillus subtilis (ATCC 9372, which is a penicillin-sensitive strain), bacillus pumilus (B.pumipius CMCC 63202), staphylococcus aureus (S.aureus ATCC25923, which is an erythromycin-sensitive strain), streptococcus pyogenes (S.pyogenes 1, which is an erythromycin-sensitive strain), enterococcus faecium (E.faecalis ATCC19434, which is a vancomycin-sensitive strain), enterococcus faecalis (E.faecalis ATCC29212, which is a vancomycin-sensitive strain), pseudomonas aeruginosa (P.aeruginosa ATCC27853, which is a penicillin-sensitive strain), and escherichia coli (E.coli ATCC25922, which is a penicillin-sensitive strain), the drug-resistant bacteria are staphylococcus aureus (S.aureus ATCC43300, which is a methicillin-resistant strain), staphylococcus aureus (S.aureus PR, which is a penicillin-resistant strain), staphylococcus aureus (S.51552), staphylococcus aureus (S.aureus, s. Pyogenes, s 2, s. Faecalis a clinical staphylococcus aureus, and a plurality of staphylococcus aureus (s. Faecalis a strain, which is a strain of staphylococcus aureus, a clinical resistant to staphylococcus aureus, a strain of staphylococcus aureus or a strain of staphylococcus aureus resistant to staphylococcus aureus, and a strain of staphylococcus aureus resistant to staphylococcus aureus, a strain of staphylococcus aureus resistant to penicillin.
The antibacterial product is one or more of medicines, washing products, medical appliances, kitchen ware, food preservatives and catering appliances; the cleaning and caring product is one or more of fruit and vegetable cleaning agent, shampoo, soap, bath lotion, laundry detergent, liquid soap, toilet cleaner, and facial cleanser.
In a seventh aspect, the present invention provides a method for inhibiting gram-positive bacteria, which comprises administering the aromatic ring-substituted pyridinium quaternary derivative of the first aspect and/or the pharmaceutical composition of the fourth aspect and/or the medicament of the seventh aspect to a subject in need thereof.
The beneficial effects obtained by one or more technical schemes of the invention are as follows:
(1) The aromatic ring-substituted quaternary pyridinium derivative, the pharmaceutical composition and the medicament provided by the invention have better effects on bacillus subtilis (B.subtilis ATCC9372, which is a penicillin-sensitive strain), bacillus pumilus (B.pumipis CMCC 63202), staphylococcus aureus (S.aureus ATCC25923, which is an erythromycin-sensitive strain), streptococcus pyogenes (S.pyogenes 1, which is an erythromycin-sensitive strain), enterococcus faecium (E.faecium ATCC19434, which is a vancomycin-sensitive strain), enterococcus faecalis (E.faecium ATCC29212, which is a vancomycin-sensitive strain), pseudomonas aeruginosa (P.aeruginosa ATCC27853, which is a penicillin-sensitive strain) and escherichia coli (E.55colii ATCC25922, which is a penicillin-sensitive strain), staphylococcus aureus (S.aurea ATCC43300, which is a methicillin-resistant strain), staphylococcus aureus (S.aurea PR, which is a penicillin-resistant strain), staphylococcus aureus (S.55coccus aureus CI, which is a clinical isolation resistant staphylococcus aureus), staphylococcus aureus (S.aurea ATCC51299, which is a pyogenes-resistant strain, staphylococcus aureus (S.55cois) and staphylococcus aureus (S.pyogenes ATCC51299, which is a pyogenes-resistant strain), and staphylococcus aureus (S.pyogenes) which is a pyogenes strain, and a pyogenic strain, which is a pyogenic strain, and a pyogenic strain with the like, and a pyogenic strain.
(2) The antibacterial activity of a plurality of compounds in the general formula Ia is better than that of a positive compound on a plurality of strains, the antibacterial effect on S.aureus ATCC25923 strain in sensitive strains is best, and the MIC values of compounds II-8, II-15 and II-19 all reach the level of 0.062 mu g/ml, and are far more than that of the existing positive compound. In addition, it is noted that the compound of formula Ia also had a relatively good antimicrobial effect against the difficult-to-kill E.faecium ATCC19434, and the MIC values for both compounds II-8 and II-15 reached a level of 0.125. Mu.g/ml.
