阅读说明：本技术 用于抗微生物应用的可降解的咪唑鎓低聚物和聚合物 (Degradable imidazolium oligomers and polymers for antimicrobial applications ) 是由 张玉根 袁媛 林淑文 于 2018-06-28 设计创作，主要内容包括：本发明涉及式(I)的咪唑鎓低聚物以及式(II)的咪唑鎓低聚物或聚合物,其中各个基团如说明书中所定义。本发明还涉及用于制备它们的方法、包含式(I)和式(II)的这些低聚物和/或聚合物的抗微生物组合物、抗微生物凝胶,以及这些低聚物和/或聚合物在治疗微生物感染或疾病中的用途。<Image he="355" wi="700" file="DDA0002337533830000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention relates to imidazolium oligomers of formula (I) as well as imidazolium oligomers or polymers of formula (II), wherein the individual groups are as defined in the description. The invention also relates to processes for their preparation, antimicrobial compositions comprising these oligomers and/or polymers of formula (I) and formula (II), antimicrobial gels, and the use of these oligomers and/or polymers in the treatment of microbial infections or diseases.)

1. An oligomer of formula (I)

Wherein linker 1 is an alkyl-aryl-alkyl group or (C)₂-C₈) An alkene;

p and q are independently integers from 2 to 6, i.e., 2,3, 4, 5 or 6;

the joint 2 is

m is 0 or 1;

a is independently aryl or heteroaryl;

b is independently O, N or S;

c is independently aryl or heteroaryl;

R₁is a bond or an alkyl group;

R₂is a bond, alkoxy or amine;

R₃is a carbonyl, a bond or an alkyl;

R₄is a bond or an alkyl group;

R₅is an alkyl group; and is

X is a halide selected from the group consisting of fluoride, chloride and bromide.

2. The oligomer of claim 1, wherein linker 2 is

m is 0 or 1;

a is aryl;

b is O or N;

c is an aryl group;

R₁is a bond, alkyl, or absent;

R₂is a bond, alkoxy or amine;

R₃is a carbonyl, a bond or an alkyl;

R₄is a bond or an alkyl group; and is

R₅Is an alkyl group.

3. The oligomer of claim 1, wherein linker 2 is selected from the group consisting of:

4. the oligomer of any one of claims 1-3, wherein when linker 1 is alkyl-aryl-alkyl, the alkyl-aryl-alkyl is C_1-6alkyl-phenyl-C_1-6An alkyl group.

5. The oligomer of claim 4, wherein said C_1-6alkyl-phenyl-C_1-6The alkyl group is selected from the group consisting of o-xylene, m-xylene, p-xylene.

6. The oligomer of any one of claims 1 to 5, wherein the oligomer has terminal groups.

7. The oligomer of claim 6, wherein the terminal group is an alkyl group.

8. The oligomer of claim 7, wherein the alkyl group is C_1-14An alkyl group.

9. The oligomer of any one of claims 1 to 8, wherein the oligomer of formula (I) is selected from the group consisting of:

10. an oligomer or polymer of formula (II)

Wherein linker 1 is an alkyl-aryl-alkyl group or (C)₂-C₈) An alkene;

n is an integer from 3 to 30, i.e. 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30;

the joint 2 is

m is 0 or 1;

a is independently aryl or heteroaryl;

b is independently O, N or S;

c is independently aryl or heteroaryl;

R₁is a bond or an alkyl group;

R₂is a bond, alkoxy or amine;

R₃is a carbonyl, a bond or an alkyl;

R₄is a bond or an alkyl group;

R₅is an alkyl group; and is

X is a halide selected from the group consisting of fluoride, chloride and bromide.

11. The oligomer or polymer of claim 10 wherein linker 2 is

m is 0 or 1;

a is aryl;

b is O or N;

c is an aryl group;

R₁is a bond or an alkyl group;

R₂is a bond, alkoxy or amine;

R₃is a carbonyl, a bond or an alkyl;

R₄is a bond or an alkyl group; and is

R₅Is an alkyl group.

12. The oligomer or polymer of claim 10 or 11 wherein linker 2 is selected from the group consisting of:

13. the oligomer of any one of claims 10-12, wherein when linker 1 is alkyl-aryl-alkyl, the alkyl-aryl-alkyl is C_1-6alkyl-phenyl-C_1-6An alkyl group.

14. The oligomer or polymer of claim 13 wherein the C is_1-6Alkyl-benzenesradical-C_1-6The alkyl group is selected from the group consisting of o-xylene, m-xylene, p-xylene.

15. The oligomer or polymer of any one of claims 10 to 14 wherein the polymer has terminal groups selected from the group consisting of: linker 2, imidazolium ring, and combinations thereof.

16. An antimicrobial composition comprising an oligomer or polymer as defined in any one of claims 1 to 15.

17. An antimicrobial composition according to claim 16 for use in inhibiting microbial activity or for use in the treatment of microbial infections or diseases.

18. The antimicrobial composition of claim 17, wherein the antimicrobial composition inhibits the activity of or treats an infection or disease caused by a microorganism selected from the group consisting of: staphylococcus aureus (Staphylococcus aureus), Escherichia coli (Escherichia coli), Pseudomonas aeruginosa (Pseudomonas aeruginosa), Bacillus subtilis (Bacillus subtilis), Klebsiella pneumoniae (Klebsiella pneumoniae), Cryptococcus neoformans (Cryptococcus neoformans) and Candida albicans (Candida albicans).

19. The antimicrobial composition of claim 18, wherein the microbial activity of the microorganism is reduced to 1%, preferably to 0.5%, more preferably to 0.1% when the microorganism is contacted with a specific concentration of the antimicrobial composition.

20. The antimicrobial composition of claim 19, wherein the particular concentration of the antimicrobial composition is in a range of about 1 μ g/ml to about 100 μ g/ml.

21. The antimicrobial composition of claim 19 or 20, wherein the reduction in microbial activity is achieved in a duration of about 0.5 minutes to about 120 minutes.

22. The antimicrobial composition of any one of claims 18 to 21, wherein the microorganism is intolerant to the antimicrobial composition.

23. Use of the antimicrobial composition of claim 16 in the manufacture of a medicament for treating a microbial infection or disease.

24. The use of claim 22, wherein the microbial infection or disease is caused by a microorganism selected from the group consisting of: staphylococcus aureus, escherichia coli, pseudomonas aeruginosa, bacillus subtilis, klebsiella pneumoniae, cryptococcus neoformans and candida albicans.

25. A method of inhibiting microbial activity or treating a microbial infection or disease comprising administering the antimicrobial composition of claim 16 to a subject or applying the antimicrobial composition of claim 16 to a surface.

