CN107098874A - N Thioacyl homoserine lactone classes compound, its preparation method and the application replaced containing phenylurea - Google Patents
N Thioacyl homoserine lactone classes compound, its preparation method and the application replaced containing phenylurea Download PDFInfo
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- CN107098874A CN107098874A CN201710475934.4A CN201710475934A CN107098874A CN 107098874 A CN107098874 A CN 107098874A CN 201710475934 A CN201710475934 A CN 201710475934A CN 107098874 A CN107098874 A CN 107098874A
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- homoserine lactone
- thioacyl
- replaced containing
- phenylurea
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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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to medicinal chemistry art, disclosing a class has the N Thioacyl homoserine lactone classes compound, its synthetic method and its application that replace containing phenylurea of quorum-quenching activity.Its preparation method is simple, mild condition, high income.Activity test in vitro result shows that the N Thioacyl homoserine lactone class compounds of present invention substitution containing phenylurea are to pseudomonas aeruginosalasSystem andpqsSystem has obvious inhibitory action, can be applied to prepare antibacterium quorum sensing, Trimethoprim and antibacterials.It has following chemical structure of general formula：。
Description
Technical field
The present invention relates to the new N- Thioacyl homoserine lactone classes compound replaced containing phenylurea of a class, its preparation
Method and application, belong to medicinal chemistry art.
Background technology
During flora growth, bacterium can constantly produce chemical signal molecule and be secreted into surrounding environment, 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 thalline related gene, biological quilt
The formation of film, expression of virulent gene etc., to adapt to the change of environment, this regulator control system is referred to as the quorum sensing of bacterium
(QS) signal system.
Late 1970s, scientists find to include using natural or artificial synthesized quorum sensing conditioning agent
Activator or inhibitor with the conduction of interference signal system, can adjust the expression of the bad gene of bacterium.Bacterial community sensing regulation
The normal physiological function of agent not interfering bodies inner cell, simply by the expression of regulation pathogen deleterious gene, so that it loses
Pathogenecity, is accordingly regarded as the new direction of antimicrobial development, wherein quorum-quenching agent can be with Antibiotic combination
Medication, improves sensitiveness of the malignant bacteria to antibiotic, strengthens curative effect of medication, a variety of Gram-negatives of primary treatment are microbial
Such as diarrhoea, septicemia disease.The acyl side-chain of homoserine lactone is modified, the derivative of the urea structure containing phenyl is synthesized
Thing, studies its quorum sensing inhibitory activity, to further studying new antibacterium quorum sensing, Trimethoprim or antimicrobial
Thing, medicine of developing one's own intellectual property is significant, has no that pertinent literature is reported at present.
The content of the invention
Present invention aims at provide a class to have the N- sulphur replaced containing phenylurea of preferable antibacterium quorum sensing activity
For acyl homoserine lactones class compound.
It is a further object to provide its new synthetic method.Further object of the present invention is to provide the compound
Application in terms of antibacterium quorum sensing, Trimethoprim or antibacterials are prepared.
To realize the object of the invention, technical scheme is as follows：
The N- Thioacyl homoserine lactone class compounds replaced containing phenylurea have following general structure：
R is selected from (a)：F, Cl, Br or I；Or (b)：NO2, Ph, methyl, ethyl, amino, methoxyl group, ethyoxyl, isopropyl,
The tert-butyl group, pyrrole radicals or piperidinyl；R is the monosubstituted base or disubstituted on phenyl ring.
