CN119330939A - A quaternary ammonium salt compound containing a cyclic dipeptide structure, and its preparation method and application - Google Patents
A quaternary ammonium salt compound containing a cyclic dipeptide structure, and its preparation method and application Download PDFInfo
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Abstract
本发明涉及生物医药技术领域，尤其涉及一种含有环状二肽结构的季铵盐化合物、其制备方法及应用，所述含有环状二肽结构的季铵盐化合物，具有式Ⅰ所示结构。与现有技术相比，本发明在结构上进行创新，以环状组氨酸二聚体为基础，首次将其修饰上多个含有季铵盐和疏水末端的取代基，得到了一系列具有良好水溶性小分子环状抗菌肽。材料的性能可以通过改变季铵盐取代基进行调控和筛选，最终得到具有良好抗菌活性、高选择性、低溶血毒性和良好生物相容性的小分子环状季铵盐抗菌材料。
The present invention relates to the field of biomedicine technology, and in particular to a quaternary ammonium salt compound containing a cyclic dipeptide structure, a preparation method and an application thereof, wherein the quaternary ammonium salt compound containing a cyclic dipeptide structure has a structure shown in Formula I. Compared with the prior art, the present invention is innovative in structure, based on a cyclic histidine dimer, and for the first time, it is modified with multiple substituents containing quaternary ammonium salts and hydrophobic ends, thereby obtaining a series of small molecule cyclic antimicrobial peptides with good water solubility. The performance of the material can be regulated and screened by changing the quaternary ammonium salt substituent, and finally a small molecule cyclic quaternary ammonium salt antimicrobial material with good antimicrobial activity, high selectivity, low hemolytic toxicity and good biocompatibility is obtained.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to a quaternary ammonium salt compound containing a cyclic dipeptide structure, a preparation method and application thereof.
Background
Since penicillin was discovered, antibiotics have played an important role in the field of antibacterial therapy. However, due to the abuse of antibiotics, microbial resistance to antibiotics is steadily increasing, resulting in the continued failure of traditional antibiotics, while the development of new antibiotics is nearly in a state of stasis. Therefore, there is an urgent need to develop a novel antibacterial agent which has broad-spectrum antibacterial properties and is not liable to induce microbial resistance.
In the last century, many studies have been conducted on the antibacterial effect of small-molecule quaternary ammonium salts, and long-chain alkyl quaternary ammonium salts such as cetyl trimethylammonium bromide and the like have been found to have a strong antibacterial effect. However, the organic small molecular quaternary ammonium salt antibacterial material generally has the defects of easy elution, easy volatilization, difficult processing, poor chemical stability and the like in long-term use, and most quaternary ammonium salt materials have strong irritation, poor biocompatibility and high hemolytic toxicity, so that the application of the organic small molecular quaternary ammonium salt antibacterial material in organisms is limited, and the organic small molecular quaternary ammonium salt antibacterial material is more applied as a medicine patch and is difficult to be orally taken or injected.
The antibacterial peptide has broad-spectrum antibacterial activity, has strong killing effect on bacteria, and is generally not easy to generate drug resistance. However, the content of the antibacterial peptide in the animal and plant bodies is very small, the yield of the antibacterial peptide extracted from the animal bodies is low, the time is long, the process is complex, the cost is high, and the large-scale production cannot be realized, so that the method becomes the biggest obstacle for restricting the antibacterial peptide to enter practical application.
Disclosure of Invention
In view of the above, the present invention provides a quaternary ammonium salt compound containing cyclic dipeptide structure with higher biocompatibility, and a preparation method and application thereof.
In order to achieve the above object, the present invention provides a quaternary ammonium salt compound having a cyclic dipeptide structure, having a structure represented by formula I:
a formula I;
Wherein N is an integer of 0 to 10, R 1 is-N +R2R3R4;
R 2、R3、R4 is independently selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C20 aryl or substituted or unsubstituted C4-C20 heteroaryl;
The substituent groups in the substituted C1-C10 alkyl, the substituted C6-C20 aryl or the substituted C4-C20 heteroaryl are respectively and independently selected from one or more of halogen, C6-C20 aryl and C4-C20 heteroaryl.
Preferably, n is 2, 4, 6 or 8.
Preferably, R 2、R3、R4 is independently selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted fused ring aryl formed by fusing 2-3 phenyl groups or substituted or unsubstituted five-membered to six-membered monocyclic heteroaryl;
the substituent groups in the substituted C1-C10 alkyl, the substituted phenyl, the substituted condensed ring aryl formed by fusing 2-3 phenyl groups or the substituted five-membered to six-membered monocyclic heteroaryl are respectively and independently selected from one or more of halogen, phenyl, condensed ring aryl formed by fusing 2-3 phenyl groups or five-membered to six-membered monocyclic heteroaryl.
Preferably, R 1 is selected from the structures shown in formula II, formula III, or formula IV:
A formula II; Formula III; A formula IV;
in the formula II, m is an integer of 1-9.
Preferably, m is 1, 3, 5, 7 or 9.
The invention also provides a preparation method of the quaternary ammonium salt compound containing the cyclic dipeptide structure, which comprises the following steps:
Carrying out substitution reaction on a cyclic histidine dipeptide iodo compound with a structure shown in a formula V and tertiary amine NR 2R3R4 to obtain a quaternary ammonium salt compound with a structure shown in a formula I and containing a cyclic dipeptide structure;
a formula V; a formula I;
Wherein N is an integer of 0 to 10, R 1 is-N +R2R3R4;
R 2、R3、R4 is independently selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C20 aryl or substituted or unsubstituted C4-C20 heteroaryl;
The substituted C1-C10 alkyl, substituted C6-C20 aryl or substituted C4-C20 heteroaryl is independently selected from one or more of halogen, C6-C20 aryl and C4-C20 heteroaryl.