26. The method of claim 24, wherein the antimicrobial composition inhibits the activity of or treats an infection or disease caused by a microorganism selected from the group consisting of: staphylococcus aureus, escherichia coli, pseudomonas aeruginosa, bacillus subtilis, klebsiella pneumoniae, cryptococcus neoformans and candida albicans.

27. The method of claim 26, wherein the activity of the microorganism is reduced to 1% when the microorganism is contacted with a specific concentration of the antimicrobial composition.

28. The method of claim 27, wherein the specific concentration of the antimicrobial composition is in the range of about 1 μ g/ml to about 100 μ g/ml.

29. The oligomer or polymer of any one of claims 1 to 15 wherein the oligomer or polymer is capable of being cleaved at linker 2.

30. The oligomer or polymer of claim 29 wherein cleavage of linker 2 is effected under neutral or basic conditions.

31. The oligomer or polymer of claim 30 wherein the basic condition is a pH of greater than 7, i.e., pH8 to pH 14.

32. The oligomer or polymer of any one of claims 29 to 31 wherein the cleaved oligomer or polymer is inactive against a microorganism.

33. A process for preparing an oligomer of formula (I):

wherein linker 1 is an alkyl-aryl-alkyl group or (C)₂-C₈) An alkene;

p and q are independently integers from 2 to 6, i.e., 2,3, 4, 5 or 6;

the joint 2 is

m is 0 or 1;

a is independently aryl or heteroaryl;

b is independently O, N or S;

c is independently aryl or heteroaryl;

R₁is a bond or an alkyl group;

R₂is a bond, alkoxy or amine;

R₃is a carbonyl, a bond or an alkyl;

R₄is a bond or an alkyl group;

R₅is an alkyl group;

x is a halide selected from the group consisting of fluoride, chloride and bromide,

the method comprises the following steps:

a) providing a linker 2-carrying diimidazole unit of formula (III);

b) mixing a diimidazole of formula (III) with an imidazolium salt dissolved in a suitable solvent to form a mixture; and

c) stirring the mixture obtained in step (b) under conditions to obtain said oligomer.

34. The method of claim 33, wherein the linker 2-carrying diimidazole unit of formula (III) is selected from the group consisting of:

35. the method of claim 33, wherein the imidazolium salt is selected from the group consisting of a bisimidazolium salt, a trisimidazolium salt, a tetramimidazolium salt, a pentaimidazolium salt, and a hexaimidazolium salt.

36. The method of any one of claims 32 to 34, wherein the solvent is selected from the group consisting of Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone, and acetonitrile.

37. The method of any one of claims 33 to 36, wherein the conditions in step (c) comprise a temperature of about 20 ℃ to about 30 ℃.

38. The method of any one of claims 33 to 37, wherein step (c) is carried out for a period of time in the range of about 18 hours to 60 hours.

39. A process for preparing an oligomer or polymer of formula (II)

Wherein linker 1 is an alkyl-aryl-alkyl group or (C)₂-C₈) An alkene;

n is an integer from 3 to 30, i.e. 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30;

the joint 2 is

m is 0 or 1;

a is independently aryl or heteroaryl;

b is independently O, N or S;

c is independently aryl or heteroaryl;

R₁is a bond or an alkyl group;

R₂is a bond, alkoxy or amine;

R₃is a carbonyl, a bond or an alkyl;

R₄is a bond or an alkyl group;

R₅is an alkyl group; and is

X is a halide selected from the group consisting of fluoride, chloride and bromide,

the method comprises the following steps:

a) reacting a linker 2-carrying diimidazole unit of formula (III) in a suitable solvent

Mixing with a linker 1-carrying precursor of formula (IV)

X-linker 1-X

Formula (IV)

To form a mixture; and

(b) stirring the mixture obtained in step (a) under conditions to obtain said polymer.

40. The method of claim 39, wherein the linker 2-carrying diimidazole unit of formula (III) is selected from the group consisting of:

41. the method of claim 39 or 40, wherein the linker 1 carrying precursor of formula (IV) is selected from the group consisting of:

42. the method of claim 39, wherein the polymer of formula (II) is selected from the group consisting of:

43. the method of any one of claims 39 to 42, wherein the conditions in step (b) comprise a temperature of about 20 ℃ to about 30 ℃.

44. The method of any one of claims 39 to 43, wherein step (b) is carried out for a period of time in the range of about 30 minutes to about 48 hours.

45. The method of any one of claims 39 to 44, optionally further comprising the step of heating the mixture.

46. An antimicrobial gel comprising an oligomer of formula (I):

wherein linker 1 is an alkyl-aryl-alkyl group or (C)₂-C₈) An alkene;

p and q are independently integers from 2 to 6, i.e., 2,3, 4, 5 or 6;

the joint 2 is

m is 0 or 1;

a is independently aryl or heteroaryl;

b is independently O, N or S;

c is independently aryl or heteroaryl;

R₁is a bond or an alkyl group;

R₂is a bond, alkoxy or amine;

R₃is a carbonyl, a bond or an alkyl;

R₄is a bond or an alkyl group;

R₅is an alkyl group; and is

X is a halide selected from the group consisting of fluoride, chloride and bromide.

47. The method of claim 46, wherein the gel is formed in an alcohol.

Technical Field

The present invention generally relates to oligomers of formula (I) or oligomers or polymers of formula (II). The invention also relates to an antimicrobial composition, an antimicrobial gel, a method for preparing an oligomer or polymer of formula (I) or of formula (II) and the use of an oligomer or polymer of formula (I) or of formula (II).

Background

One of the most critical challenges facing modern society today is antimicrobial resistance (AMR) against microorganisms that develop resistance to antimicrobial drugs such that the antimicrobial drugs do not work against such microorganisms or require higher doses of antimicrobial drugs to have an effective therapeutic effect or outcome. This has led to a prediction that by 2050, the number of deaths due to AMR annually is 1000 tens of thousands. The cost of treating antibiotic-resistant infections ranges from $ 1.5 million to $ 300 million per year due to longer hospital stays and higher morbidity. Most alarming is that newly emerging reports of bacterial infections of strains resistant to all existing drugs emphasize the urgent need to address bacterial antibiotic resistance.

Bacteria may acquire resistance when antibiotics are abused or used for a long time in clinical treatment. Drug resistant strains can also be infected directly from animals, water and air or communities. In addition, overuse of antibiotics for non-therapeutic applications, such as agricultural and environmental disinfection, increases drug resistance options and results in low levels of antibiotics accumulating in the ecosystem for a long time. These antibiotic residues eventually enter the food chain where they continue to contaminate downstream agricultural products. To prevent drug resistance, it is crucial to develop new antimicrobial technologies that circumvent or reduce the selection of drug-resistant microbial strains. One such technique is an antimicrobial material that will self-destruct after treatment, leaving no active residue with the potential for secondary environmental contamination. This is especially important in the context of agriculture and environmental disinfection.