It is preferably as follows 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 preferably as follows particular compound：
The preparation method for the above-claimed cpd that the present invention is provided, is realized by following reaction scheme：
Homoserine lactone hydrochloride is dissolved in organic solvent, CS is added2With acid binding agent room temperature reaction, then add
Compound 1 obtains the N- Thioacyl homoserine lactone class compounds replaced containing phenylurea shown in formula 2；
Compound 1 used：R is selected from (a)：F, Cl, Br or I；Or (b)：NO2, Ph, methyl, ethyl, amino, methoxy
Base, ethyoxyl, isopropyl, the tert-butyl group, 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 kind in sodium acid carbonate
Or two kinds；
Organic solvent used is methanol, ethanol, acetonitrile, acetone, methyl formate, Ethyl formate, ethyl acetate, acetic acid fourth
One or both of ester, dichloromethane, 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 new N- Thioacyl homoserine lactone class compounds replaced containing phenylurea of one class of present invention design synthesis, and
Its quorum sensing inhibitory activity is studied, its mechanism of action is analyzed, to further studying new antibacterium quorum sensing, antibacterial synergy
Agent or antibacterials, medicine of developing one's own intellectual property are significant, and patent CN 201610986981.0 is inventor group
Team early stage achievement in research, it was recently reported that containing benzheterocycle replace N- acyl homoserine lactones class compounds synthetic method and
It is sensed in bacterial community, the application in terms of Trimethoprim or antibacterials, and in the research and development in later stage, inventor team enters again
One step develops the new construction of such compound, it is found that it has more preferable external activity and application effect.
Brief description of the drawings
Fig. 1 is the influence that the compounds of this invention grows to 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 is moved to pseudomonas aeruginosa PAOI Swarming；
Fig. 4 is mRNA level in-site of the compounds of this invention to intervention school-based signaling molecule synthetic gene lasI in PAOI
Influence；
Fig. 5 is influence of the compounds of this invention to intervention school-based modulin lasR mRNA levels in PAOI；
Fig. 6 is mRNA level in-site of the compounds of this invention to PAOI intervention school-based signaling molecule synthetic genes pqsA
Influence；
Fig. 7 is influence of the compounds of this invention to PAOI intervention school-based modulins pqsR mRNA level in-site；
Fig. 8 is mRNA level in-site of the compounds of this invention to intervention school-based signaling molecule synthetic gene rhlI in PAOI
Influence；
Fig. 9 is influence of the compounds of this invention to PAOI intervention school-based modulins rhlR mRNA level in-site.
Embodiment
The present invention is described further with reference to embodiment.
Embodiment 1：Prepare the derivative (2-a) shown by formula 2
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, 2- chloro- N- ((2- anisyls) amino first is added
Acyl) acetamide (291mg, 1.20mmol), 6h is reacted at room temperature, system is evaporated, ethyl acetate is extracted with water, organic layer washing
It is spin-dried for, crude product separates (eluant, eluent through silica gel column chromatography：Ethyl acetate/petroleum ether=1/1), light yellow solid is obtained, that is, is changed
Compound (2-a) 271mg, yield 65%.
Embodiment 2：Prepare the derivative (2-b, 2-c) shown by formula 4
2- chloro- N- ((2- anisyls) carbamyl) acetyl is substituted with the chloro- N- of 2- (naphthyl -1- carbamyls) acetamide
Amine, using the methods described prepare compound 2-b of embodiment 1.
The chloro- N- of 2- ((2- anisyls) carbamyl) are substituted with the chloro- N- of 2- ((3- tolyls) carbamyl) acetamide
Acetamide, using the methods described prepare compound 2-c of embodiment 1.
The chemical constitution for the part preferred compound that the present invention is synthesized, nuclear magnetic data such as table 1 below：
Embodiment 3：The external anti-quorum sensing screening test of the compounds of this invention
The influence that detection compound grows to pseudomonas aeruginosa PAO1, under subinhibitory concentration, detection compound is to copper
The influence of green pseudomonad pyo and Swarming motion (see Fig. 1-Fig. 3).Detection compound is to pseudomonas aeruginosa
The influence of PAO1 intervention school-based mRNA expression of gene associated levels, i.e. real-time fluorescence quantitative PCR detect pseudomonas aeruginosa
The mRNA expressions of QS related genes in PAOI, the formation of these genes mainly with bacterium composite signal molecule, biofilm
Etc. relevant, including lasI, lasR, pqsA, pqsR, rhlI, rhlR (see Fig. 4-Fig. 9).