Preferably, the molar ratio of the cyclic histidine dipeptide iodo compound with the structure shown in formula V to the tertiary amine NR 2R3R4 is 1:4-20;
The tertiary amine has a structure represented by formula VI, formula VII or formula VIII:
Formula VI; formula VII; Formula VIII;
The solvent for the substitution reaction comprises one or more of dimethyl sulfoxide, N-dimethylformamide and acetonitrile;
The temperature of the substitution reaction is 40-100 ℃, and the time of the substitution reaction is 12-72 hours.
Preferably, the cyclic histidine dipeptide iodo compound having the structure of formula V is prepared according to the following method:
Reacting a cyclic histidine dipeptide with a structure of formula IX with diiodoalkane with a structure of formula X under alkaline conditions to obtain a cyclic histidine dipeptide iodo compound with a structure of formula V;
formula IX; Formula X.
Preferably, the molar ratio of the cyclic histidine dipeptide with the structure shown in the formula IX to the diiodoalkane with the structure shown in the formula X is 1 (4-20);
The alkaline condition is provided by alkaline substances, wherein the alkaline substances are selected from one or more of potassium carbonate, sodium hydroxide and potassium hydroxide;
The molar ratio of the cyclic histidine dipeptide with the structure shown in the formula IX to the alkaline substance is 1 (2-8);
the solvent for the reaction comprises one or more of acetone, N-dimethylformamide and acetonitrile;
the reaction temperature is 60-100 ℃, and the reaction time is 24-72 hours.
The invention also provides application of the quaternary ammonium salt compound containing the cyclic dipeptide structure as an antibacterial material.
The invention provides a quaternary ammonium salt compound containing a cyclic dipeptide structure, which has a structure shown in a formula I. Compared with the prior art, the invention is innovated in structure, and based on the cyclic histidine dimer, a plurality of substituents containing quaternary ammonium salt and hydrophobic terminal are modified for the first time, thus obtaining a series of small molecular cyclic antibacterial peptides with good water solubility. The performance of the material can be regulated and screened by changing quaternary ammonium salt substituents, and the small-molecule cyclic quaternary ammonium salt antibacterial material with good antibacterial activity, high selectivity, low hemolytic toxicity and good biocompatibility is finally obtained. Experimental results show that the quaternary ammonium salt compound containing the cyclic dipeptide structure provided by the invention has excellent antibacterial activity and high selectivity on gram-positive bacteria staphylococcus aureus (S. Aureus) and gram-negative bacteria escherichia coli (E. Coli), can destroy the integrity of bacterial cell membranes through physical interaction, and has the characteristic of rapidly killing bacteria. The quaternary ammonium salt material containing the cyclic dipeptide provided by the invention can inhibit the survival rate of various bacteria to below 1% within 30 min.
Drawings
FIG. 1 is a chart showing the hydrogen nuclear magnetic resonance spectrum of a quaternary ammonium salt material containing cyclic dipeptide prepared in example 21 of the present invention;
FIG. 2 is a bar graph showing the minimum inhibitory concentration of cyclic dipeptide-containing quaternary ammonium salt material prepared in examples 5-32 of the present invention on Staphylococcus aureus;
FIG. 3 is a histogram of minimum inhibitory concentration of cyclic dipeptide-containing quaternary ammonium salt material prepared in examples 5-32 of the present invention on E.coli;
FIG. 4 is a diagram showing the morphology of bacteria after the treatment of the cyclic dipeptide containing quaternary ammonium material of example 21 of the present invention;
FIG. 5 is a graph showing colony count at various time points after treatment of cyclic dipeptide-containing quaternary ammonium material of example 21 of the present invention;
FIG. 6 is a graph showing the results of characterization of hemolytic toxicity of cyclic dipeptide-containing quaternary ammonium salt materials prepared in some examples of the present invention.
Detailed Description
In order to further illustrate the invention, a detailed description is provided below in connection with the examples. It should be understood that the description is only intended to further illustrate the features and advantages of the invention, and not to limit the invention to the claims.
The invention provides a quaternary ammonium salt compound containing a cyclic dipeptide structure, which has a structure shown in a formula I:
a formula I;
Wherein N is an integer of 0 to 10, R 1 is-N +R2R3R4;
R 2、R3、R4 is independently selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C20 aryl or substituted or unsubstituted C4-C20 heteroaryl;
The substituent groups in the substituted C1-C10 alkyl, the substituted C6-C20 aryl or the substituted C4-C20 heteroaryl are respectively and independently selected from one or more of halogen, C6-C20 aryl and C4-C20 heteroaryl.
In some embodiments of the present invention, n is 2, 4, 6, or 8, or a range value with any of the above values as an upper limit or a lower limit.
In a specific embodiment provided by the invention, R 2、R3、R4 is independently selected from one or more of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C20 aryl or substituted or unsubstituted C4-C20 heteroaryl, the substituent of the substituted C1-C10 alkyl, substituted C6-C20 aryl or substituted C4-C20 heteroaryl is independently selected from halogen, one or more of C6-C20 aryl and C4-C20 heteroaryl, preferably the substituent of the substituted C1-C10 alkyl, substituted C6-C20 aryl or substituted C4-C20 heteroaryl is independently selected from halogen, one or more of C6-C10 aryl and C4-C10 heteroaryl, more preferably the substituent of the substituted C1-C10 alkyl, substituted C6-C20 aryl and substituted C4-C20 heteroaryl is independently selected from halogen, one or more of the substituents of the halogen, the substituent of the substituted C4-C20 aryl and C4-C20 heteroaryl is independently selected from halogen, one or more of the substituents of the halogen, the phenyl, and the substituent of the substituted C4-C20 heteroaryl is independently selected from halogen, the substituent of the substituted C4-C20 heteroaryl is independently selected from halogen, and the substituent of the C4-C20 heteroaryl is selected from halogen, and the substituent of the phenyl, and the substituent of the C4-C20 heteroaryl is independently selected from the halogen, and the substituent of the C3-C20 heteroaryl is independently selected from the halogen, and the C3-C20 heteroaryl.