(3) The drug-resistant strains of the compound in the general formula Ia also have good antibacterial activity, wherein the MIC value of the compound II-8II-16 to the S.aureus ATCC43300 strain reaches the level of 0.125 mu g/ml, and the antibacterial activity is respectively 128, 4, 64 and 512 times of that of positive ciprofloxacin (Cip), linezolid (Lin), sanguinarine (San) and berberine (Ber). The MIC value of the compound II-8 to the S.aureus CI strain reaches a level of 0.062. Mu.g/ml, and the antibacterial activity is 256, 32, 128 and 1024 times that of ciprofloxacin (Cip), linezolid (Lin), sanguinarine (San) and berberine (Ber) which are positive compounds respectively.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
FIG. 1 is a synthetic route of an aromatic ring-substituted pyridinium quaternary derivative of general formula I in the present invention;
FIG. 2 is a synthetic route of the aromatic ring-substituted pyridinium quaternary derivative of the general formula II in the present invention;
FIG. 3 is a chemical formula of an aromatic ring-substituted pyridinium quaternary derivative of general formula I in the present invention;
FIG. 4 shows the chemical formula of the aromatic ring-substituted pyridinium quaternary derivative of the general formula II in the present invention.
Detailed Description
In order to make the technical solution of the present invention more clearly understood by those skilled in the art, the technical solution of the present invention will be described in detail below with reference to specific examples and comparative examples.
Example 1
Step a: preparation of 2-chloro-4-methyl-5-phenylpyridine (intermediate 2)
5-bromo-2-chloro-3-methylpyridine (2.05g, 10mmol), phenylboronic acid (1.34g, 111mmol), potassium carbonate (2.76g, 20mmol) and a catalytic amount of [1,1' -bis (diphenylphosphino) ferrocene were weighed]Palladium dichloride (0.07g, 0.1mmol) was dissolved in 80mL of 1,4-dioxane: h 2 O = 10. The reaction was heated to 80 ℃ for 8h, and after completion of the reaction was monitored by TLC, the cooled reaction solution was subjected to reduced pressure rotary evaporation to remove the reaction solvent, dissolved in dichloromethane, washed with water three times, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, filtered under reduced pressure, and purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate = 200) to give 1.75g of a white solid, intermediate 2, yield 86%.
Step b: preparation of 3-methyl-2,5-diphenylpyridine (intermediate 3)
Weighing 2-chloro-4-methyl-5-phenylpyridine (2.03g, 10mmol), phenylboronic acid (1.34g, 11mmol), potassium carbonate (2.76g, 20mmol) and a catalytic amount of tetratriphenylphosphine palladium (0.12g, 0.10mmol) in 80mL of 1,4-dioxane: h 2 O = 10. The reaction was heated to 80 ℃ for 12h, and after completion of the reaction was monitored by TLC, the reaction solvent was removed by rotary evaporation under reduced pressure from the cooled reaction solution, dissolved in dichloromethane and washed repeatedly three times with water, dried over anhydrous sodium sulfate, filtered under vacuum to remove anhydrous sodium sulfate, filtered under reduced pressure, and purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate = 200) to give 1.98g of a white solid, i.e., intermediate 3, in 81% yield.
Step c: preparation of 3- (bromomethyl) -2,5-diphenylpyridine (intermediate 4)
3-methyl-2,5-diphenylpyridine (1.80g, 7.3mmol) was weighed, 100mL of carbon tetrachloride was added thereto as a solvent, and the temperature was raised to 60 ℃. Azobisisobutyronitrile (0.12g, 0.7 mmol) was added to the solution as an initiator, and stirred at this temperature for 30min. N-bromosuccinimide (0.12g, 8.01mmol) was then added and the mixture was heated to reflux and heating continued for 4h. After completion of the reaction was monitored by TLC, dichloromethane was added for dilution. Separating organic phase, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain crude product. Separation by silica gel column chromatography (petroleum ether/ethyl acetate = 100) again afforded intermediate 4 as a yellow solid 1.79g in 76% yield.
Step d: preparation of diethyl ((2,5-diphenylpyridin-3-yl) methyl) phosphonate (intermediate 5)
3- (bromomethyl) -2,5-diphenylpyridine (1.5g, 4.6mmol) was weighed and dissolved in 4mL triethyl phosphite, and the reaction solution was heated to reflux state and reacted for 4h. After completion of the reaction was monitored by TLC, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove excess triethyl phosphite to give 1.6g of oil, intermediate 5, yield 93%.
Step e: (E) Preparation of (E) -3- (4-methylstyryl) -2,5-diphenylpyridine (intermediate 6-1)
Diethyl ((2,5-diphenylpyridin-3-yl) methyl) phosphonate (0.20g, 0.52mmol) and 4-methylbenzaldehyde (0.074g, 0.64mmol) were weighed out and dissolved in dry tetrahydrofuran (25 mL), sodium hydrogen (0.025g, 1.04mmol) was added carefully under ice bath at 0 ℃ and stirred for 15min, after which the reaction solution was allowed to warm to room temperature and stirred overnight. After the reaction was monitored by TLC, after quenching with water, the resulting mixture was extracted 3 times with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. Further separation by silica gel column chromatography (dichloromethane/methanol = 80) gave 0.12g of solid, i.e. intermediate 6-1, yield 72%.