Previously, we have developed a series of backbone imidazolium polymers and oligomers for antimicrobial applications. These polyimidazolium materials exhibit high efficacy, high selectivity and rapid kill kinetics for a wide variety of bacteria and fungi. In the present invention, a series of new imidazole polymers and oligomers with various degradable linkers have been developed. The novel imidazolium materials retain the previously reported excellent antimicrobial properties of the materials against a wide range of microorganisms, yet have the requisite degradability and non-drug resistant properties. The novel imidazolium materials have an adjustable degradation curve under different conditions, which will have a wide range of applications in agriculture and environmental disinfection.

Accordingly, there is a need for novel imidazolium compounds that address or mitigate one or more of the above-mentioned disadvantages. It is desirable to provide antimicrobial compounds having desirable properties.

SUMMARY

According to a first aspect, there is provided an oligomer of formula (I)

Wherein the linker 1 is an alkyl-arylAlkyl radical or (C)₂-C₈) An alkene;

p and q are independently integers from 2 to 6, i.e., 2,3, 4, 5 or 6;

the joint 2 is

m is 0 or 1;

a is independently aryl or heteroaryl;

b is independently O, N or S;

c is independently aryl or heteroaryl;

R₁is a bond or an alkyl group;

r2 is a bond, alkoxy, or amine;

R₃is a carbonyl, a bond or an alkyl;

R₄is a bond or an alkyl group;

R₅is an alkyl group; and is

X is a halide selected from the group consisting of fluoride, chloride and bromide.

According to another aspect, there is provided an oligomer or polymer of formula (II)

Wherein linker 1 is an alkyl-aryl-alkyl group or (C)₂-C₈) An alkene;

n is an integer from 3 to 30, i.e. 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30;

the joint 2 is

m is 0 or 1;

a is independently aryl or heteroaryl;

b is independently O, N or S;

c is independently aryl or heteroaryl;

R₁is a bond or an alkyl group;

R₂is a bond, alkoxy or amine;

R₃is a carbonyl, a bond or an alkyl;

R₄is a bond or an alkyl group;

R₅is an alkyl group; and is

X is a halide selected from the group consisting of fluoride, chloride and bromide.

Advantageously, the antimicrobial compositions defined herein may exhibit excellent antimicrobial activity against a wide range of microorganisms. More advantageously, the oligomer may be degradable and may have non-drug resistant properties. The oligomers described herein can have degradation profiles that can be adjusted under different conditions.

According to another aspect, there is provided an antimicrobial composition comprising an oligomer or polymer as defined herein.

Advantageously, this means that the antimicrobial composition may not have antimicrobial resistance. More advantageously, when the oligomer or polymer is used against the same surface or subject for an extended period of time against the same microorganism, it may not be necessary to increase the dose or concentration of the oligomer or polymer. Thus, the antimicrobial composition can be used against microorganisms that develop resistance to conventional antimicrobial drugs.

According to another aspect, there is provided an antimicrobial composition as defined herein for use in inhibiting microbial activity or for use in the treatment of a microbial infection or disease.

According to another aspect, there is provided the use of an antimicrobial composition as defined herein in the manufacture of a medicament for the treatment of a microbial infection or disease.

According to another aspect, there is provided a method of inhibiting microbial activity or treating a microbial infection or disease, the method comprising administering an antimicrobial composition as defined herein to a subject or applying an antimicrobial composition as defined herein to a surface.

According to another aspect, there is provided a process for preparing an oligomer of formula (I)

Wherein linker 1 is an alkyl-aryl-alkyl group or (C)₂-C₈) An alkene;

p and q are independently integers from 2 to 6, i.e., 2,3, 4, 5 or 6;

the joint 2 is

m is 0 or 1;

a is independently aryl or heteroaryl;

b is independently O, N or S;

c is independently aryl or heteroaryl;

R₁is a bond or an alkyl group;

R₂is a bond, alkoxy or amine;

R₃is a carbonyl, a bond or an alkyl;

R₄is a bond or an alkyl group;

R₅is an alkyl group;

x is a halide selected from the group consisting of fluoride, chloride and bromide,

the method comprises the following steps:

a) providing a linker 2-carrying diimidazole unit of formula (III);

b) mixing a diimidazole of formula (III) with an imidazolium salt dissolved in a suitable solvent to form a mixture; and

c) stirring the mixture obtained in step (b) under conditions to obtain said oligomer.

According to another aspect, there is provided a process for preparing an oligomer or polymer of formula (II)

Wherein linker 1 is an alkyl-aryl-alkyl group or (C)₂-C₈) An alkene;

n is an integer from 3 to 30, i.e. 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30;

the joint 2 is

m is 0 or 1;

a is independently aryl or heteroaryl;

b is independently O, N or S;

c is independently aryl or heteroaryl;

R₁is a bond or an alkyl group;

R₂is a bond, alkoxy or amine;

R₃is a carbonyl, a bond or an alkyl;

R₄is a bond or an alkyl group;

R₅is an alkyl group; and is

X is a halide selected from the group consisting of fluoride, chloride and bromide,

the method comprises the following steps:

a) reacting a linker 2-carrying diimidazole unit of formula (III) in a suitable solvent

Mixing with a linker 1-carrying precursor of formula (IV)

x-linker 1-x

Formula (IV)

Forming a mixture; and

b) stirring the mixture obtained in step (a) under conditions to obtain said polymer. According to another aspect, there is provided an antimicrobial gel comprising an oligomer of formula (I)

Wherein linker 1 is an alkyl-aryl-alkyl group or (C)₂-C₈) An alkene;

p and q are independently integers from 2 to 6, i.e., 2,3, 4, 5 or 6;

the joint 2 is

m is 0 or 1;

a is independently aryl or heteroaryl;

b is independently O, N or S;

c is independently aryl or heteroaryl;

R₁is a bond or an alkyl group;

R₂is a bond, alkoxy or amine;

R₃is a carbonyl, a bond or an alkyl;

R₄is a bond or an alkyl group;

R₅is an alkyl group; and is

X is a halide selected from the group consisting of fluoride, chloride and bromide.

Definition of

The following words and terms used herein shall have the indicated meanings:

the term "oligomer" as used herein refers to an oligomer whose molecule consists of relatively few repeating units, up to five identical repeating units in total, i.e., the repeating units may be imidazolium, linker 1 or linker 2 of formula (I), linker 1 or linker 2 of formula (II), formula (I), formula (II), or any combination thereof.

