CN108478574B - Quinoline promise woods class compound is hydrogenated in enhancing bacterium to the application in polymyxins sensibility - Google Patents

Quinoline promise woods class compound is hydrogenated in enhancing bacterium to the application in polymyxins sensibility Download PDF

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CN108478574B
CN108478574B CN201810494214.7A CN201810494214A CN108478574B CN 108478574 B CN108478574 B CN 108478574B CN 201810494214 A CN201810494214 A CN 201810494214A CN 108478574 B CN108478574 B CN 108478574B
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polymyxins
mcr
class compound
quinoline promise
promise woods
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CN108478574A (en
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柏川
田国宝
劳楚瑜
钟兰兰
温馨
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National Sun Yat Sen University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • 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

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  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

The invention discloses hydrogenation quinoline promise woods class compound in enhancing bacterium to the application in polymyxins sensibility, the present invention passes through in the experiment of the minimum inhibitory concentration of more plants of MCR-1 positive drug-fast bacterias, it was found that hydrogenation quinoline promise woods class compound can make MCR-1 positive drug-fast bacteria multiple to polymyxins quick, to be pushed further into the research and development that MCR-1 positive drug-fast bacteria carries out treatment new strategy, the strong theoretical basis and practical basis for promoting the clinical conversion of therapeutic agent to provide, have important research and development value and development significance.