Step f: (E) Preparation of (E) -1-methyl-3- (4-methylstyryl) -2,5-diphenylpyridine iodonium salt (I-1)
(E) -3- (4-Methylstyryl) -2,5-diphenylpyridine (100mg, 0.29mmol) was dissolved in a sealed tube, and excess iodomethane (0.41g, 2.9mmol) was added. The mixture was heated at 85 ℃ for 24 hours, and after completion of the reaction was monitored by TLC, isopropyl ether (50 mL) was added to isolate a brown solid. The crude product was purified by silica gel column chromatography (dichloromethane/methanol = 15) to give 98mg, i.e. I-1, of the corresponding target product of general formula I in 69% yield.
Example 2
In contrast to example 1, 4-methylbenzaldehyde was replaced with the same molar amount of 4-ethylbenzaldehyde in step e to give I-2.
Example 3
In contrast to example 1, 4-methylbenzaldehyde was replaced with the same molar amount of 4-isopropylbenzaldehyde in step e to give I-3.
Example 4
In contrast to example 1, 4-methylbenzaldehyde was replaced with the same molar amount of 4-tert-butylbenzaldehyde in step e to give I-4.
Example 5
In contrast to example 1, 4-methylbenzaldehyde was replaced with the same molar amount of 4-chlorobenzaldehyde in step e to give I-5.
Example 6
In contrast to example 1, the 4-methylbenzaldehyde in step e was replaced with the same molar amount of 2-nitrobenzaldehyde to give I-6.
Example 7
In contrast to example 1, 4-methylbenzaldehyde in step e was replaced with the same molar amount of 4-cyanobenzaldehyde to give I-7.
Example 8
In contrast to example 1, 4-methylbenzaldehyde in step e was replaced with the same molar amount of 4-trifluoromethylbenzaldehyde to give I-8.
Example 9
In contrast to example 1, the 4-methylbenzaldehyde in step e was replaced with the same molar amount of 3,4-dichlorobenzaldehyde to give I-9.
Example 10
In contrast to example 1, the 4-methylbenzaldehyde in step e was replaced with the same molar amount of 4-bromobenzaldehyde to give I-10.
Example 11
In contrast to example 1, 4-methylbenzaldehyde was replaced with the same molar amount of 3-bromobenzaldehyde in step e to give I-11.
Example 12
In contrast to example 1, the 4-methylbenzaldehyde in step e was replaced with the same molar amount of 3,4,5-trimethoxybenzaldehyde to give I-12.
Example 13
In contrast to example 1, 4-methylbenzaldehyde was replaced with the same molar amount of 4-fluorobenzaldehyde in step e to give I-13.
Example 14
In contrast to example 1, 4-methylbenzaldehyde was replaced with the same molar amount of 4-methoxybenzaldehyde in step e to give I-14.
Example 15
In contrast to example 1, 4-methylbenzaldehyde was replaced with the same molar amount of 4-ethoxybenzaldehyde in step e, giving I-15.
Example 16
In contrast to example 1, 4-methylbenzaldehyde in step e was replaced with the same molar amount of 4-propoxybenzaldehyde to give I-16.
Example 17
In contrast to example 1, the 4-methylbenzaldehyde in step e was replaced with the same molar amount of 4-butoxybenzaldehyde to give I-17.
Example 18
In contrast to example 1, 4-methylbenzaldehyde was replaced with the same molar amount of 4-pentyloxybenzaldehyde in step e to give I-18.
Example 19
In contrast to example 1, the 4-methylbenzaldehyde in step e was replaced with the same molar amount of 4-hexyloxybenzaldehyde to give I-19.
Example 20
In contrast to example 1, 4-methylbenzaldehyde in step e was replaced with the same molar amount of 4-heptyloxybenzaldehyde to give I-20.
The chemical formulas of the target products of the general formula I, namely I-1 to I-20 are shown in figure 3, and the related nuclear magnetism information is shown in table 1.