The term "polymer" as used herein refers to a macromolecule or macromolecule composed of a number of repeating units, up to a total of 30 identical repeating units, i.e., the repeating units may be imidazolium, linker 1 or linker 2 of formula (II), or any combination thereof.

As used herein, the term "degradation" refers to the ability of a compound, particularly complex substances such as polymers and proteins, to decompose under certain conditions, showing well-defined intermediates depending on the stage. During degradation, it is the conversion of the reactive oligomer to less reactive degradation products that indicates a change in the MIC value. Once degraded, the intermediates obtained from the degradation process will be labeled as degradation products. These specific conditions may be neutral and/or alkaline conditions.

Unless otherwise specified, "alkyl" as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group having 1 to 16 carbon atoms, e.g., 1,2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 carbon atoms, preferably C₁-C₁₆Alkyl radical, C₁-C₁₂Alkyl, more preferably C₁-C₁₀Alkyl, most preferably C₁-C₆An alkyl group. Examples of suitable straight and branched alkyl substituents include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, pentyl (amyl), 1, 2-dimethylpropyl, 1-dimethylpropyl, pentyl (amyl), isopentyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 2-dimethylbutyl, 3-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 5-methylheptyl, 1-methylheptyl, octyl, nonyl, decyl, undecyl, 2, 3-trimethylundecyl, dodecyl, 2-dimethyldodecyl, tridecyl, 2-methyltridecyl, tetradecyl, 2-methyl-tetradecyl, pentadecyl, 2-methyl-pentadecyl, hexadecyl, 2-methyl-hexadecyl, and the like. The alkyl group may be optionally substituted with one or more groups as defined according to the term "optionally substituted" below.

"aryl" as a group or part of a group is to be understood broadly and means (i) an optionally substituted monocyclic or fused polycyclic aromatic carbocyclic ring (having a ring structure in which the ring atoms are all carbon), each ring preferably having from 5 to 12 atoms, wherein the optional substitution may be di-or tri-substituted. Examples of aryl groups include phenyl, naphthyl, and the like; (ii) optionally substituted partially saturated bicyclic aromaticCarbocyclic moiety wherein phenyl and C_5-7Cycloalkyl or C_5-7Cycloalkenyl groups are fused together to form a ring structure, such as tetrahydronaphthyl, indenyl, or indanyl. The group may be a terminal group or a bridging group. Typically, aryl is C₆-C₁₈And (4) an aryl group. Aryl groups may be optionally substituted with one or more groups as defined by the term "optionally substituted" below.

"alkoxy" or "alkoxy" refers to the broadly understood alkyl-O-group, wherein alkyl is as defined herein. Alkoxy is C₁-C₁₆Alkoxy radical, C₁-C₁₂Alkoxy, more preferably C₁-C₁₀Alkoxy, most preferably C₁-C₆An alkoxy group. Examples include, but are not limited to, methoxy and ethoxy. The group may be a terminal group or a bridging group. The term alkoxy (alkoxy) may be used interchangeably with the term alkoxy (alkoxy). The alkoxy (alkyloxy) or alkoxy (alkyloxyxy) group may be optionally substituted by one or more groups as defined by the term "optionally substituted" hereinafter.

"amine" is understood in a broad sense as-NR_aR_bR_cA radical of the form (I) in which R_a、R_bAnd R_cIndividually selected from the group including but not limited to: hydrogen, optionally substituted alkyl, optionally substituted carbonyl, optionally substituted alkenyl, and optionally substituted aryl. Where "amine" is a terminal group, a bridging group as used herein will be considered an "amino group" (which refers to-NR)_aR_bA radical of the form (I) in which R_aAnd R_bIndividually selected from the group including but not limited to: hydrogen, optionally substituted alkyl, optionally substituted carbonyl, optionally substituted alkenyl, and optionally substituted aryl.

A "bond" is a linkage between atoms of a compound or molecule. The bond may be a single bond, a double bond, or a triple bond.

"halide" or "halogen" means chlorine, fluorine, bromine or iodine.

Unless otherwise indicated, "heteroalkanesBy "radical" is meant a straight-chain or branched alkyl radical understood in a broad sense having from 1 to 16 carbon atoms, for example 1,2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 carbon atoms, preferably C₁-C₁₆Alkyl radical, C₁-C₁₂Alkyl, more preferably C₁-C₁₀Alkyl, most preferably C₁-C₆Alkyl wherein one or more carbon atoms are substituted with a heteroatom selected from S, O, P and N. Exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like. Examples of heteroalkyl groups also include hydroxy C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical C₁-C₆Alkyl, amino C₁-C₆Alkyl radical, C₁-C₆Alkylamino radical C₁-C₆Alkyl and di (C)₁-C₆Alkyl) amino C₁-C₆An alkyl group. The group may be a terminal group or a bridging group. Heteroalkyl groups may be optionally substituted with one or more groups as defined according to the term "optionally substituted" below.

"heteroaryl", alone or as part of a group, refers to a group that is broadly understood to include aromatic rings (preferably 5-or 6-membered aromatic rings) having one or more heteroatoms as ring atoms in the aromatic ring, with the remaining ring atoms being carbon atoms. The aromatic ring may be monocyclic, fused or bridged, or a spirocyclic polycyclic ring fused to another aromatic ring, preferably a 5-or 6-membered aromatic ring. Suitable heteroatoms include nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include tetrazolyl, triazolyl, pyrimidinyl, pyrazinyl, thienyl, furyl, indazolyl, benzoxazolyl, benzofuryl, benzothienyl, indolyl, pyrrolyl, oxazolyl, pyrazolyl, thiazolyl, quinolinyl, imidazolyl, purinyl, oxadiazolonyl (oxadiazolonyl). Heteroaryl is usually C₁-C₁₈A heteroaryl group. Heteroaryl groups may contain 3 to 8 ring atoms. The heteroaryl group may contain 1-3 heteroatoms independently selected from the group consisting of N, O and S. The group may be a terminal group or a bridging group. Heteroaryl groups may be optionally substituted as defined by the term "optionally substituted" according to the followingSubstituted with one or more groups of (a).