Description

Quinoline promise woods class compound is hydrogenated in enhancing bacterium to the application in polymyxins sensibility
Technical field
The present invention relates to a kind of new opplications of compound, in particular to hydrogenation quinoline promise woods class compound is in enhancing MCR-1 sun Application in the polymyxins sensibility of property drug-fast bacteria.
Background technique
Mcr-1 gene (mobile colistin resistance, moveable polymyxins drug resistant gene) coding produces Raw MCR-1 enzyme has phosphoric acid ethyl alcohol ammonia transferase active, can be catalyzed phosphatidyl-ethanolamine (PEA) and be transferred to epicyte On the 4th phosphate group of lipoid A so that the structure of epicyte lipoid A changes, thus reduce polymyxins with The affinity of lipopolysaccharides changes polymyxins action target spot, and then mediated drug resistance.Also, Feng Youjun etc. has found, MCR-1's The correct expression of transmembrane region and 5 key amino acids (E246, T285, H395,465D, 466H) is that it plays phosphoric acid ethyl alcohol ammonia turn Move the basis of enzymatic activity.
China is one of serious country of bacterial resistance problem, and multidrug resistant and general drug-fast bacteria force doctor's selection " last One line " drug is treated.Polymyxins (Polymyxins) is the most effective " last of clinical treatment severe drug-fast bacteria infection One of one line " drug.Applicant has found mcr-1 gene (the mobile colistin that plasmid carries for the first time in early-stage study Resistance, moveable polymyxins drug resistant gene) polymyxins drug resistance can be mediated.And it is plasmid-mediated can be with level Propagate, cause drug resistance spread speed faster, range it is wider, be to cause the clinical drug resistance circulation way for endangering most serious at present.Value It is noted that applicant reports MCR-1 in the Local primitive exponent in China for the first time and causes infected patient dead, report simultaneously Field planting rate of nearly 2 years MCR-1 in Guangdong Province inpatient and Healthy People enteron aisle significantly increases.Further, applicant reports MCR-1 is easy to coexist to form multidrug resistant and general drug resistance with other " super drug resistant genes ".The above research achievement of applicant It prompts MCR-1 that there is potential fashion trend, is likely to result in the harm of more bad clinical if do not contained.Therefore, research is directed to The new drug of MCR-1 resistance mechanism just becomes the important means for coping with this great basic research problems and public health challenge.So And having currently without any information alert or report hydrogenation quinoline promise woods class compound makes MCR-1 positive drug-fast bacteria to more Acarasiales The multiple quick effect of element.
Summary of the invention
The purpose of the present invention is to provide hydrogenation quinoline promise woods class compound in enhancing bacterium in polymyxins sensibility Using.
The technical solution used in the present invention is:
Hydrogenate the antimicrobial that quinoline promise woods class compound or its acceptable pharmaceutical salts inhibit MCR-1 positive drug-fast bacteria in preparation Application in object, the hydrogenation quinoline promise woods class compound are shown in formula I:
In Formulas I:
R1 and R ' 1 is one kind of H, C1~C4 alkyl, phenyl, halogenophenyl, heterocycle；
R2 is phenyl or heterocycle；
R3 is H or C1~C4 alkyl；
R4 is phenyl, halogenophenyl；
X is NH or O.
Further, R1 is methyl or phenyl.
Further, R ' 1 is H or methyl.
Further, R2 is 3- pyridyl group or 5- pyridyl group.
Further, 2 R4,4- difluorophenyl.
Further, hydrogenation quinoline promise woods class compound is
Further, the acceptable pharmaceutical salts for hydrogenating quinoline promise woods class compound are its Na, K, Ca salt.
Further, also contain polymyxins in the antibacterials.
A kind of antibacterials inhibiting MCR-1 positive drug-fast bacteria, hydrogenation quinoline described above is contained in the antibacterials Promise woods class compound or its acceptable pharmaceutical salts and polymyxins.
Further, in above-mentioned antibacterials, the concentration of polymyxins is 0.5~64mg/L, hydrogenates quinoline promise woods class chemical combination The concentration of object or its acceptable pharmaceutical salts is 5~50 μM.
The beneficial effects of the present invention are:
(1) inventor is with hydrogenation quinoline promise woods class screening compound system, it was confirmed that the present invention hydrogenates quinoline promise woods class chemical combination Object or its acceptable pharmaceutical salts are able to suppress the activity of MCR-1 positive drug-fast bacteria proliferation, cause to inhibit MCR-1 positive drug-fast bacteria It is multiple to polymyxins quick.
(2) present invention is by the way that in the minimum inhibitory concentration of more plants of MCR-1 positive drug-fast bacterias experiment (MIC), discovery is hydrogenated Quinoline promise woods class compound can make MCR-1 positive drug-fast bacteria multiple to polymyxins quick, open to be pushed further into MCR-1 positive drug-fast bacteria The research and development of exhibition treatment new strategy, the strong theoretical basis for promoting the clinical conversion of therapeutic agent to provide and practical basis, tool There are important research and development value and development significance.