In a specific embodiment provided by the invention, R 2、R3、R4 is independently selected from one or more of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C10 aryl or substituted or unsubstituted C4-C10 heteroaryl, the substituent of the substituted C1-C10 alkyl, substituted C6-C10 aryl or substituted C4-C10 heteroaryl is independently selected from halogen, one or more of C6-C20 aryl and C4-C20 heteroaryl, preferably the substituent of the substituted C1-C10 alkyl, substituted C6-C10 aryl or substituted C4-C10 heteroaryl is independently selected from halogen, one or more of C6-C10 aryl and C4-C10 heteroaryl, more preferably the substituent of the substituted C1-C10 alkyl, substituted C6-C10 aryl and substituted C4-C10 heteroaryl is independently selected from halogen, one or more of the substituents of the substituted C4-C10 aryl and C4-C10 heteroaryl is independently selected from halogen, one or more of the substituents of the halogen, the phenyl, the substituent of the substituted C4-C10 heteroaryl and the substituent is independently selected from halogen, the substituent of the C4-C10 heteroaryl and the substituent of the aryl is independently selected from halogen, the phenyl, and the substituent of the C4-C10 heteroaryl is independently selected from halogen, and the substituent of the C10 phenyl and the substituent of C10 is independently selected from one or more of the substituents of the C10 aryl and C10 heteroaryl.
In a specific embodiment provided by the invention, R 2、R3、R4 is independently selected from one or more of substituted or unsubstituted C1-C10 alkyl groups, substituted or unsubstituted phenyl groups, substituted or unsubstituted fused ring aryl groups formed by 2-3 phenyl groups or substituted or unsubstituted five-membered monocyclic heteroaryl groups, the substituted C1-C10 alkyl groups, substituted phenyl groups, substituted fused ring aryl groups formed by 2-3 phenyl groups or substituted five-membered monocyclic heteroaryl groups are independently selected from halogen, one or more of C6-C20 aryl groups and C4-C20 heteroaryl groups, preferably, the substituted fused ring aryl groups formed by 2-3 phenyl groups or substituted five-membered heteroaryl groups are independently selected from halogen, one or more of C6-C10 aryl groups and C4-C10 heteroaryl groups, preferably, the fused ring aryl groups formed by one or more of C1-C10 phenyl groups and substituted five-membered heteroaryl groups are independently selected from halogen, the fused ring aryl groups formed by 2-C3 phenyl groups or substituted five-membered heteroaryl groups are independently selected from halogen, the fused ring aryl groups formed by one or substituted five-membered phenyl groups formed by 2-C3 phenyl groups and the fused ring aryl groups are independently selected from halogen, the substituted or the fused ring aryl groups formed by one or more of C6-C10 phenyl groups are independently selected from halogen, the substituted or the fused ring aryl groups formed by one or more of C10 phenyl groups are independently selected from halogen, the three or the three-membered phenyl groups formed by three-membered phenyl groups.
In a specific embodiment provided by the present invention, R 1 is selected from the structures represented by formula II, formula III, or formula IV:
A formula II; Formula III; A formula IV;
In the formula II, m is an integer of 1-9. In some embodiments of the invention, m is 1,3, 5, 7, 9, or a range value having the above value as an upper or lower limit.
The curved line indicates the connection location.
The quaternary ammonium salt compound provided by the invention is based on cyclic histidine dimer, and is subjected to quaternary ammonium salt modification to obtain the organic small molecule antibacterial material with good antibacterial activity, high selectivity and low toxicity, and has good biocompatibility due to the cyclic dipeptide structure, so that the hemolytic toxicity is greatly reduced.
The quaternary ammonium salt compound containing the cyclic dipeptide provided by the invention has excellent antibacterial activity and high selectivity on gram-positive bacteria staphylococcus aureus (S. Aureus) and gram-negative bacteria escherichia coli (E. Coli), can destroy the integrity of bacterial cell membranes through physical interaction, and shows the characteristic of rapidly killing bacteria. The quaternary ammonium salt compound containing the cyclic dipeptide provided by the invention can inhibit the survival rate of various bacteria to below 1% within 30 min.
The invention also provides a preparation method of the quaternary ammonium salt compound containing the cyclic dipeptide structure, which comprises the following steps of carrying out substitution reaction on the cyclic histidine dipeptide iodo compound with the structure shown in the formula V and tertiary amine NR 2R3R4 to obtain the quaternary ammonium salt compound containing the cyclic dipeptide structure shown in the formula I;
a formula V; a formula I;
Wherein N is an integer of 0 to 10, R 1 is-N +R2R3R4;
R 2、R3、R4 is independently selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C20 aryl or substituted or unsubstituted C4-C20 heteroaryl;
The substituted C1-C10 alkyl, substituted C6-C20 aryl or substituted C4-C20 heteroaryl is independently selected from one or more of halogen, C6-C20 aryl and C4-C20 heteroaryl.
The range of n in the cyclic histidine dipeptide iodo compound having the structure of formula V is as described above, and will not be described in detail herein.
In the tertiary amine NR 2R3R4, the range of R 2、R3、R4 is as described above, and the description thereof is omitted.
In some embodiments of the invention, the tertiary amine NR 2R3R4 has a structure of formula VI, formula VII, or formula VIII:
Formula VI; formula VII; Formula VIII;
m is an integer of 1 to 9. The range of m is the same as that described above, and is not repeated here.
The source of the tertiary amine is not particularly limited and may be generally commercially available.
According to the invention, the molar ratio of the cyclic histidine dipeptide iodo compound with the structure of formula V to the tertiary amine NR 2R3R4 is preferably 1:4-20, more preferably 1 (5-15), still more preferably 1 (8-12), and most preferably 1:10.
According to the invention, the cyclic histidine dipeptide iodo compound with the structure shown in formula V and tertiary amine NR 2R3R4 are subjected to substitution reaction in a solvent, wherein the solvent for the substitution reaction preferably comprises one or more of dimethyl sulfoxide, N-dimethylformamide and acetonitrile.
The amount of the solvent used in the present invention is not particularly limited, and the reaction raw material may be dissolved. In a specific embodiment of the present invention, the ratio of the cyclic histidine dipeptide iodo compound with the structure of formula V to the solvent is preferably 1-5 g:10-50 mL, more preferably 1-3 g:10-50 mL, still more preferably 1 g:10-50 mL, and most preferably 1 g:30-40 mL.
