CN107098874B - N- Thioacyl homoserine lactone class compound, preparation method and the application replaced containing phenylurea - Google Patents
N- Thioacyl homoserine lactone class compound, preparation method and the application replaced containing phenylurea Download PDFInfo
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- CN107098874B CN107098874B CN201710475934.4A CN201710475934A CN107098874B CN 107098874 B CN107098874 B CN 107098874B CN 201710475934 A CN201710475934 A CN 201710475934A CN 107098874 B CN107098874 B CN 107098874B
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- homoserine lactone
- thioacyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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Abstract
The invention belongs to field of medicinal chemistry, disclose a kind of N- Thioacyl homoserine lactone class compound, its synthetic method and its application with the active substitution containing phenylurea of quorum-quenching.Preparation method is simple, mild condition, high income.Activity test in vitro the result shows that, the N- Thioacyl homoserine lactone class compound that the present invention replaces containing phenylurea is to pseudomonas aeruginosalasSystem andpqsSystem significantly inhibits, and can be applied to preparation antibacterium quorum sensing, Trimethoprim and antibacterials.It is with following general formula of the chemical structure:。
Description
Technical field
The present invention relates to a kind of novel N- Thioacyl homoserine lactone class compounds replaced containing phenylurea, its preparation
Method and application, belong to field of medicinal chemistry.
Background technique
During flora growth, bacterium can constantly generate chemical signal molecule and be secreted into ambient enviroment, work as letter
When the concentration of number molecule reaches certain threshold value, it will regulate and control or start the expression such as bioluminescence of thallus related gene, biological quilt
Formation, expression of virulent gene of film etc., to adapt to the variation of environment, this regulator control system is referred to as the quorum sensing of bacterium
(QS) signal system.
Late 1970s, scientists discovery include using natural or artificial synthesized quorum sensing regulator
Agonist or inhibitor can adjust the expression of the bad gene of bacterium with the conduction of interference signal system.Bacterial community induction is adjusted
The normal physiological function of agent not interfering bodies inner cell, simply by the expression for adjusting pathogen deleterious gene, so that it be made to lose
Pathogenecity is accordingly regarded as the new direction of antimicrobial development, and wherein quorum-quenching agent can be with Antibiotic combination
Medication improves pathogenic bacteria to the sensibility of antibiotic, enhances curative effect of medication, a variety of Gram-negatives of primary treatment are microbial
Such as diarrhea, septicemia disease.The acyl side-chain of homoserine lactone is modified, the derivative of the urea structure containing phenyl is synthesized
Object studies its quorum sensing inhibitory activity, to further studying novel antibacterium quorum sensing, Trimethoprim or antimicrobial
Object, drug of developing one's own intellectual property are of great significance, and have no that pertinent literature is reported at present.
Summary of the invention
There is the active N- sulphur replaced containing phenylurea of preferable antibacterium quorum sensing it is an object of that present invention to provide a kind of
For acyl homoserine lactones class compound.
It is a further object to provide its new synthetic methods.Further object of the present invention is to provide the compound
Application in terms of preparation antibacterium quorum sensing, Trimethoprim or antibacterials.
Purpose to realize the present invention, technical solution are as follows:
The N- Thioacyl homoserine lactone class compound replaced containing phenylurea has the following structure general formula:
R is selected from (a): F, Cl, Br or I；Or (b): NO2, Ph, methyl, ethyl, amino, methoxyl group, ethyoxyl, isopropyl,
Tert-butyl, pyrrole radicals or piperidinyl；R is the monosubstituted base or disubstituted on phenyl ring.
It is preferred that following compound:
R is the monosubstituted base on phenyl ring；R substituent is selected from 2,3-Ph, methyl, ethyl, ethyoxyl or methoxyl group.
It is preferred that following particular compound:
The preparation method of above compound provided by the invention is realized by following reaction route:
Homoserine lactone hydrochloride is dissolved in organic solvent, CS is added2It reacts at room temperature with acid binding agent, then adds
Compound 1 obtains the N- Thioacyl homoserine lactone class compound replaced shown in general formula 2 containing phenylurea；
Compound 1:R used is selected from (a): F, Cl, Br or I；Or (b): NO2, Ph, methyl, ethyl, amino, methoxy
Base, ethyoxyl, isopropyl, tert-butyl, pyrrole radicals or piperidinyl；R is the monosubstituted base or disubstituted on phenyl ring.
Acid binding agent used is potassium carbonate, ten phosphate dihydrate trisodiums, sodium carbonate, saleratus, one of sodium bicarbonate
Or two kinds；
Organic solvent used is methanol, ethyl alcohol, acetonitrile, acetone, methyl formate, Ethyl formate, ethyl acetate, acetic acid fourth
One or both of ester, methylene chloride, 1,2- dichloroethanes.