Tables 2I-1 to I-20H 1 NMR nuclear magnetic information
Example 21
Step g: preparation of 2-chloro-4-methyl-5-phenylpyridine (intermediate 8-1)
5-bromo-2-chloro-4-methylpyridine (2.05g, 10mmol), phenylboronic acid (1.34g, 111mmol), potassium carbonate (2.76g, 20mmol) and a catalytic amount of [1,1' -bis (diphenylphosphino) ferrocene were weighed]Palladium dichloride (0.07g, 0.1mmol) was dissolved in 80mL of 1,4-dioxane: h 2 O = 10. Heating the reaction at 80 deg.C, reacting for 8h, monitoring reaction completion by TLC, removing reaction solvent by rotary evaporation under reduced pressure, dissolving with dichloromethane, repeatedly washing with water for three times, drying with anhydrous sodium sulfate, vacuum filtering to remove anhydrous sodium sulfate, filtering under reduced pressure, filtering, and filteringPurification by silica gel column chromatography (eluent petroleum ether/ethyl acetate = 200) gave 1.81g of white solid, i.e. intermediate 8-1, yield 89%.
Step h: preparation of 4-methyl-2,5-diphenylpyridine (intermediate 9-1)
Weighing 2-chloro-4-methyl-5-phenylpyridine (2.03g, 10mmol), phenylboronic acid (1.34g, 11mmol), potassium carbonate (2.76g, 20mmol) and a catalytic amount of tetratriphenylphosphine palladium (0.12g, 0.10mmol) in 80mL of 1,4-dioxane: h 2 O = 10. The reaction was heated to 80 ℃ for 12h, and after completion of the reaction was monitored by TLC, the reaction solvent was removed by rotary evaporation under reduced pressure from the cooled reaction solution, dissolved in dichloromethane and washed repeatedly three times with water, dried over anhydrous sodium sulfate, filtered under vacuum to remove anhydrous sodium sulfate, filtered under reduced pressure, and purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate = 200) to give 2.07g of a white solid, i.e., intermediate 9-1, with a yield of 85%.
Step i: preparation of 1,4-dimethyl-2,5-diphenylpyridine iodonium salt (intermediate 10-1)
4-methyl-2,5-diphenylpyridine (2g, 8.2mmol) was dissolved in a sealed tube, and excess methyl iodide (11.64g, 82mmol) was added. The mixture was heated at 85 ℃ for 24 hours and after monitoring the reaction by TLC to completion isopropyl ether (200 mL) was added to isolate a brown solid. The crude product was purified by silica gel column chromatography (dichloromethane/methanol = 15) to give 2.41g of the product, i.e., intermediate 10-1, in 76% yield.
Step j: (E) Preparation of (E) -1-methyl-2,5-diphenyl-4-styrylpyridinium iodide (II-1)
1,4-dimethyl-2,5-diphenylpyridine iodonium salt (0.2g, 0.52mmol) was dissolved in n-butanol (25 ml), 4-tert-butylbenzaldehyde (0.1g, 0.62mmol) was added, and a catalytic amount of 4-methylpiperidine (0.01g, 0.1mmol) was added. The mixture was heated at 100 ℃ for 12 hours and after monitoring the reaction by TLC, crude product was obtained as a black oil after rotary evaporation under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane/methanol = 15) to give the corresponding target product of general formula II 0.17g, a yellow solid, i.e. II-1, in 62% yield.
Example 22
In contrast to example 21, 4-tert-butylbenzaldehyde was replaced in step j with the same molar amount of 4-hydroxybenzaldehyde to give II-2.
Example 23
In contrast to example 21, 4-tert-butylbenzaldehyde was replaced with the same molar amount of 4-pentylbenzaldehyde in step j, giving II-3.
Example 24
In contrast to example 21, 4-tert-butylbenzaldehyde was replaced by the same molar amount of 4-hexylbenzaldehyde in step j to give II-4.
Example 25
In contrast to example 21, 4-tert-butylbenzaldehyde was replaced with the same molar amount of 4-diethylaminobenzaldehyde in step j to give II-5.
Example 26
In contrast to example 21, 4-tert-butylbenzaldehyde was replaced in step j with the same molar amount of 4-fluorobenzaldehyde to give II-6.
Example 27
In contrast to example 21, 4-tert-butylbenzaldehyde was replaced with the same molar amount of 4-aminobenzaldehyde in step j to give II-7.
Example 28
In contrast to example 21, the phenylboronic acid was replaced in step h with the same molar amount of 4-tert-butylboronic acid to give II-8.
Example 29
In contrast to example 28, 4-tert-butylbenzaldehyde was replaced in step j with the same molar amount of 4-hydroxybenzaldehyde to give II-9.
Example 30
In contrast to example 28, 4-tert-butylbenzaldehyde was replaced with the same molar amount of 4-ethoxybenzaldehyde in step j, giving II-10.
Example 31
In contrast to example 28, 4-tert-butylbenzaldehyde was replaced by the same molar amount of 4-isopropylbenzaldehyde in step j, giving II-11.