According to the invention, the temperature of the substitution reaction is preferably 40-100 ℃, more preferably 60-90 ℃, still more preferably 70-80 ℃, and most preferably 75 ℃, and the time of the substitution reaction is preferably 12-72 h, more preferably 24-72 h, and still more preferably 48 h.
In some embodiments of the present invention, after the substitution reaction, the method further comprises:
And (3) settling, washing and drying the reacted product solution by diethyl ether to obtain the quaternary ammonium salt compound containing the cyclic dipeptide structure with the structure shown in the formula I.
In some embodiments of the present invention, the volume ratio of the solvent to diethyl ether in the substitution reaction is preferably 1:5-10, more preferably 1:8-10.
The method of sedimentation, washing and drying is not particularly limited, and methods of sedimentation, washing and drying known to those skilled in the art may be adopted.
The method for preparing the cyclic histidine dipeptide iodo compound with the structure of formula V is not particularly limited, and the cyclic histidine dipeptide iodo compound with the structure of formula V can be prepared according to a method well known to a person skilled in the art, preferably according to the following method, the cyclic histidine dipeptide with the structure of formula IX and diiodoalkane with the structure of formula X are reacted under alkaline conditions to obtain the cyclic histidine dipeptide iodo compound with the structure of formula V;
formula IX; Formula X.
Wherein n is any integer of 0 to 10.
The range of n is the same as that described above, and will not be described in detail here.
In some embodiments of the invention, the diiodoalkane is specifically 1, 4-diiodobutane, 1, 6-diiodohexane, 1, 8-diiodooctane or 1, 10-diiododecane.
According to the invention, the molar ratio of the cyclic histidine dipeptide of formula IX to the diiodoalkane of formula X is preferably 1 (4-20), more preferably 1 (4-15), still more preferably 1 (4-10), still more preferably 1 (4-8), and most preferably 1:6.
According to the invention, the alkaline condition is preferably provided by an alkaline substance, the alkaline substance is preferably one or more of potassium carbonate, sodium hydroxide and potassium hydroxide, and the molar ratio of the cyclic histidine dipeptide with the structure of formula IX to the alkaline substance is preferably 1 (2-8), more preferably 1 (2-5), still more preferably 1 (2-4), and most preferably 1:3.
According to the invention, the reaction is preferably carried out in an organic solvent, the solvent of the reaction preferably comprising one or more of acetone, N-dimethylformamide and acetonitrile.
The amount of the solvent used in the present invention is not particularly limited, and the reaction raw material may be dissolved. In a specific embodiment provided by the invention, 1-5 g/10-50 mL, more preferably 1-3 g/10-50 mL, still more preferably 1 g/10-50 mL, and most preferably 1 g/20-30 mL.
According to the invention, the reaction temperature is preferably 60-100 ℃, more preferably 60-90 ℃, still more preferably 70-80 ℃, and most preferably 75 ℃, and the reaction time is preferably 24-72 hours, more preferably 36-72 hours, still more preferably 48 h.
In some embodiments of the present invention, after the reaction, the method further comprises:
and (3) settling, washing and drying the reacted product solution by diethyl ether to obtain the cyclic histidine dipeptide iodo compound with the structure shown in the formula V.
In some embodiments of the present invention, the volume ratio of the solvent to diethyl ether in the reaction is preferably 1:5-10, more preferably 1:8-10.
The method of sedimentation, washing and drying is not particularly limited, and methods of sedimentation, washing and drying known to those skilled in the art may be adopted.
The source of the cyclic histidine dipeptide having the structure of formula IX is not particularly limited, and the cyclic histidine dipeptide having the structure of formula IX may be prepared according to the method disclosed in chinese patent publication No. CN 113754598B.
In one specific embodiment provided by the invention, the cyclic histidine dipeptide having the structure of formula IX is prepared by adding 45 g L-histidine starting material and 180 mL ethylene glycol to a round bottom flask, heating on, setting heating temperature at 197 ℃, and refluxing for 24h. Pouring the reaction solution into 800 mL deionized water for sedimentation, filtering, stirring and washing with 800 mL deionized water, repeating for three times, and vacuum drying to obtain the product, namely the cyclic histidine dipeptide with the structure shown in formula (IX).
The quaternary ammonium salt compound containing the cyclic dipeptide structure provided by the invention is simple to synthesize and easy to process, and has good biocompatibility due to the cyclic peptide structure.
The quaternary ammonium salt compound containing the cyclic dipeptide provided by the invention can show good in-vitro sterilization effect on gram-positive and gram-negative bacteria, can interact with bacterial cell membranes to cause bacterial death, shows rapid sterilization kinetics, and can kill more than 99% of bacteria within 30 minutes.
Based on the above, the invention also provides application of the quaternary ammonium salt compound containing the cyclic dipeptide structure as an antibacterial material.
The invention also provides application of the quaternary ammonium salt compound containing the cyclic dipeptide structure in preparation of antibacterial drugs.
In order to further illustrate the present invention, the following examples are provided to describe in detail a quaternary ammonium compound containing a cyclic dipeptide structure, its preparation method and application.
The present invention is not particularly limited in terms of all raw materials, and sources thereof are commercially available or may be prepared according to conventional methods well known to those skilled in the art.
The staphylococcus aureus (ATCC 25923) standard strain and escherichia coli (ATCC 25922) standard strain were purchased from shandong lupulus biotechnology limited. Methicillin resistant staphylococcus aureus (MRSA ATCC 43300) was offered by the first clinical hospital at Jilin university.
Example 1
Synthesis of cyclic histidine dipeptide iodo having the structure of formula (V), wherein n=2:
The cyclic histidine dimer 1.0 g (3.65 mmol) with the structure of formula (IX) was weighed, 20. 20 mL DMF and 1.51 g (10.95 mmol) potassium carbonate were added, then 6.77 g (21.9 mmol) 1, 4-diiodobutane with the structure of formula (X) was added thereto, stirred at 75 ℃ for reaction 48 h, then poured into 160 mL diethyl ether for sedimentation, and after centrifugation, the sediment was washed with diethyl ether and dried to obtain yellow powdery product, namely cyclic histidine dipeptide iodo with the structure of formula (V).