Molar ratio is homoserine lactone hydrochloride: CS2: compound 1: acid binding agent=1:1.1~2:1.1~2:
1.2~3；Reaction time is 2~20 hours.
The present invention designs a kind of novel N- Thioacyl homoserine lactone class compound replaced containing phenylurea of synthesis, and
Its quorum sensing inhibitory activity is studied, its mechanism of action is analyzed, to further studying novel antibacterium quorum sensing, antibacterial synergy
Agent or antibacterials, drug of developing one's own intellectual property are of great significance, and patent CN 201610986981.0 is inventor group
Team early period research achievement, it was recently reported that containing benzheterocycle replace N- acyl homoserine lactones class compound synthetic method and
It incudes in bacterial community, application in terms of Trimethoprim or antibacterials, in the research and development in later period, inventor team again into
One step develops the new construction of such compound, it is found that it has better external activity and application effect.
Detailed description of the invention
Fig. 1 is the influence that the compounds of this invention grows pseudomonas aeruginosa PAOI；
Fig. 2 is influence of the compounds of this invention to pseudomonas aeruginosa PAOI pyo yield；
Fig. 3 is the influence that the compounds of this invention moves pseudomonas aeruginosa PAOI Swarming；
Fig. 4 is the mRNA level in-site that the compounds of this invention synthesizes gene lasI to intervention school-based signaling molecule in PAOI
Influence；
Fig. 5 is influence of the compounds of this invention to the mRNA level of intervention school-based modulin lasR in PAOI；
Fig. 6 is the mRNA level in-site that the compounds of this invention synthesizes gene pqsA to PAOI intervention school-based signaling molecule
It influences；
Fig. 7 is influence of the compounds of this invention to the mRNA level in-site of PAOI intervention school-based modulin pqsR；
Fig. 8 is the mRNA level in-site that the compounds of this invention synthesizes gene rhlI to intervention school-based signaling molecule in PAOI
Influence；
Fig. 9 is influence of the compounds of this invention to the mRNA level in-site of PAOI intervention school-based modulin rhlR.
Specific embodiment
The present invention is described further below with reference to embodiment.
Embodiment 1: derivative shown by general formula 2 (2-a) is prepared
Homoserine lactone hydrochloride (150mg, 1.09mmol) is dissolved in 8mL acetone, ten phosphate dihydrates three are added
Sodium (620mg, 1.63mmol) and CS2(160 μ L), is stirred at room temperature 2h.Then, the chloro- N- of 2- ((2- anisyl) amino first is added
Acyl) acetamide (291mg, 1.20mmol), 6h is reacted at room temperature, system is evaporated, ethyl acetate and water extract, organic layer washing
It is spin-dried for, crude product separates (eluant, eluent: ethyl acetate/petroleum ether=1/1) through silica gel column chromatography, obtains light yellow solid, that is, changes
Close object (2-a) 271mg, yield 65%.
Embodiment 2: derivative shown by general formula 4 (2-b, 2-c) is prepared
The chloro- N- of 2- ((2- anisyl) carbamyl) acetyl is substituted with the chloro- N- of 2- (naphthalene -1- carbamyl) acetamide
Amine, using 1 the method prepare compound 2-b of embodiment.
The chloro- N- of 2- ((2- anisyl) carbamyl) is substituted with the chloro- N- of 2- ((3- tolyl) carbamyl) acetamide
Acetamide, using 1 the method prepare compound 2-c of embodiment.
The chemical structure for the part preferred compound that the present invention synthesizes, nuclear magnetic data such as the following table 1:
Embodiment 3: the compounds of this invention anti-quorum sensing screening test in vitro
The influence that detection compound grows pseudomonas aeruginosa PAO1, under subinhibitory concentration, detection compound is to copper
The influence of green pseudomonad pyo and Swarming movement (see Fig. 1-Fig. 3).Detection compound is to pseudomonas aeruginosa
The influence of PAO1 intervention school-based mRNA expression of gene associated level, i.e. real-time fluorescence quantitative PCR detect pseudomonas aeruginosa
The mRNA expression of QS related gene in PAOI, the mainly formation with bacterium composite signal molecule, biofilm of these genes
Etc. related, including lasI, lasR, pqsA, pqsR, rhlI, rhlR (see Fig. 4-Fig. 9).
The results showed that having compared with the compounds of this invention compound shown by the patent CN 2016109869810
The quorum sensing inhibitory activity become apparent.Under subinhibitory concentration, it is possible to find the compounds of this invention 2-a, 2-b, 2-c are to PAOI
The inhibiting effect of pyo yield is better than the compound 3-a, 3-e (see patent CN 2016109869810) of synthesis early period,
And the compound 3-a, 3-e of synthesis early period are also significantly stronger than (see patent CN to the inhibiting effect of Swarming movement
2016109869810)。
In the influence to pseudomonas aeruginosa PAO1 intervention school-based mRNA expression of gene associated level, with compound
3-a, 3-e (see patent CN 2016109869810) are compared, compound 2-a, 2-b, 2-c to lasI, lasR, pqsA, pqsR,
The inhibiting effect of rhlI, rhlR are more obvious, especially compound 2-b.