Example 32
In contrast to example 28, 4-tert-butylbenzaldehyde was replaced in step j with the same molar amount of 4-dimethylaminobenzaldehyde to give II-12.
Example 33
In contrast to example 28, 4-tert-butylbenzaldehyde was replaced by the same molar amount of 4-fluorobenzaldehyde in step j to give II-13.
Example 34
In contrast to example 28, 4-tert-butylbenzaldehyde was replaced with the same molar amount of 4-aminobenzaldehyde in step j to give II-14.
Example 35
In contrast to example 28, 4-tert-butylbenzaldehyde was replaced with the same molar amount of 4-pyrrolidinobenzaldehyde in step j to give II-15.
Example 36
In contrast to example 28, 4-tert-butylbenzaldehyde was replaced with the same molar amount of 4-piperidinobenzaldehyde in step j to give II-16.
Example 37
In contrast to example 28, 4-tert-butylbenzaldehyde was replaced in step j with the same molar amount of 3,4-dichlorobenzaldehyde, giving II-17.
Example 38
In contrast to example 28, phenylboronic acid was replaced in step g with the same molar amount of 2-methylphenylboronic acid to give II-18.
Example 39
In contrast to example 38, 4-tert-butylbenzaldehyde was replaced in step j with the same molar amount of 4-hydroxybenzaldehyde to give II-19.
Example 40
In contrast to example 38, 4-tert-butylbenzaldehyde was replaced with the same molar amount of 4-ethylbenzaldehyde in step j to give II-20.
EXAMPLE 41
In contrast to example 38, 4-tert-butylbenzaldehyde was replaced with the same molar amount of 4-methylbenzaldehyde in step j to give II-21.
Example 42
In contrast to example 38, 4-tert-butylbenzaldehyde was replaced in step j with the same molar amount of 4-dimethylaminobenzaldehyde to give II-22.
Example 43
In contrast to example 38, 4-tert-butylbenzaldehyde was replaced in step j with the same molar amount of 4-fluorobenzaldehyde to give II-23.
Example 44
In contrast to example 21, phenylboronic acid was replaced with the same molar amount of 1-naphthalene boronic acid in step h to give II-24.
Example 45
In contrast to example 44, 4-tert-butylbenzaldehyde was replaced by the same molar amount of 4-isopropylbenzaldehyde in step j, giving II-25.
Example 46
In contrast to example 44, 4-tert-butylbenzaldehyde was replaced with the same molar amount of 4-acetylbenzaldehyde in step j, giving II-26.
Example 47
In contrast to example 44, 4-tert-butylbenzaldehyde was replaced with the same molar amount of 4-pyrrolidinobenzaldehyde in step j to give II-27.
Example 48
In contrast to example 44, 4-tert-butylbenzaldehyde was replaced with the same molar amount of 4-piperidinobenzaldehyde in step j to give II-28.
The target products of formula II, i.e., the chemical formulas II-1 to II-28, are shown in FIG. 4, and the associated nuclear magnetic information is shown in Table 2.
Tables 2H of II-1 to II-28 1 NMR nuclear magnetic information
Example 49
In this example, compounds I-1 through I-20 and II-1 through II-28 were selected for their inhibitory activity against sensitive and resistant strains of bacteria. The sensitive strains comprise eight sensitive strains: sensitive bacillus subtilis ATCC9372, which is a penicillin sensitive strain), bacillus pumilus (b.pumilus CMCC 63202), staphylococcus aureus (s.aureus ATCC25923, which is an erythromycin sensitive strain), streptococcus pyogenes (s.pyogenes 1, which is an erythromycin sensitive strain), enterococcus faecium (e.faecium ATCC19434, which is a vancomycin sensitive strain), enterococcus faecalis (e.faecium ATCC29212, which is a vancomycin sensitive strain), pseudomonas aeruginosa (p.aeruginosa ATCC27853, which is a penicillin sensitive strain), and escherichia coli (e.coli ATCC25922, which is a penicillin sensitive strain); the drug-resistant strains comprise seven drug-resistant strains: drug-resistant staphylococcus aureus (s.aureus ATCC43300, a methicillin-resistant strain), staphylococcus aureus (s.aureus PR, a penicillin-resistant strain), staphylococcus aureus (s.aureus CI, a clinically isolated drug-resistant strain), staphylococcus epidermidis (s.epidermidis, a penicillin-resistant strain), drug-resistant streptococcus pyogenes (s.pyogenes 2, a erythromycin-resistant strain), enterococcus faecalis (e.faecalis ATCC51299, a vancomycin-resistant strain), and enterococcus faecium (e.faecium ATCC51559, a vancomycin-resistant strain).