Example 2
Synthesis of cyclic histidine dipeptide iodo having the structure of formula (V), wherein n=4:
The cyclic histidine dimer 1.0 g (3.65 mmol) with the structure of formula (IX) was weighed, 20. 20 mL DMF and 1.51 g (10.95 mmol) potassium carbonate were added, then 7.39 g (21.9 mmol) 1, 6-diiodohexane with the structure of formula (X) was added thereto, stirred at 75 ℃ for reaction 48 h, then poured into 160 mL diethyl ether for sedimentation, and after centrifugation, the sediment was washed with diethyl ether and dried to obtain yellow powdery product, namely cyclic histidine dipeptide iodo with the structure of formula (V).
Example 3
Synthesis of cyclic histidine dipeptide iodo with structure of formula (V), wherein n=6:
The cyclic histidine dimer 1.0 g (3.65 mmol) with the structure of formula (IX) is weighed, 20. 20 mL DMF and 1.51 g (10.95 mmol) potassium carbonate are added, then 8.00 g (21.9 mmol) 1, 8-diiodooctane with the structure of formula (X) are added, stirring reaction is carried out at 75 ℃ for 48 h, then the mixture is poured into 160 mL diethyl ether for sedimentation, and after centrifugation, the sediment is washed with diethyl ether and dried, thus obtaining yellow powdery product, namely the cyclic histidine dipeptide iodo compound with the structure of formula (V).
Example 4
Synthesis of cyclic histidine dipeptide iodo with structure of formula (V), wherein n=8:
the cyclic histidine dimer 1.0 g (3.65 mmol) with the structure of formula (IX) was weighed, 20. 20 mL DMF and 1.51 g (10.95 mmol) potassium carbonate were added, then 8.62 g (21.9 mmol) of 1, 10-diiododecane with the structure of formula (X) were added thereto, stirred at 75 ℃ for reaction 48h, then poured into 160 mL diethyl ether for sedimentation, and after centrifugation, the sediment was washed with diethyl ether and dried to obtain yellow powdery product, namely cyclic histidine dipeptide iodo with the structure of formula (V).
Example 5
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=2:
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.301 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethylethylamine of 0.219 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48h, the solution is poured into 80 mL diethyl ether to settle, and the sediment is washed by diethyl ether and dried after centrifugation, so that a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 6
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=2:
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.301 g (0.300 mmol) is dissolved by using DMF of 10mL, then N, N-dimethylbutylamine of 0.304 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, the solution is poured into 80 mL diethyl ether to settle, and the sediment is washed by diethyl ether and dried after centrifugation, so that a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 7
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=2:
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.301 g (0.300 mmol) is dissolved by using DMF of 10mL, then N, N-dimethylhexylamine of 0.388 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, then the solution is poured into 80 mL diethyl ether to settle, and after centrifugation, the sediment is washed by diethyl ether and dried, and the yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 8
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=2:
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.301 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethyl octylamine of 0.472 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, the solution is poured into 80mL diethyl ether to settle, and the sediment is washed by diethyl ether and dried after centrifugation, so that a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 9
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=2:
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.301 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethyl decylamine of 0.556 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, the solution is poured into 80mL diethyl ether to settle, and after centrifugation, the sediment is washed by diethyl ether and dried, and a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 10
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=2:
the cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.301 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethylbenzylamine of 0.406 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48h, the solution is poured into diethyl ether of 160 mL for sedimentation, and the sediment is washed by diethyl ether and dried after centrifugation, so that a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 11
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=2:
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.301 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethyl-2-phenethylamine of 0.448 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, then the solution is poured into diethyl ether of 160 mL for sedimentation, and after centrifugation, the sediment is washed by diethyl ether and dried, and a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 12
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=4:
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.335 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethylethylamine of 0.219 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, the solution is poured into 80mL diethyl ether to settle, the sediment is washed by diethyl ether after centrifugation and dried, and the yellow powdery product is the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 13
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=4:
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.335 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethylbutylamine of 0.304 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, the solution is poured into 80mL diethyl ether to settle, and the sediment is washed by diethyl ether and dried after centrifugation, thus obtaining yellow powdery product, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 14
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=4:
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.335 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethylhexylamine of 0.388 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, then the solution is poured into 80mL diethyl ether to settle, and after centrifugation, the sediment is washed by diethyl ether and dried, and the yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 15
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=4:
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.335 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethyl octylamine of 0.472 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, the solution is poured into 80mL diethyl ether to settle, and the sediment is washed by diethyl ether and dried after centrifugation, so that a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 16
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=4:
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.335 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethyl decylamine of 0.556 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, then the solution is poured into 80mL diethyl ether to settle, and after centrifugation, the sediment is washed by diethyl ether and dried, and a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 17
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=4:
the cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.335 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethylbenzylamine of 0.406 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48h, the solution is poured into diethyl ether of 160 mL for sedimentation, and the sediment is washed by diethyl ether and dried after centrifugation, so that a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 18
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=4:
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.335 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethyl-2-phenethylamine of 0.448 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, then the solution is poured into diethyl ether of 160 mL for sedimentation, and after centrifugation, the sediment is washed by diethyl ether and dried, and a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 19
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=6 in both the structures of formula (I) and formula (V):
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.369 g (0.300 mmol) is dissolved by using DMF of 10mL, then N, N-dimethylethylamine of 0.219 g (3.00 mmol) is added into the solution to react with stirring at 75 ℃ for 48 h, the solution is poured into 80 mL diethyl ether to settle, and after centrifugation, the sediment is washed by diethyl ether and dried, and the yellow powdery product is the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 20
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=6 in both the structures of formula (I) and formula (V):