Detailed description of the invention
Fig. 1 is that chessboard analytic approach (checkerboard assay) research present invention hydrogenation quinoline promise woods class antifungal is living The design diagram of property.
Specific embodiment
Hydrogenate the antimicrobial that quinoline promise woods class compound or its acceptable pharmaceutical salts inhibit MCR-1 positive drug-fast bacteria in preparation Application in object, the hydrogenation quinoline promise woods class compound are shown in formula I:
In Formulas I:
R1 and R ' 1 is one kind of H, C1~C4 alkyl, phenyl, halogenophenyl, heterocycle；
R2 is phenyl or heterocycle；
R3 is H or C1~C4 alkyl；
R4 is phenyl, halogenophenyl；
X is NH or O.
Preferably, R1 is methyl or phenyl.
Preferably, R ' 1 is H or methyl.
Preferably, R2 is 3- pyridyl group or 5- pyridyl group.
Preferably, R3 is H or methyl.
Preferably, 2 R4,4- difluorophenyl.
Preferably, hydrogenation quinoline promise woods class compound is
Preferably, the acceptable pharmaceutical salts for hydrogenating quinoline promise woods class compound are its Na, K, Ca salt.
Preferably, also contain polymyxins in the antibacterials.
A kind of antibacterials inhibiting MCR-1 positive drug-fast bacteria, hydrogenation quinoline described above is contained in the antibacterials Promise woods class compound or its acceptable pharmaceutical salts and polymyxins.
Preferably, in above-mentioned antibacterials, the concentration of polymyxins is 0.5~64mg/L (preferably 14~18mg/L), The concentration for hydrogenating quinoline promise woods class compound or its acceptable pharmaceutical salts is 5~50 μM.
The present invention is further illustrated combined with specific embodiments below.
Embodiment 1 hydrogenates influence of the quinoline promise woods class compound to bacterial growth
1) 4 plants of MCR-1 positive drug-fast bacterias and Escherichia coli type strain ATCC25922 Bacteria Culture: are chosen as experiment.Gu After the recovery of body LB plate, picking individual colonies, are incubated overnight with MH culture medium respectively, increase bacterium.
2) prepared by bacteria suspension: by 0.5 Maxwell turbidity bacteria suspension of normal saline, being diluted, is made with MH culture solution 1:100 Its bacterial content is 1.5 × 106Cfu/ml, every hole is inoculated with 50 μ l in 96 orifice plates.
3) the various hydrogenation quinoline promise woods class compounds (as shown in table 1) that 50 μ l concentration are 100 μM are added in 96 orifice plates, respectively 4 plants of MCR-1 positive drug-fast bacterias and ATCC25922 are inoculated into 96 holes, every plant of bacterium is inoculated with 50 μ l bacterium solutions, makes every hole total volume 100 μ l, each quinoline promise woods class compound concentration that hydrogenates is 50 μM.Positive control is isometric tested bacterium that compound is not added, yin Property control be 100 μ l MH culture mediums.
4) after 37 DEG C of 16~20h of culture, visually observe in the hole of 96 orifice plates that whether there is or not bacterial growths.
The structural formula of the 1 representative hydrogenation quinoline promise woods class compound in present invention part of table
Experimental result is shown, when the above-mentioned each hydrogenation quinoline promise woods class compound concentration of the present invention is 50 μM, the equal energy of each group bacterium Normal growth, proliferation.Illustrate that present invention hydrogenation quinoline promise woods class compound has no toxic action to bacterium normal growth.
2 high concentration of embodiment hydrogenates effect of the quinoline promise woods class compound enhancing bacterium to polymyxins sensibility
1) Bacteria Culture: 4 plants of MCR-1 positive drug-fast bacterias are chosen and make to be used as experimental strain, Escherichia coli type strain ATCC25922 is as Quality Control bacterium.After the recovery of solid LB plate, picking individual colonies, are incubated overnight with MH culture medium respectively, increase bacterium.
2) prepared by bacteria suspension: by 0.5 Maxwell turbidity bacteria suspension of normal saline, being diluted, is made with MH culture solution 1:100 Its bacterial content is 1.5 × 106Cfu/ml, every hole is inoculated with 50 μ l in 96 orifice plates.
3) polymyxins for being 64mg/ml in the concentration that 25 μ l volumes are added in 96 orifice plates.It then proceedes to add into 96 orifice plates Enter the various hydrogenation quinoline promise woods class compounds (being shown in Table 1) that the concentration of 25 μ l volumes is 200 μM, respectively 4 plants of MCR-1 positive drug resistances Bacterium and ATCC25922 are inoculated into 96 holes, and every plant of bacterium is inoculated with 50 μ l bacterium solutions, make every 100 μ l of hole total volume, polymyxins concentration For 16mg/l, each quinoline promise woods class compound concentration that hydrogenates is 50 μM.Control is set simultaneously, only adds colistin for isometric Medical fluid hole (hole MIC when for independent medication) every plant of bacterium is repeated 3 times in parallel.Positive control be it is isometric be not added compound by Bacterium is tried, negative control is 100 μ l MH culture mediums.