MIC of each aromatic ring substituted pyridine quaternary ammonium salt derivative (namely compounds I-1 to I-20 and II-1 to II-28 of the invention) and sanguinarine (San), berberine (Ber), linezolid (Lin) and ciprofloxacin (ciprofloxacin) is determined by adopting a continuous micropore double dilution method, and a compound with strong antibacterial action is screened according to the result of the MIC. Control sanguinarine, berberine, linezolid, ciprofloxacin were purchased from annaiji chemistry.
Table 3. Investigation result of antibacterial activity of compound of general formula Ia in the application on sensitive strains
Table 4. Investigation result of antibacterial activity of compound of general formula Ia in the application on drug-resistant strains
As can be seen from the above experimental results, the aromatic ring-substituted quaternary pyridinium derivative of the present invention has excellent antibacterial activity against sensitive strains such as sensitive bacillus subtilis (b.subtilis ATCC9372, which is a penicillin sensitive strain), bacillus pumilus (b.pumilus CMCC 63202), staphylococcus aureus (s.aureus ATCC25923, which is an erythromycin sensitive strain), streptococcus pyogenes (s.pyogenes 1, which is an erythromycin sensitive strain), enterococcus faecium (e.faecium ATCC19434, which is a vancomycin sensitive strain), enterococcus faecalis (e.faecium ATCC29212, which is a vancomycin sensitive strain), pseudomonas aeruginosa (p.aeruginosa ATCC27853, which is a penicillin sensitive strain), and escherichia coli (e.coli ATCC25922, which is a penicillin sensitive strain). The antibacterial activity of a plurality of compounds in the general formula Ia is better than that of a positive compound on a plurality of strains, the antibacterial effect on S.aureus ATCC25923 strain in a sensitive strain is best, wherein the MIC values of the compounds II-8, II-15 and II-19 reach the level of 0.062 mu g/ml and are far more than that of the positive compound. In addition, it is noted that the compound of formula Ia also has a relatively good antibacterial effect on the E.faeciumATCC19434 which is difficult to kill, and the MIC values of the compounds II-8 and II-15 both reach the level of 0.125. Mu.g/ml.
Meanwhile, the aromatic ring-substituted quaternary pyridinium derivative of the present invention has good antibacterial activity against drug-resistant strains such as drug-resistant staphylococcus aureus (s.aureus ATCC43300, which is a methicillin-resistant strain), staphylococcus aureus (s.aureus PR, which is a penicillin-resistant strain), staphylococcus aureus (s.aureus CI, which is a clinically isolated drug-resistant strain), staphylococcus epidermidis (s.epidermidis, which is a penicillin-resistant strain), drug-resistant streptococcus pyogenes (s.pyogenes 2, which is a erythromycin-resistant strain), enterococcus faecalis (e.faecalis ATCC51299, which is a vancomycin-resistant strain), and enterococcus faecium (e.faecium ATCC51559, which is a vancomycin-resistant strain). Wherein the MIC values of compounds II-8 and II-16 to S.aureus ATCC43300 strain reached a level of 0.125. Mu.g/ml, and the antibacterial activities were 128, 4, 64 and 512 times those of the positive compounds ciprofloxacin (Cip), linezolid (Lin), sanguinarine (San) and berberine (Ber), respectively. The MIC value of the compound II-8 to the S.aureus CI strain reaches a level of 0.062. Mu.g/ml, and the antibacterial activity is 256, 32, 128 and 1024 times that of ciprofloxacin (Cip), linezolid (Lin), sanguinarine (San) and berberine (Ber) which are positive compounds respectively.
Example 50: measurement of Minimum Bactericidal Concentration (MBC) of aromatic ring-substituted pyridinium Quaternary salt derivative
This example measured the Minimum Bactericidal Concentration (MBC) of the aromatic ring-substituted pyridinium quaternary derivative (compounds I-1 to I-20 and II-1 to II-28 of the present invention). The minimum bactericidal concentration (meaning the minimum concentration of drug required to kill 99.9% of the bacteria in the medium (i.e., by 3 orders of magnitude) is usually expressed in μ g/mL. This index can be used to judge the degree of in vitro bactericidal effect of a drug, as with MIC, the smaller the number, the stronger the effect of the drug. The plating method can measure the MBC value, and based on the MIC measured by the broth dilution method, the drug and bacterial liquid at the full concentration without bacterial growth are inoculated onto a new agar plate for culture, after 18-24h of culture, if bacteria grow again, the drug shows only bacteriostatic effect at this concentration, and if bacteria grow aseptically, the drug is considered to have bactericidal effect, and the minimum drug concentration for aseptic growth is expressed as MBC. Compounds II-8, II-12, II-15, II-18, II-19 and II-22 in the in vitro antibacterial activity test, we further measure both MBC, judge its bacteriostatic properties, or the bactericidal properties of ATCC 25923.923, ATCC 439372, ATCC 72.