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.369 g (0.300 mmol) is dissolved by using DMF of 10mL, then N, N-dimethylbutylamine of 0.304 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, then the solution is poured into 80 mL diethyl ether to settle, and after centrifugation, the sediment is washed by diethyl ether and dried, and the yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 21
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=6 in both the structures of formula (I) and formula (V):
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.369 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethylhexylamine of 0.388 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, the solution is poured into 80mL diethyl ether to settle, and the sediment is washed by diethyl ether and dried after centrifugation, so that a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 22
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=6 in both the structures of formula (I) and formula (V):
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.369 g (0.300 mmol) is dissolved by DMF of 10 mL, then N, N-dimethyl octylamine of 0.472 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, the solution is poured into 80mL diethyl ether to settle, the sediment is washed by diethyl ether after centrifugation, and the yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 23
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=6 in both the structures of formula (I) and formula (V):
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.369 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethyl decylamine of 0.556 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, the solution is poured into 80mL diethyl ether to settle, and the sediment is washed by diethyl ether and dried after centrifugation, so that a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 24
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=6 in both the structures of formula (I) and formula (V):
the cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.369 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethylbenzylamine of 0.406 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48h, the solution is poured into 160 mL diethyl ether to settle, and the sediment is washed by diethyl ether and dried after centrifugation, so that a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 25
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=6 in both the structures of formula (I) and formula (V):
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.369 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethyl-2-phenethylamine of 0.448 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, then the solution is poured into 160 mL diethyl ether to settle, and after centrifugation, the sediment is washed by diethyl ether and dried, and a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 26
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=8 in both the structures of formula (I) and formula (V):
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.403 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethylethylamine of 0.219 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, the solution is poured into 80mL diethyl ether to settle, and the sediment is washed by diethyl ether and dried after centrifugation, so that a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 27
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=8 in both the structures of formula (I) and formula (V):
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.403 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethylbutylamine of 0.304 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, the solution is poured into 80mL diethyl ether to settle, and the sediment is washed by diethyl ether and dried after centrifugation, so that a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 28
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=8 in both the structures of formula (I) and formula (V):
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.403 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethylhexylamine of 0.388 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, the solution is poured into 80mL diethyl ether to settle, and the sediment is washed by diethyl ether and dried after centrifugation, so that a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 29
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=8 in both the structures of formula (I) and formula (V):
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.403 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethyl octylamine of 0.472 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, the solution is poured into 80mL diethyl ether to settle, and the sediment is washed by diethyl ether and dried after centrifugation, so that a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 30
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=8 in both the structures of formula (I) and formula (V):
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.403 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethyl decylamine of 0.556 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, the solution is poured into 80mL diethyl ether to settle, and after centrifugation, the sediment is washed by diethyl ether and dried, and a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 31
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=8 in both the structures of formula (I) and formula (V):
The cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.403 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethylbenzylamine of 0.406 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48h, the solution is poured into diethyl ether of 160 mL for sedimentation, and the sediment is washed by diethyl ether and dried after centrifugation, so that a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Example 32
Synthesis of cyclic dipeptide containing quaternary ammonium salt materials having the structure of formula (I), wherein n=8 in both the structures of formula (I) and formula (V):
the cyclic histidine dipeptide iodo compound with the structure of formula (V) is weighed, 0.403 g (0.300 mmol) is dissolved by using DMF of 10 mL, then N, N-dimethyl-2-phenethylamine of 0.448 g (3.00 mmol) is added into the solution, the solution is stirred at 75 ℃ to react for 48 h, then the solution is poured into diethyl ether of 160 mL for sedimentation, and after centrifugation, the sediment is washed by diethyl ether and dried, and a yellow powdery product is obtained, namely the quaternary ammonium salt material containing the cyclic dipeptide with the structure of formula (I).
Detection examples
The quaternary ammonium salt material containing cyclic dipeptide having the structure of formula (I) obtained in the above example of the present invention was examined.
Referring to fig. 1, fig. 1 is a nuclear magnetic resonance hydrogen spectrum of a quaternary ammonium salt material containing cyclic dipeptide prepared in example 21 of the present invention. From fig. 1, it can be seen that the substitution of the pendant group of the cyclic histidine dipeptide iodo was successful to the quaternary ammonium salt form, resulting in a quaternary ammonium salt material having the structure of formula (I).
The in vitro antimicrobial activity of quaternary ammonium salt materials containing cyclic dipeptides was tested by the well plate assay:
The quaternary ammonium salt material containing cyclic dipeptide and having the structure of formula (I) prepared in some examples of the invention is co-cultured with staphylococcus aureus (ATCC 25923), escherichia coli (ATCC 25922) or methicillin-resistant staphylococcus aureus (ATCC 43300), and the Minimum Inhibitory Concentration (MIC) is detected:
First, staphylococcus aureus (s. Aureus), escherichia coli (e. Coli), or methicillin-resistant staphylococcus aureus (MRSA) was inoculated in fresh MH medium and cultured at 37 ℃ for 12 h, bacteria in log phase were diluted with fresh medium, and bacteria (100.0 μl,1×10 6 CFU/mL) were added to 96-well plates. The quaternary ammonium salt material containing cyclic dipeptide was diluted with PBS (ph=7.4) using a gradient dilution method. PBS (ph=7.4) as a control group and the diluted quaternary ammonium salt material containing cyclic dipeptide were then added to a 96-well plate, and mixed uniformly by shaking 60 s using a microplate reader, and the optical density at 600 nm was measured. The plates were incubated at 37 ℃ for 24h, followed by measuring the optical density of the microbial solution at 600 nm. MIC is the lowest concentration at which no bacterial growth is detected.
The results of minimum inhibitory concentration of the cyclic dipeptide-containing quaternary ammonium salt material prepared in examples 5 to 32 and having the structure of formula (I) on different bacteria are shown in Table 1.