4) after 37 DEG C of 16~20h of culture, visually observe in the hole of 96 orifice plates that whether there is or not bacterial growths.
Experimental result is shown, is only added the control group of colistin and is not added in the positive controls of compound, 96 orifice plates There are a large amount of bacterial growths by Kong Zhongjun；And quinoline promise woods class compound and polymyxins are respectively hydrogenated added with 50 μM of present invention simultaneously Experimental group, the Kong Zhongjun of 96 orifice plates is without bacterial growth.The result illustrates that each hydrogenation quinoline promise woods class compound of the invention is in concentration All having at 50 μM can allow MCR-1 positive drug-fast bacteria multiple to polymyxins quick, i.e. each hydrogenation quinoline promise woods class compound energy of the present invention Enough enhancing MCR-1 positive drug-resistant bacteria is realized with polymyxins collective effect to the sensibility of polymyxins and inhibits MCR-1 sun Property drug-resistant bacteria growth and proliferation effect.
3 low concentration of embodiment hydrogenates effect of the quinoline promise woods class compound enhancing bacterium to polymyxins sensibility
1) Bacteria Culture: choosing 4 plants of MCR-1 positive drug-fast bacterias and Escherichia coli type strain ATCC25922 (is free of mcr-1 Gene) it is used as experimental strain, after the recovery of solid LB plate, picking individual colonies, are incubated overnight with MH culture medium respectively, increase bacterium.
2) prepared by bacteria suspension: by 0.5 Maxwell turbidity bacteria suspension of normal saline, being diluted, is made with MH culture solution 1:100 Its bacterial content is 1.5 × 106Cfu/ml, every hole is inoculated with 50 μ l in 96 orifice plates.
3) respectively each hydrogenation quinoline promise woods class compound of the dilution present invention and polymyxins (6 dilutions, 2 times of MIC value, 1 Times, 1/2,1/4,1/8,1/16 concentration dilution).Laterally it is that gradient direction drops in antibiotic, is longitudinally the drop gradient side of compound To form the various concentration gradient combination of two kinds of substances.Compound is capable of allowing under 50 μM of concentration of proving in embodiment 2 MCR-1 positive drug-fast bacteria is to the multiple quick compound of polymyxins.Every hole is separately added into hydrogenation quinoline promise woods class compound and more Acarasiales Element each 25 μ L, 50 μ L of bacterium solution, 100 μ L of total volume.Control is set simultaneously, " 0 row " is isometric only plus hydrogenated quinoline promise woods class It closes object or only adds the medical fluid hole (hole MIC when for independent medication) of colistin.Positive control is isometric medical fluid to be not added Tested bacterium, negative control are isometric MH culture medium (such as Fig. 1).
4) after 37 DEG C of 16~20h of culture, statistical result.Inhibitor is evaluated according to inhibitory effect.
Experimental result further displays, compound 1:When concentration is 16 μM, i.e., It is multiple to polymyxins quick that example MCR-1 positive drug-fast bacteria can be achieved.When illustrating 16 μM of compound 1 and polymyxins collective effect, It can have the function that inhibit the growth of MCR-1 positive drug-resistant bacteria and proliferation.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention, It should be equivalent substitute mode, be included within the scope of the present invention.

Claims (4)

1. application of the quinoline promise woods class compound in the antibacterials that preparation inhibits MCR-1 positive drug-fast bacteria is hydrogenated, it is described
Hydrogenating quinoline promise woods class compound is
2. application according to claim 1, which is characterized in that also contain polymyxins in the antibacterials.
3. a kind of antibacterials for inhibiting MCR-1 positive drug-fast bacteria, which is characterized in that contain claim in the antibacterials Hydrogenation quinoline promise woods class compound and polymyxins described in 1.
4. a kind of antibacterials for inhibiting MCR-1 positive drug-fast bacteria according to claim 3, which is characterized in that described anti- In bacterium drug, the concentration of polymyxins is 0.5~64mg/L, hydrogenation quinoline promise woods class compound salt described in claim 1 Concentration is 5~50 μM.
CN201810494214.7A 2018-05-22 2018-05-22 Quinoline promise woods class compound is hydrogenated in enhancing bacterium to the application in polymyxins sensibility Active CN108478574B (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104603128A (en) * 2012-06-29 2015-05-06 杜邦公司 Fungicidal heterocyclic carboxamides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104603128A (en) * 2012-06-29 2015-05-06 杜邦公司 Fungicidal heterocyclic carboxamides

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