According to the standards of the Clinical and Laboratory Standards Institute (CLSI), MBC/MIC ≦ 4 is considered a bactericidal behavior, while MBC/MIC ≧ 8 is considered a bacteriostatic behavior. The results shown in Table 5 indicate that II-8 and II-22 showed their bactericidal characteristics against all strains tested, and that II-8 and II-22 showed bactericidal effects both against sensitive and resistant strains, clearly indicating their bactericidal patterns. Other compounds exhibit varying degrees of bactericidal or bacteriostatic effects. The control drugs sanguinarine and linezolid showed bacteriostatic effects on most of the strains tested, with the MBC of sanguinarine even being >64 μ g/mL.
TABLE 5 comparison of MIC and MBC for Compounds II-8, II-12, II-15, II-18, II-19 and II-22 against 3 strains
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. An aromatic ring-substituted quaternary pyridinium salt derivative, wherein the aromatic ring-substituted quaternary pyridinium salt derivative is selected from a compound shown in formula Ia, or a pharmaceutically acceptable salt, ester, solvate, tautomer, mesomer, racemate, stereoisomer, metabolite or prodrug thereof; the formula Ia is shown below:
wherein R in Ia 1 The number of the substituent groups on the benzene ring can be one or more, and each substituent group is one of C1-C8 straight-chain or branched alkyl, alkoxy, alkylamino, halogen, nitro, fluoroalkyl, fluoroalkoxy and acetyl independently; x in Ia is halogen; r in Ia 2 Is an aromatic substituent comprising substituted phenyl, unsubstituted phenyl and naphthyl; r in Ia 3 Selected from methyl, or the site has no group.
2. The aromatic ring-substituted pyridinium quaternary derivative according to claim 1, wherein in the compound of formula Ia, R is the 3-position substituted styryl group 2 Is substituted by benzene ring, R 3 When the compound is at the hydrogen position, the structure of the compound is shown as the following formula I:
wherein R is 1 One or more selected from C1-C8 straight chain or branched chain alkyl, alkoxy, halogen, nitro, fluoroalkyl and fluoroalkoxy,the R is 1 The substitution site is one or more of C-2, C-3, C-4 and C-5 positions; the X is I; further, said R 1 One of 4-methyl, 4-ethyl, 4-isopropyl, 4-tert-butyl, 4-chloro, 2-nitro, 4-cyano, 4-trifluoromethyl, 3,4-dichloro, 4-bromo, 3-bromo, 3,4,5-trimethoxy, 4-fluoro, 4-methoxy, 4-ethoxy, 4-propoxy, 4-butoxy, 4-pentyloxy, 4-hexyloxy, 4-heptyloxy.
3. The aromatic ring-substituted pyridinium quaternary derivative according to claim 1, wherein in the compound of formula Ia, when the styryl group is substituted at the 4-position, the compound has the following formula II:
wherein R is 1 One or more selected from C1-C8 straight chain or branched chain alkyl, alkoxy, alkylamino, halogen, acetyl and hydroxyl, and R is 1 The substitution site is one or two of C-3 and C-4; the X is I; further, said R 1 One selected from the group consisting of 4-tert-butyl, 4-hydroxy, 4-pentyloxy, 4-hexyloxy, 4-dimethylamino, 2-nitro, 4-fluoro, 4-amino, 3,4-dichloro, 4-isopropyl, 4-ethoxy, 4-isopropyl, 4-pyrrolidinyl, 4-piperidinylalkyl, 4-acetyl and 4-diacetamido; said R is 2 One selected from phenyl, 4-tert-butylphenyl and naphthyl; the R is 3 One selected from hydrogen and methyl.