Test result indicates that：The compounds of this invention has with the compound phase ratio shown by 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 inhibitory action of pyo yield is better than the compound 3-a, 3-e (see patent CN 2016109869810) of early stage synthesis,
And the compound 3-a, 3-e of early stage synthesis are also significantly stronger than to the Swarming inhibitory action moved (see patent CN
2016109869810)。
In the influence to pseudomonas aeruginosa PAO1 intervention school-based mRNA expression of gene associated levels, with compound
3-a, 3-e (see patent CN 2016109869810) are compared, compound 2-a, 2-b, 2-c to lasI, lasR, pqsA, pqsR,
RhlI, rhlR inhibitory action 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 factors, it can be found that the N- Thioacyl homoserine lactone class compounds replaced containing phenyl ureas
Main to suppress the intervention school-based of bacterium by suppressing 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 suppressing las systems, pqs systems and rhl system related genes
The expression of mRNA level in-site, so that suppress the formation of biofilm, and because it suppresses lasI, rhlR, so as to suppress bacterium letter
The generation of number molecule, destroys the intervention school-based of bacterium.These compounds are further developed, can as active component or with
Other drugs are combined, after acceptable auxiliary and/or adding ingredient are mixed in pharmacy, and routinely pharmaceutical methods and technique will
Ask, can be made into for antibacterium quorum sensing, Trimethoprim, antibacterial or anti-tumor drug preparation.
Claims (6)
1. the N- Thioacyl homoserine lactone class compounds replaced containing phenylurea, it is characterised in that with below 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 compounds according to claim 1 replaced containing phenylurea, its feature
It is,
R is the monosubstituted base on phenyl ring；R substituent is selected from 2,3-Ph, methyl, ethyl, ethyoxyl or methoxyl group.
3. the N- Thioacyl homoserine lactone class compounds according to claim 1 replaced containing phenylurea, its feature
It is, is one of following compound：
。
4. the method for the N- Thioacyl homoserine lactone class compounds replaced containing phenylurea described in claim 1 is prepared,
Characterized in that, being realized by following steps：
Homoserine lactone hydrochloride is dissolved in organic solvent, CS is added2With acid binding agent room temperature reaction, chemical combination is then added
Thing 1 obtains the N- Thioacyl homoserine lactone class compounds replaced containing phenylurea shown in formula 2；
Compound 1 used：R is selected from（a）：F, Cl, Br or I;Or（b）：NO2, Ph, methyl, ethyl, amino, methoxyl group, ethoxy
Base, isopropyl, the tert-butyl group, 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 kind or two in sodium acid carbonate
Kind；
Organic solvent used be methanol, ethanol, acetonitrile, acetone, methyl formate, Ethyl formate, ethyl acetate, butyl acetate,
One or both of dichloromethane, 1,2- dichloroethanes.
5. the side according to claim 4 for preparing the N- Thioacyl homoserine lactone class compounds replaced containing phenylurea
Method, it is characterised 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 claim 1 ~ 3
Application of the thing in medicine preparation, it is characterised in that combined as active component or with other drugs, and can be with medicine
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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| CN107098874A true CN107098874A (en) | 2017-08-29 |
| CN107098874B CN107098874B (en) | 2019-04-30 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103980219A (en) * | 2013-02-08 | 2014-08-13 | 中国人民解放军军事医学科学院毒物药物研究所 | New bacterial quorum sensing conditioning agent and medical use thereof |
| CN106518861A (en) * | 2016-11-01 | 2017-03-22 | 郑州大学 | N-acyl-homoserine lactones substituted by benzo-heterocycle and preparation method and application thereof |
| CN106749119A (en) * | 2016-11-01 | 2017-05-31 | 郑州大学 | N acyl homoserine lactones classes compound, its preparation method and application that class containing phenyl ring replaces |
-
2017
- 2017-06-21 CN CN201710475934.4A patent/CN107098874B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103980219A (en) * | 2013-02-08 | 2014-08-13 | 中国人民解放军军事医学科学院毒物药物研究所 | New bacterial quorum sensing conditioning agent and medical use thereof |
| CN106518861A (en) * | 2016-11-01 | 2017-03-22 | 郑州大学 | N-acyl-homoserine lactones substituted by benzo-heterocycle and preparation method and application thereof |
| CN106749119A (en) * | 2016-11-01 | 2017-05-31 | 郑州大学 | N acyl homoserine lactones classes compound, its preparation method and application that class containing phenyl ring replaces |
Non-Patent Citations (1)
| Title |
|---|
| 余斌等: "微生物群体感应调节信号分子N-酰化高丝氨酸内酯研究进展", 《国际药学研究杂志》 * |
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