The term "optionally substituted" as used herein means that the group to which the term refers may be unsubstituted or may be substituted with one or more groups independently selected from: alkyl, alkenyl, alkynyl, thioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkenyl, heterocycloalkyl, cycloalkylheteroalkyl, cycloalkoxy, cycloalkenyloxy, cycloaminoxy, halo, carboxy, haloalkyl, haloalkynyl, alkynoxy, heteroalkyl, heteroalkoxy, hydroxy, hydroxyalkyl, alkoxy, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyl, haloalkynyl, haloalkenyloxy, nitro, amino, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroheterocyclyl, alkylamino, dialkylamino, alkenylamine, aminoalkyl, alkynylamino, acyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxycarbonyl, alkoxycycloalkyl, alkoxyheteroaryl, alkoxyheterocycloalkyl, alkenoyl, alkynoyl, alkylamino, diacylamino, acyloxy, heterocycloalkyl, alkenoyl, alkynoyl, alkylamino, dialkylamino, acyloxyalkoxy, heterocycloalkyl, heterocycloalkoxy, haloalkoxy, amino, haloalkoxy, alkylsulfonyloxy, heterocyclyl, heterocycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkenyl, heterocycloalkylheteroalkyl, heterocycloalkoxy, heterocycloalkenyloxy, heterocyclyloxy, heterocyclylamino, haloheterocycloalkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkylcarbonyloxy, alkylthio, acylthio, aminosulfonyl, phosphorus-containing groups such as phosphono, phosphinyl, sulfinyl, sulfinylamino, sulfonyl, sulfonylamino, aryl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroalkyl, heteroarylamino, heteroaryloxy, arylalkenyl, arylalkyl, alkylaryl, alkylheteroaryl, aryloxy, arylsulfonyl, cyano, cyanate, isocyanate, -C (O) NH (alkyl), and-C (O) N (alkyl)₂. When the term "substituted" is used, the group to which the term refers may be substituted with one or more of the same groups mentioned above.

The word "substantially" does not exclude "completely", e.g., a composition that is "substantially free" of Y may be completely free of Y. The word "substantially" may be omitted from the definition of the invention, if necessary.

Unless otherwise specified, the terms "comprising" and "including" and grammatical variations thereof are intended to mean "open" or "inclusive" language such that they include recited elements but also allow inclusion of other, non-recited elements.

As used herein, the term "about" in the context of concentration of a formulation ingredient generally refers to +/-5% of the stated value, more generally +/-4% of the stated value, more generally +/-3% of the stated value, more generally +/-2% of the stated value, even more generally +/-1% of the stated value, and even more generally +/-0.5% of the stated value.

Throughout this disclosure, certain examples may be disclosed in a range format. It should be understood that the description of the range format is merely for convenience and brevity and should not be construed as a rigid limitation on the scope (scope) of the disclosed range. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, a description of a range such as from 1 to 6 should be read as having explicitly disclosed the sub-ranges from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as the various numbers within that range, such as 1,2, 3,4, 5, and 6. This applies regardless of the breadth of the range.

Certain embodiments may also be broadly and broadly described herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the disclosure. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein. .

Detailed disclosure of alternative embodiments

Exemplary, non-limiting embodiments of the oligomers of formula (I) will now be disclosed.

The oligomer may have the following formula (I)

Wherein linker 1 is an alkyl-aryl-alkyl group or (C)₂-C₈) An alkene;

p and q are independently integers from 2 to 6, i.e., 2,3, 4, 5 or 6;

the joint 2 is

m is 0 or 1;

a is independently aryl or heteroaryl;

b is independently O, N or S;

c is independently aryl or heteroaryl;

R₁is a bond or an alkyl group;

R₂is a bond, alkoxy or amine;

R₃is a carbonyl, a bond or an alkyl;

R₄is a bond or an alkyl group;

R₅is an alkyl group; and is

X is a halide selected from the group consisting of fluoride, chloride and bromide.

In the oligomer of formula (I), linker 1 may be an alkyl-aryl-alkyl group. The alkyl-aryl-alkyl group may be C_1-6alkyl-phenyl-C_1-6An alkyl group. C_1-6The alkyl group may be methyl, ethyl, propyl, butyl, pentyl or hexyl. C_1-6alkyl-phenyl-C_1-6The alkyl group may be selected from the group consisting of o-xylene, m-xylene, p-xylene. In the oligomer of formula (I), linker 1 may be an alkenyl group. The joint 1 may be (C)₂-C₈) An alkenyl group. The aryl group may also be optionally substituted in general.

In the oligomer of formula (I), p and q may independently be integers from 2 to 6, i.e. 2,3, 4, 5 or 6.

In the oligomer of formula (I), the linker 2 may be

The m integer may be 0 or 1. Joint2a may independently be aryl or heteroaryl. The aryl group may be selected from the group consisting of o-xylene, m-xylene, p-xylene. B of linker 2 may independently be O, N or S. C of linker 2 may independently be aryl or heteroaryl. The aryl group may be selected from the group consisting of o-xylene, m-xylene, p-xylene. R of the linker 2₁May be a bond or an alkyl group. R of the linker 2₂May be a bond, alkoxy or amine. When the amine is a terminal group, it may be an amino group. R of the linker 2₃May be a carbonyl, a bond or an alkyl. R of the linker 2₄May be a bond or an alkyl group; r₅May be an alkyl group. The linker 2 may preferably be selected from the group consisting of:

the aryl group may also be optionally substituted in general.

In the oligomer of formula (I), X may be a halogen of group VII of the periodic Table of the elements. X may be a halide selected from fluoride, chloride and bromide.

In the oligomer of formula (I), the oligomer may comprise end groups. The terminal group may be an alkyl group. The alkyl group may be C_1-14An alkyl group. The alkyl group may be methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl or dodecyl. The alkyl group may preferably be-C₈H₁₇。

The oligomer of formula (I) may be selected from the group consisting of:

exemplary, non-limiting embodiments of the oligomers or polymers of formula (II) will now be disclosed.

The oligomer or polymer may have formula (II):

wherein linker 1 is an alkyl-aryl-alkyl group or (C)₂-C₈) An alkene;

n is an integer from 3 to 30, i.e. 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30;

the joint 2 is

m is 0 or 1;

a is independently aryl or heteroaryl;

b is independently O, N or S;

c is independently aryl or heteroaryl;

R₁is a bond or an alkyl group;

R₂is a bond, alkoxy or amine;

R₃is a carbonyl, a bond or an alkyl;

R₄is a bond or an alkyl group;

R₅is an alkyl group; and is

X is a halide selected from the group consisting of fluoride, chloride and bromide.