The compound synthesized in the present invention has significant quorum sensing activity and antibacterial activity, by false single to verdigris
The detection of born of the same parents' bacterium PAOI virulence factor, it can be found that the N- Thioacyl homoserine lactone class compound replaced containing phenyl ureas
Mainly inhibit the intervention school-based of bacterium by inhibiting the formation of biofilm, further detection is to intervention school-based phase
The detection of correlation gene, it is possible to find the compounds of this invention is by inhibiting las system, pqs system and rhl system related genes
The expression of mRNA level in-site, to inhibit the formation of biofilm, and since it inhibits lasI, rhlR, so that bacterium be inhibited to believe
The generation of number molecule, destroys the intervention school-based of bacterium.These compounds are further developed, can be used as active constituent or with
Other drugs combination, after acceptable auxiliary and/or adding ingredient mix in pharmacy, routinely pharmaceutical methods and technique are wanted
It asks, can be made into for antibacterium quorum sensing, Trimethoprim, antibacterial or anti-tumor drug preparation.
Claims (6)
1. the N- Thioacyl homoserine lactone class compound replaced containing phenylurea, which is characterized in that have following general formula institute
Show structure:
R is selected from (a): F, Cl, Br or I；Or (b): NO2, Ph, methyl, ethyl, amino, methoxyl group, ethyoxyl, isopropyl, tertiary fourth
Base, pyrrole radicals or piperidinyl；R is the monosubstituted base or disubstituted on phenyl ring.
2. the N- Thioacyl homoserine lactone class compound according to claim 1 replaced containing phenylurea, feature
It is,
R is the monosubstituted base on phenyl ring；R substituent is selected from methyl, ethyl, ethyoxyl or methoxyl group.
3. containing phenylurea replace N- Thioacyl homoserine lactone class compound, which is characterized in that for following compound it
One:
2-a
2-b
2-c
4. the method for preparing the N- Thioacyl homoserine lactone class compound described in claim 1 replaced containing phenylurea,
It is characterized in that, being realized by following steps:
Homoserine lactone hydrochloride is dissolved in organic solvent, CS is added2It is reacted at room temperature with acid binding agent, then adds chemical combination
Object 1 obtains the N- Thioacyl homoserine lactone class compound replaced shown in general formula 2 containing phenylurea；
Compound 1:R used is selected from (a): F, Cl, Br or I；Or (b): NO2, Ph, methyl, ethyl, amino, methoxyl group, ethoxy
Base, isopropyl, tert-butyl, pyrrole radicals or piperidinyl；R is the monosubstituted base or disubstituted on phenyl ring；
Acid binding agent used is potassium carbonate, ten phosphate dihydrate trisodiums, sodium carbonate, saleratus, one of sodium bicarbonate or two
Kind；
Organic solvent used be methanol, ethyl alcohol, acetonitrile, acetone, methyl formate, Ethyl formate, ethyl acetate, butyl acetate,
One or both of methylene chloride, 1,2- dichloroethanes.
5. the side according to claim 4 for preparing the N- Thioacyl homoserine lactone class compound replaced containing phenylurea
Method, which is characterized in that molar ratio is homoserine lactone hydrochloride: CS2: compound 1: acid binding agent=1:1.1~2:1.1
~2:1.2~3.
6. the N- Thioacyl homoserine lactone class chemical combination replaced containing phenylurea as described in one of claims 1 to 3
Application of the object in medicine preparation, which is characterized in that it is combined as active constituent or with other drugs, and it can be in drug
After auxiliary and/or the adding ingredient mixing of receiving, routinely pharmaceutical methods and technique, are made for antibacterium quorum sensing, resist
Bacterium synergist or antibacterial medicine preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710475934.4A CN107098874B (en) | 2017-06-21 | 2017-06-21 | N- Thioacyl homoserine lactone class compound, preparation method and the application replaced containing phenylurea |
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|---|---|---|---|
| CN201710475934.4A CN107098874B (en) | 2017-06-21 | 2017-06-21 | N- Thioacyl homoserine lactone class compound, preparation method and the application replaced containing phenylurea |
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Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103980219B (en) * | 2013-02-08 | 2016-12-28 | 中国人民解放军军事医学科学院毒物药物研究所 | A kind of novel bacterial quorum sensing regulator and medical application thereof |
| CN106518861B (en) * | 2016-11-01 | 2019-03-26 | 郑州大学 | N- acyl homoserine lactones class compound, preparation method and the application replaced containing benzheterocycle |
| CN106749119B (en) * | 2016-11-01 | 2019-02-01 | 郑州大学 | N- acyl homoserine lactones class compound, preparation method and the application that class containing phenyl ring replaces |
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