Table 1 minimum inhibitory concentration (MIC, μg/mL) of cyclic dipeptide containing quaternary ammonium salt material prepared in examples 5-32 for different bacteria
As can be seen from Table 1, the cyclic dipeptide-containing quaternary ammonium salt materials prepared in examples 5-32 have antibacterial activity against both Staphylococcus aureus (ATCC 25923) and Escherichia coli (ATCC 25922), and the MIC value of the materials can reach 2 mug/mL at the lowest. The histogram graphs drawn according to the experimental results of table 1 are shown in fig. 2 and 3, wherein fig. 2 is a histogram graph of minimum inhibitory concentration of the cyclic dipeptide-containing quaternary ammonium salt material prepared in examples 5 to 32 against staphylococcus aureus, and fig. 3 is a histogram graph of minimum inhibitory concentration of the cyclic dipeptide-containing quaternary ammonium salt material prepared in examples 5 to 32 against escherichia coli. For some of the materials with excellent antimicrobial effect, the minimum inhibitory concentration against MRSA was further characterized and the results are shown in table 2.
TABLE 2 minimum inhibitory concentration (MIC, μg/mL) of quaternary ammonium salt materials prepared in part of the examples against MRSA
As can be seen from Table 2, some of the quaternary ammonium salt materials prepared in the examples, especially example 21, have good antimicrobial activity against methicillin-resistant Staphylococcus aureus (ATCC 43300).
The bacterial cell membrane disruption ability of the quaternary ammonium salt material containing cyclic dipeptide was verified by photographing the morphology of the bacterial cell membrane after material treatment using a scanning electron microscope:
First, staphylococcus aureus and escherichia coli were inoculated in fresh MH medium and cultured at 37 ℃ for 12 h, washed three times with PBS (ph=7.4) and resuspended, and the final bacterial solution concentration was 2×10 6 CFU/mL. After incubation of 120 min at 37 ℃ 500.0 μl of bacterial suspension and 500.0 μl of quaternary ammonium salt material solution containing cyclic dipeptide at a concentration of 20 μg/mL were mixed well, the treated bacterial samples were collected by centrifugation and then washed twice with PBS. Next, the solution was fixed with 4% paraformaldehyde at 25℃for 12 h. Subsequently, the samples were washed once with PBS and dehydrated with gradient ethanol solutions (25%, 50%, 75% and 100%). And finally, dripping the bacterial sample on a silicon wafer, and observing the treated bacterial sample by a Scanning Electron Microscope (SEM).
Referring to FIG. 4, FIG. 4 shows the bacterial morphology after treatment with a cyclic dipeptide containing quaternary ammonium material in example 21 of the present invention.
From FIG. 4, it is clear that the quaternary ammonium salt material containing cyclic dipeptide has excellent ability to destroy bacterial cell membrane.
The bactericidal kinetics of cyclic dipeptide containing quaternary ammonium materials against staphylococcus aureus and escherichia coli were verified by using bacterial plate counting:
Bacteria (staphylococcus aureus or escherichia coli) were inoculated in fresh MH medium and incubated at 37 ℃ for 12 h, washed three times with PBS (ph=7.4) and resuspended to give a bacterial solution at a concentration of 1×10 6 CFU/mL. Quaternary ammonium salt material containing cyclic dipeptide was dissolved in PBS to prepare solutions at concentrations of 2 XMIC and 4 XMIC, and ofloxacin was dissolved in PBS to prepare a solution of 2. Mu.g/mL using ofloxacin as a control, which is a clinically usual antibiotic. The three solutions and PBS 1mL were placed in centrifuge tubes, and the four groups were added with 1mL of the bacterial suspension, mixed well, and treated with 2, 5, 10, 20, 30, 60 and 120 min, respectively. At each time point, 100.0. Mu.L of the mixture was dropped onto LB agar plates and spread uniformly, and cultured at 37℃for 24h, and the sterilization rate of the quaternary ammonium salt material containing cyclic dipeptide was calculated by colony counting. Each group was designated as 1 XMIC group, 2 XMIC group, ofloxacin group, PBS group, respectively, depending on the final concentration of each group of materials after mixing with the bacterial liquid.
Referring to FIG. 5, FIG. 5 shows the statistics of colony counts at various time points after treatment of the cyclic dipeptide-containing quaternary ammonium material of example 21 of the present invention, and the data corresponding to each point is shown in Table 3.
TABLE 3 statistical Table of the bactericidal kinetics of the quaternary ammonium salt material prepared in example 21 against Staphylococcus aureus and Escherichia coli
From fig. 5, it can be seen that the quaternary ammonium salt material containing cyclic dipeptide has rapid sterilization kinetics.
The biocompatibility of the quaternary ammonium salt material containing the cyclic dipeptide was verified by characterizing the hemolytic toxicity of the material to sheep erythrocytes:
First, a volume of 4% sheep red blood cells was centrifuged, washed three times with PBS (ph=7.4), and resuspended in an equal volume of PBS solution. The materials prepared in each example listed in Table 1 were dissolved in PBS to prepare solutions having a concentration of 1 mg/mL, 500. Mu.L of each group of materials was placed in a centrifuge tube, and 500. Mu.L of the sheep red blood cell suspension was added and mixed. 500. Mu.L of deionized water was mixed with sheep red blood cells in equal volumes as a positive control group, and 500. Mu.L of PBS was mixed with sheep red blood cells in equal volumes as a negative control group. Each group was incubated in a 37 ℃ incubator for 2 hours, after which centrifugation, the color shade of the supernatant in the centrifuge tube was recorded by photographing. The darker the supernatant color, the closer to the positive control group, indicating that the more red blood cells burst, the greater the hemolytic toxicity of the corresponding material.
Referring to fig. 6, fig. 6 is a graph showing the results of characterization of hemolytic toxicity of cyclic dipeptide-containing quaternary ammonium salt materials prepared in the various examples listed in table 2.
As can be seen from FIG. 6, the quaternary ammonium salt materials containing cyclic dipeptide prepared in examples 15, 20, 21, 24, 25 and 27 have good biocompatibility and low hemolytic toxicity, and hardly cause rupture of erythrocytes at a sterilizing concentration (500. Mu.g/mL) far higher than that of the materials.
The present invention provides a quaternary ammonium salt antibacterial material containing cyclic dipeptide structures, its preparation method and application, and specific examples are set forth herein to illustrate the principles and embodiments of the invention, and the above examples are provided to assist in understanding the methods of the invention and their core ideas, including the best mode, and to enable any person skilled in the art to practice the invention, including making and using any devices or systems, and performing any incorporated methods. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims. The scope of the patent protection is defined by the claims and may include other embodiments that occur to those skilled in the art. Such other embodiments are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal language of the claims.