In the oligomer or polymer of formula (II), linker 1 may be an alkyl-aryl-alkyl group. The alkyl-aryl-alkyl group may be C_1-6alkyl-phenyl-C_1-6An alkyl group. C_1-6The alkyl group may be methyl, ethyl, propyl, butyl, pentyl or hexyl. C_1-6alkyl-phenyl-C_1-6The alkyl group may preferably be selected from the group consisting of ortho-xylene, meta-xylene, para-xylene. In the oligomer or polymer of formula (II), linker 1 may be an alkenyl group. The joint 1 may be (C)₂-C₈) An alkenyl group. Joint 1 may preferably be C₄An alkenyl group. The aryl group may also be generally optionally substituted.

In the oligomer or polymer of formula (II), n may be an integer from 3 to 30, i.e. 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30.

In the oligomer or polymer of formula (II), the linker 2 may be

The m integer may be 0 or 1. A of linker 2 may independently be aryl or heteroaryl. The aryl group may be selected from the group consisting of o-xylene, m-xylene, p-xylene. B of linker 2 may independently be O, N or S. C of linker 2 may independently be aryl or heteroaryl. The aryl group may be selected from the group consisting of o-xylene, m-xylene, p-xylene. R of the linker 2₁May be a bond or an alkyl group. R of the linker 2₂May be a bond, alkoxy or amine. When the amine is a terminal group, it may be an amino group. R of the linker 2₃May be a carbonyl, a bond or an alkyl. R of the linker 2₄May be a bond or an alkyl group; r₅May be an alkyl group. The linker 2 may preferably be selected from the group consisting of:

the aryl group may also be optionally substituted in general.

In the oligomer or polymer of formula (II), X may be a halogen of group VII of the periodic Table of the elements. X may be a halide selected from fluoride, chloride and bromide.

In the oligomer or polymer of formula (II), the polymer may have a terminal group selected from the group consisting of a linker 2, an imidazolium ring, an imidazole, and a combination thereof. The one or more terminal groups may be the same as each other, or may be different from each other. The end group may be an imidazolium ring at one end of the polymer, while the other end group may be a "linker 2 conjugated to an imidazolium ring" at the other end of the polymer.

The oligomer of formula (I) may be capable of being cleaved at linker 2. The oligomer or polymer of formula (II) may be capable of being cleaved at the linker 2. Wherein cleavage of linker 2 is effected under neutral or basic conditions. Neutral conditions may be at pH 7. The basic conditions may be at a pH value of greater than 7, i.e. pH8, pH 9, pH 10, pH 11, pH 12, pH 13 and pH 14. If the oligomer of formula (I) or the oligomer or polymer of formula (II) is cleaved, the cleaved moiety may not be active against microorganisms.

The polymer of formula (II) may be selected from the group consisting of:

exemplary, non-limiting embodiments of antimicrobial compositions will now be disclosed.

The antimicrobial composition may comprise an oligomer of formula (I). The antimicrobial composition may comprise an oligomer or polymer of formula (II).

The antimicrobial compositions defined herein are useful for inhibiting microbial activity. The antimicrobial compositions defined herein may be used to treat microbial infections or diseases.

Advantageously, the antimicrobial compositions defined herein may exhibit excellent antimicrobial activity against a wide range of microorganisms. More advantageously, the oligomer may be degradable and may have non-drug resistant properties. The oligomers described herein can have degradation profiles that can be adjusted under different conditions.

The antimicrobial composition as defined herein may inhibit the activity of or treat an infection or disease caused by a microorganism selected from the group consisting of staphylococcus aureus (staphylococcus aureus), Escherichia coli (Escherichia coli), Pseudomonas aeruginosa (Pseudomonas aeruginosa), Bacillus subtilis (Bacillus subtilis), Klebsiella pneumoniae (Klebsiella pneumoniae), Cryptococcus neoformans (cryptococci neoformans), and Candida albicans (Candida albicans). When a microorganism is contacted with a defined concentration of the antimicrobial composition, the microbial activity of the microorganism may be reduced to a range of about 1% to about 0.1%, a range of about 0.5% to about 0.1%, a range of about 1% to about 0.5%, preferably about 0.5%, more preferably about 0.1%. The specific concentration of the antimicrobial composition may be in the following ranges: about 1 to about 100. mu.g/ml, about 1 to about 10. mu.g/ml, about 1 to about 20. mu.g/ml, about 1 to about 50. mu.g/ml, about 5 to about 10. mu.g/ml, about 5 to about 20. mu.g/ml, about 5 to about 50. mu.g/ml, about 5 to about 100. mu.g/ml, about 10 to about 20. mu.g/ml, about 10 to about 50. mu.g/ml, about 10 to about 100. mu.g/ml, about 50 to about 60. mu.g/ml, about 50 to about 70. mu.g/ml, about 50 to about 80. mu.g/ml, About 50 μ g/ml to about 90 μ g/ml, about 60 μ g/ml to about 100 μ g/ml, about 70 μ g/ml to about 100 μ g/ml, about 80 μ g/ml to about 100 μ g/ml, about 90 μ g/ml to about 100 μ g/ml, or preferably about 60 μ g/ml to about 65 μ g/ml. The reduction in microbial activity can be achieved within a duration of about 0.5 minutes to about 120 minutes, about 0.5 minutes to about 1 minute, about 1 minute to about 2 minutes, about 0.5 minutes to about 2 minutes, about 1 minute to about 10 minutes, about 1 minute to about 20 minutes, about 1 minute to about 30 minutes, about 1 minute to about 60 minutes, about 1 minute to about 120 minutes, about 2 minutes to about 10 minutes, about 2 minutes to about 30 minutes, about 2 minutes to about 60 minutes, about 2 minutes to about 120 minutes, about 5 minutes to about 10 minutes, about 5 minutes to about 30 minutes, about 5 minutes to about 60 minutes, about 5 minutes to about 120 minutes, about 10 minutes to about 60 minutes, about 30 minutes to about 60 minutes, or about 60 minutes to about 120 minutes, or preferably about 0.5 minutes to about 2 minutes.

The antimicrobial composition may not be tolerated by microorganisms. Advantageously, this means that the antimicrobial composition may be unaffected by antimicrobial resistance. More advantageously, when using oligomers or polymers for the same microorganism on the same surface or object for a prolonged period of time, it may not be necessary to increase the dose or concentration of the oligomers or polymers. Thus, the antimicrobial composition can be used to combat microorganisms that have developed resistance to conventional antimicrobial drugs.

Exemplary, non-limiting embodiments of the use of the antimicrobial composition as defined herein will now be disclosed.

There is provided the use of an antimicrobial composition as defined herein in the manufacture of a medicament for the treatment of a microbial infection or disease. The microbial infection or disease may be caused by a microorganism selected from the group consisting of staphylococcus aureus, escherichia coli, pseudomonas aeruginosa, bacillus subtilis, klebsiella pneumoniae, cryptococcus neoformans and candida albicans.