4. The method for preparing an aromatic ring-substituted pyridinium quaternary derivative according to claim 2, comprising the steps of:
the operation mode of the step a is as follows: dissolving Compound 1 in 1,4-dioxygenSix rings of H 2 O =10, 1 in [1,1' -bis (diphenylphosphino) ferrocene]Under the condition of palladium dichloride catalysis, K is added 2 CO 3 Reacting with phenylboronic acid by heating to generate an intermediate 2; further, the heating temperature is 70-90 ℃, and the reaction time is 6-12 hours;
the operation of step b is as follows: dissolving Compound 2 in 1,4-dioxane H 2 In a mixed solvent of O =10 and 1, adding K under the catalysis of palladium tetratriphenylphosphine 2 CO 3 And phenylboronic acid, heating and reacting to generate an intermediate 3; further, the heating temperature is 70-90 ℃, and the reaction time is 8-16 hours;
the operation of step c is as follows: dissolving the intermediate 3 in carbon tetrachloride or chloroform, and adding N-bromosuccinimide to react under the initiation condition of azodiisobutyronitrile to generate an intermediate 4; further, the reaction temperature is 60-80 ℃, and the reaction time is 4-8 hours;
the operation of step d is as follows: dissolving the intermediate 4 in triethyl phosphite, and heating to react to generate an intermediate 5; further, the heating reaction time is 120-150 ℃, and the reaction time is 2-6 hours;
the procedure of step e is as follows: dissolving the intermediate 5 in tetrahydrofuran, and adding aldehydes to react in the presence of inorganic base to generate an intermediate 6; further, the reaction heating temperature is 25-40 ℃, and the reaction time is 8-12 hours;
the operation of step f is as follows: and dissolving the intermediate 6 in a polar aprotic solvent, adding excessive methyl iodide, and reacting at 42-80 ℃ for 15-24 hours to generate the compound shown in the formula I.
5. The method for preparing an aromatic ring-substituted quaternary pyridinium derivative according to claim 3, comprising the steps of:
operation of step gThe method is as follows: dissolving Compound 7 in 1,4-dioxane H 2 O =10, 1 in [1,1' -bis (diphenylphosphino) ferrocene]Under the condition of palladium dichloride catalysis, K is added 2 CO 3 Reacting with phenylboronic acid by heating to generate an intermediate 8; further, the heating temperature is 70-90 ℃, and the reaction time is 6-12 hours;
the operation of step h is as follows: dissolving intermediate 8 in 1,4-dioxane H 2 In a mixed solvent of O =10 and 1, adding K under the catalysis of palladium tetratriphenylphosphine 2 CO 3 Reacting with phenylboronic acid by heating to generate an intermediate 9; further, the heating temperature is 70-90 ℃, and the reaction time is 8-16 hours;
the operation of step i is as follows: dissolving the intermediate 9 in a polar aprotic solvent, adding excessive methyl iodide, and reacting at 42-80 ℃ for 15-24 hours to generate an intermediate 10;
the operation of step j is as follows: dissolving the intermediate 10 in n-butanol, and heating to react under the condition of catalysis of tetramethyl piperidine to generate a compound shown as a formula II; further, the heating temperature is 90-110 ℃, and the reaction time is 12-24 hours.
6. A pharmaceutical composition comprising the aromatic ring-substituted quaternary pyridinium derivative according to any one of claims 1-3 and a carrier.
7. A pharmaceutical comprising the aromatic ring-substituted quaternary ammonium salt derivative according to any one of claims 1 to 3 and/or the pharmaceutical composition according to claim 6.
8. Use of the aromatic ring-substituted quaternary pyridinium salt derivative according to any one of claims 1-3 and/or the pharmaceutical composition according to claim 6 and/or the pharmaceutical according to claim 7 for the preparation of an antibacterial product.
9. The use of claim 8, wherein the bacteria are susceptible bacteria and resistant bacteria, the susceptible bacteria are one or more of bacillus subtilis, bacillus pumilus, staphylococcus aureus, streptococcus pyogenes, enterococcus faecium, enterococcus faecalis, pseudomonas aeruginosa, and escherichia coli, and the resistant bacteria are one or more of staphylococcus aureus, staphylococcus epidermidis, drug-resistant streptococcus pyogenes, enterococcus faecalis, and enterococcus faecium;
the antibacterial product is one or more of medicines, washing products, medical appliances, kitchen ware, food preservatives and catering appliances; the cleaning and caring product is one or more of fruit and vegetable cleaning agent, shampoo, soap, bath lotion, laundry detergent, liquid soap, toilet cleaner, and facial cleanser.
10. A method for inhibiting gram-positive bacteria, which comprises administering the aromatic ring-substituted quaternary pyridinium derivative according to any one of claims 1-3 and/or the pharmaceutical composition according to claim 6 and/or the pharmaceutical according to claim 7 to a subject in need thereof.
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| CN112939964A (en) * | 2021-03-09 | 2021-06-11 | 山东大学 | Benzo-heterocycle substituted phenanthridine quaternary ammonium salt derivative and preparation method and application thereof |
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| CN112939964A (en) * | 2021-03-09 | 2021-06-11 | 山东大学 | Benzo-heterocycle substituted phenanthridine quaternary ammonium salt derivative and preparation method and application thereof |
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