Claims (10)
1. A quaternary ammonium salt compound having a cyclic dipeptide structure, characterized by having a structure represented by formula I:
a formula I;
Wherein N is an integer of 0 to 10, R 1 is-N +R2R3R4;
r 2、R3、R4 is independently selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C20 aryl or substituted or unsubstituted C4-C20 heteroaryl;
The substituent groups in the substituted C1-C10 alkyl, the substituted C6-C20 aryl or the substituted C4-C20 heteroaryl are respectively and independently selected from one or more of halogen, C6-C20 aryl and C4-C20 heteroaryl.
2. The quaternary ammonium salt compound according to claim 1, wherein n is 2, 4, 6 or 8.
3. The quaternary ammonium salt compound according to claim 1, wherein R 2、R3、R4 is independently selected from a substituted or unsubstituted C1 to C10 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted fused ring aryl group formed by 2 to 3 phenyl groups, or a substituted or unsubstituted five-membered to six-membered monocyclic heteroaryl group;
the substituent groups in the substituted C1-C10 alkyl, the substituted phenyl, the substituted condensed ring aryl formed by fusing 2-3 phenyl groups or the substituted five-membered to six-membered monocyclic heteroaryl are respectively and independently selected from one or more of halogen, phenyl, condensed ring aryl formed by fusing 2-3 phenyl groups or five-membered to six-membered monocyclic heteroaryl.
4. The quaternary ammonium salt compound according to claim 1, wherein R 1 is selected from the structures represented by formula II, formula III, or formula IV:
A formula II; Formula III; A formula IV;
in the formula II, m is an integer of 1-9.
5. The quaternary ammonium compound of claim 4, wherein m is 1, 3, 5, 7 or 9.
6. A process for the preparation of a quaternary ammonium compound containing a cyclic dipeptide structure as claimed in claim 1 comprising the steps of:
Carrying out substitution reaction on a cyclic histidine dipeptide iodo compound with a structure shown in a formula V and tertiary amine NR 2R3R4 to obtain a quaternary ammonium salt compound with a structure shown in a formula I and containing a cyclic dipeptide structure;
a formula V; a formula I;
Wherein N is an integer of 0 to 10, R 1 is-N +R2R3R4;
R 2、R3、R4 is independently selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C20 aryl or substituted or unsubstituted C4-C20 heteroaryl;
The substituted C1-C10 alkyl, substituted C6-C20 aryl or substituted C4-C20 heteroaryl is independently selected from one or more of halogen, C6-C20 aryl and C4-C20 heteroaryl.
7. The method according to claim 6, wherein the molar ratio of cyclic histidine dipeptide iodo of the structure of formula V to tertiary amine NR 2R3R4 is 1:4-20;
The tertiary amine has a structure represented by formula VI, formula VII or formula VIII:
Formula VI; formula VII; Formula VIII;
The solvent for the substitution reaction comprises one or more of dimethyl sulfoxide, N-dimethylformamide and acetonitrile;
The temperature of the substitution reaction is 40-100 ℃, and the time of the substitution reaction is 12-72 hours.
8. The method of claim 6, wherein the cyclic histidine dipeptide iodo of formula V is prepared as follows:
Reacting a cyclic histidine dipeptide with a structure of formula IX with diiodoalkane with a structure of formula X under alkaline conditions to obtain a cyclic histidine dipeptide iodo compound with a structure of formula V;
formula IX; Formula X.
9. The preparation method according to claim 8, wherein the molar ratio of the cyclic histidine dipeptide having the structure of formula IX to the diiodoalkane having the structure of formula X is 1 (4-20);
The alkaline condition is provided by alkaline substances, wherein the alkaline substances are selected from one or more of potassium carbonate, sodium hydroxide and potassium hydroxide;
The molar ratio of the cyclic histidine dipeptide with the structure shown in the formula IX to the alkaline substance is 1 (2-8);
the solvent for the reaction comprises one or more of acetone, N-dimethylformamide and acetonitrile;
the reaction temperature is 60-100 ℃, and the reaction time is 24-72 hours.
10. Use of the quaternary ammonium compound containing a cyclic dipeptide structure according to any one of claims 1 to 4 or the quaternary ammonium compound containing a cyclic dipeptide structure according to any one of claims 5 to 9 as an antibacterial material.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108929247A (en) * | 2018-06-08 | 2018-12-04 | 中南大学 | A kind of NαAlkyl acyl arginine ester antibacterial agent and its preparation and application |
| CN114014908A (en) * | 2021-11-05 | 2022-02-08 | 中国科学院过程工程研究所 | Cyclic peptide glass and pharmaceutical composition glass containing cyclic peptide |
| CN115286692A (en) * | 2022-06-30 | 2022-11-04 | 四川大学 | Antibacterial peptide mimetic structure modified by quaternary ammonium salt, preparation method and application thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108929247A (en) * | 2018-06-08 | 2018-12-04 | 中南大学 | A kind of NαAlkyl acyl arginine ester antibacterial agent and its preparation and application |
| CN114014908A (en) * | 2021-11-05 | 2022-02-08 | 中国科学院过程工程研究所 | Cyclic peptide glass and pharmaceutical composition glass containing cyclic peptide |
| CN115286692A (en) * | 2022-06-30 | 2022-11-04 | 四川大学 | Antibacterial peptide mimetic structure modified by quaternary ammonium salt, preparation method and application thereof |
Non-Patent Citations (2)
| Title |
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| JING SUN ET AL.: "High Antibacterial Activity and Selectivity of the Versatile Polysulfoniums that Combat Drug Resistance", 《ADV. MATER.》, 31 December 2021 (2021-12-31), pages 1 - 11 * |
| 万朋奇: "抗菌聚氨基酸的合成及其构效关系的研究", 《中国博士学位论文全文数据库 工程科技I辑》, 15 February 2023 (2023-02-15), pages 0 * |
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