Exemplary, non-limiting embodiments of methods of inhibiting microbial activity or treating microbial infections or diseases will now be disclosed.

A method of inhibiting microbial activity or treating a microbial infection or disease may comprise administering to a subject or applying on a surface an antimicrobial composition as defined herein. The antimicrobial composition can inhibit the activity of or treat an infection or disease caused by a microorganism selected from the group consisting of staphylococcus aureus, escherichia coli, pseudomonas aeruginosa, bacillus subtilis, klebsiella pneumoniae, cryptococcus neoformans, and candida albicans.

The subject may be a cell. The subject may be a human or animal body. The cell may be present in a cell culture in vitro. The cell may be from a cell line. The cell line may be an immortalized cell line, a genetically modified cell line or a primary cell line. The cell may be from a tissue of a subject. The cell may be within a subject.

The surface may be the surface of a cell. The surface may be a surface on a human or animal body.

The surface may be that of an inanimate object and, thus, the method of inhibiting microbial activity may not be considered a method of treatment when the method comprises applying an antimicrobial composition as defined herein to a surface. Here, the antimicrobial composition may be a disinfectant or antimicrobial food preservative, which is applied to the surface of an inanimate object for conventional disinfection or sterilization.

The inhibition method or the treatment method may preferably be an in vitro method. The inhibition method or treatment method may also be an in vivo method.

A method of inhibiting microbial activity in a cell may comprise administering an antimicrobial composition as defined herein to a cell as defined herein. A method of treating a microbial infection or disease in a cell may comprise administering an antimicrobial composition as defined herein to a cell as defined herein.

The microorganisms may be contacted with the antimicrobial composition at a specific concentration and the microbial activity may be reduced to a level in the range of about 1% to about 0.1%, in the range of about 0.5% to about 0.1%, in the range of about 1% to about 0.5%, preferably about 0.5%, more preferably about 0.1%. Specific concentrations of the antimicrobial composition can be in the range of about 1 μ g/ml to 100 μ g/ml, about 1 μ g/ml to about 10 μ g/ml, about 1 μ g/ml to about 20 μ g/ml, about 1 μ g/ml to about 50 μ g/ml, about 5 μ g/ml to about 10 μ g/ml, about 5 μ g/ml to about 20 μ g/ml, about 5 μ g/ml to about 50 μ g/ml, about 5 μ g/ml to about 100 μ g/ml, about 10 μ g/ml to about 20 μ g/ml, about 10 μ g/ml to about 50 μ g/ml, about 10 μ g/ml to about 100 μ g/ml, about 50 μ g/ml to about 60 μ g/ml, about 50 μ g/ml to about 70 μ g/ml, about 1 μ g/ml to about 10 μ g/ml, or about 1 μ g/ml, or about 50 μ g/ml, or, About 50 μ g/ml to about 80 μ g/ml, about 50 μ g/ml to about 90 μ g/ml, about 60 μ g/ml to about 100 μ g/ml, about 70 μ g/ml to about 100 μ g/ml, about 80 μ g/ml to about 100 μ g/ml, about 90 μ g/ml to about 100 μ g/ml, or preferably about 60 μ g/ml to about 65 μ g/ml.

Exemplary, non-limiting embodiments of methods of producing the oligomers of formula (I) will now be disclosed.

Process for producing oligomers of the following formula (I)

Wherein linker 1 is an alkyl-aryl-alkyl group or (C)₂-C₈) An alkene;

p and q are independently integers from 2 to 6, i.e., 2,3, 4, 5 or 6;

the joint 2 is

m is 0 or 1;

a is independently aryl or heteroaryl;

b is independently O, N or S;

c is independently aryl or heteroaryl;

R₁is a bond or an alkyl group;

R₂is a bond, alkoxy or amine;

R₃is a carbonyl, a bond or an alkyl;

R₄is a bond or an alkyl group;

R₅is an alkyl group;

x is a halide selected from the group consisting of fluoride, chloride and bromide,

the method may comprise the steps of:

a) providing a linker 2-carrying diimidazole unit of formula (III);

b) mixing a diimidazole of formula (III) with an imidazolium salt dissolved in a suitable solvent to form a mixture; and

c) stirring the mixture obtained in step (b) under conditions to obtain said oligomer.

The formula (III) in step (a) of the process as defined herein may be selected from the group consisting of:

the imidazolium salt in step (b) of the process as defined herein may be selected from the group consisting of a bisimidazolium salt, a trisimidazolium salt, a tetraimidazolium salt, a pentaimidazolium salt and a hexaimidazolium salt.

The solvent in step (b) of the process as defined herein may be an organic solvent. The organic solvent may be a polar aprotic solvent. The polar aprotic solvent may be selected from the group consisting of Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone, and acetonitrile.

The conditions as mentioned in step (c) of the process as defined herein may comprise a temperature in the range of from about 20 ℃ to about 30 ℃, from about 20 ℃ to about 22 ℃, from about 20 ℃ to about 25 ℃, from about 25 ℃ to about 30 ℃, from about 28 ℃ to about 30 ℃ or preferably a temperature in the range of from about 22 ℃ to about 28 ℃.

The conditions mentioned in step (c) of the process as defined herein may be carried out for a period of time in the range of about 18 hours to 60 hours, for about 18 hours, about 20 hours, about 22 hours, about 24 hours, 26 hours, about 28 hours, about 30 hours, about 32 hours, about 34 hours, about 36 hours, about 38 hours, about 40 hours, about 42 hours, about 44 hours, about 46 hours, about 48 hours, about 50 hours, about 52 hours, about 54 hours, about 56 hours, about 58 hours, about 60 hours, preferably about 24 hours or more preferably about 48 hours.

An exemplary, non-limiting embodiment of a method of making the oligomer or polymer of formula (II) will now be disclosed.

Process for preparing an oligomer or polymer of the formula (II)

Wherein linker 1 is an alkyl-aryl-alkyl group or (C)₂-C₈) An alkene;

n is an integer from 3 to 30, i.e. 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30;

the joint 2 is

m is 0 or 1;

a is independently aryl or heteroaryl;

b is independently O, N or S;

c is independently aryl or heteroaryl;

R₁is a bond or an alkyl group;

R₂is a bond, alkoxy or amine;

R₃is a carbonyl, a bond or an alkyl;

R₄is a bond or an alkyl group;

R₅is an alkyl group; and is

X is a halide selected from the group consisting of fluoride, chloride and bromide,

the method may comprise the steps of:

a) reacting a linker 2-carrying diimidazole unit of formula (III) in a suitable solvent

With a precursor carrying the linker 1 of formula (IV)

x-linker 1-x

Formula (IV)

Mixing to form a mixture; and

b) stirring the mixture obtained in step (a) under conditions to obtain said polymer.

The formula (III) in step (a) of the process as defined herein may be selected from the group consisting of:

formula (IV) in step (a) of the process as defined herein may be selected from the group consisting of:

the solvent in step (a) of the process as defined herein may be an organic solvent. The organic solvent may be a polar aprotic solvent. The polar aprotic solvent may be selected from the group consisting of Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone, and acetonitrile.

The conditions referred to in step (b) of the process as defined herein may comprise a temperature in the range of from about 20 ℃ to about 30 ℃, from about 20 ℃ to about 22 ℃, from about 20 ℃ to about 25 ℃, from about 25 ℃ to about 30 ℃, from about 28 ℃ to about 30 ℃ or preferably from about 22 ℃ to about 28 ℃.

The conditions referred to in step (b) of the process as defined herein may be carried out for a period of time in the range of from about 30 minutes to about 48 hours, for about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 26 hours, about 28 hours, about 30 hours, about 32 hours, about 34 hours, about 36 hours, about 38 hours, about 40 hours, about 42 hours, about 44 hours, about 46 hours, about 48 hours, preferably about 1 hour, preferably about 12 hours or more preferably about 48 hours.

The conditions referred to in step (b) of the process as defined herein may optionally further comprise the step of heating the mixture. The temperature at which the mixture is heated may be in the range of about 40 ℃ to about 80 ℃, about 40 ℃ to about 45 ℃, about 40 ℃ to about 50 ℃, about 40 ℃ to about 55 ℃, about 40 ℃ to about 60 ℃, about 40 ℃ to about 65 ℃, about 40 ℃ to about 70 ℃, about 40 ℃ to about 75 ℃, about 40 ℃ to about 80 ℃, about 45 ℃ to about 80 ℃, about 50 ℃ to about 80 ℃, about 55 ℃ to about 80 ℃, about 60 ℃ to about 80 ℃, about 65 ℃ to about 80 ℃, about 70 ℃ to about 80 ℃, about 75 ℃ to about 80 ℃, preferably about 65 ℃ or more preferably about 70 ℃.

Exemplary, non-limiting embodiments of antimicrobial gels will now be disclosed.

The antimicrobial gel may comprise an oligomer of formula (I)

Wherein linker 1 is an alkyl-aryl-alkyl group or (C)₂-C₈) An alkene;

p and q are independently integers from 2 to 6, i.e., 2,3, 4, 5 or 6;

the joint 2 is

m is 0 or 1;

a is independently aryl or heteroaryl;

b is independently O, N or S;

c is independently aryl or heteroaryl;

R₁is a bond or an alkyl group;

R₂is a bond, alkoxy or amine;

R₃is a carbonyl, a bond or an alkyl;

R₄is a bond or an alkyl group;

R₅is an alkyl group; and is

X is a halide selected from the group consisting of fluoride, chloride and bromide.

A gel as defined herein may be formed in an alcohol. The alcohol may be selected from the group consisting of ethanol, methanol, n-propanol, and n-butanol.

Other applications for the polymer composition will be discussed further below.

Brief Description of Drawings

Examples

Non-limiting examples of the present invention will be described in further detail by reference to specific examples, which should not be construed as limiting the scope of the invention in any way.

List of abbreviations used

ACN: acetonitrile

AcOEt: ethyl acetate

AcOH: acetic acid

NH₄Cl: ammonium chloride

AUC: area under curve

Saline water: saturated aqueous NaCl solution

bs: wide range signal (broad peak)¹H NMR

And cat: catalyst and process for preparing same

Cs₂CO₃: cesium carbonate

CH₂Cl₂Or DCM: methylene chloride or methylene chloride

DBU: 1, 8-diazabicycloundec-7-enes

DCC: n, N' -dicyclohexylcarbodiimide

Deionized water: deionized water

DMAP: 4-dimethylaminopyridine

DMF: n, N-dimethylformamide

DMSO, DMSO: dimethyl sulfoxide

DMSO-d₆: deuterated dimethyl sulfoxide

Diethyl Ether (Ether): diethyl ether (diethyl ether)

EtOH: ethanol

HPLC: high pressure liquid chromatography

IPA: isopropanol (2-propanol)

KOH: potassium hydroxide

L: lifting of wine

LiAlH₄: lithium aluminum hydride

LC-MS: liquid chromatography-mass spectrometry

Me: methyl radical

MeOH: methanol

m.p.: melting Point

MS: mass spectrometry

NBS: n-bromosuccinimide

Et₃N: triethylamine

Na₂CO₃: sodium carbonate

NaHCO₃: sodium bicarbonate

NaH: sodium hydride

NaOH: sodium hydroxide

Na2SO 4: sodium sulfate

NIS: n-iodosuccinimide

NMM: n-methylmorpholine

NMR: nuclear magnetic resonance

Pd(dppf)Cl₂: [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (II)

Rt: at room temperature

TBAF: tetrabutylammonium iodide

TEA: triethylamine

THF: tetrahydrofuran (THF)

TLC: thin layer chromatography

TMS: trimethylsilyl group

SOCl₂: thionyl chloride

Materials and methods

All anhydrous solvents were purchased from Sigma-Aldrich Corp. (st.louis, MO, u.s.a.) and used without further purification. All other reagents were used as received unless otherwise stated below.

Analytical Thin Layer Chromatography (TLC) was carried out using Merck 60F-254 silica gel plates and by UV light (C: (R))254nm) and/or with 20% KMnO₄H of w/v₂The plates were heated after O solution dyeing. Flash column chromatography was performed on Kieselgel 60(0.040-0.063mm) from Merck (Burlington, MA, USA).

Recording on a Bruker AV-400(400MHz) spectrometer¹H and¹³c Nuclear Magnetic Resonance (NMR) spectrum. Chemical shifts (δ) are reported in parts per million (ppm) with the residual solvent peak of tetramethylsilane at 0.00ppm used as an internal standard.¹HNMR data are reported in the following order: chemical shift, multiplicities (br ═ broad, s ═ unimodal, d ═ bimodal, t ═ trimodal, q ═ tetramodal and m ═ multimodal), coupling constants (J, Hz), integrals and assignments. High Resolution Mass Spectra (HRMS) were recorded on a Bruker MicroTOF-Q system. Samples were run at 20. mu.L/min^-1Directly into the chamber. Typical instrument parameters: capillary voltage, 4 kV; atomizer, 0.4 bar; dry gas, at 120 ℃ for 2 L.min^-1(ii) a The m/z range is 40-3000.