CN111517971A - Antifungal compound, synthesis method and application thereof - Google Patents

Antifungal compound, synthesis method and application thereof Download PDF

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CN111517971A
CN111517971A CN202010405895.2A CN202010405895A CN111517971A CN 111517971 A CN111517971 A CN 111517971A CN 202010405895 A CN202010405895 A CN 202010405895A CN 111517971 A CN111517971 A CN 111517971A
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antifungal
amino acid
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antifungal compound
leucine
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裴泽军
孙欣
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Wuxi No 2 Peoples Hospital
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Abstract

The invention belongs to the technical field of drug synthesis, and relates to an antifungal compound, in particular to an antifungal compound, a synthesis method and an application thereof, wherein the antifungal compound is amino acid carbon ester or pharmaceutically acceptable salt thereof, and the amino acid carbon ester has the following structural formula:
Figure DDA0002491259960000011
wherein R is1Is one of C5-C17 alkyl or C5-C17 alkenyl; the R is2Is an amino acid side chain group; also provides a synthetic method of the antifungal compound and application in the antifungal field.

Description

Antifungal compound, synthesis method and application thereof
Technical Field
The invention belongs to the technical field of drug synthesis, and relates to an antifungal compound, in particular to an antifungal compound, a synthesis method and application thereof.
Background
Fungal infections are one of the major infectious diseases in the clinic, which are classified into superficial mycoses and invasive mycoses. The incidence and the fatality rate of invasive mycosis both rise year by year in recent decades. Especially in some special patient populations, such as: the incidence rate of organ transplantation patients, ICU severe patients, patients with hypoimmunity such as hematopathy and the like is up to about 29 percent, and the fatality rate is higher up to 49 percent.
At present, the types of drugs which can be clinically selected for treating fungal infection are not many, and mainly comprise polyenes, pyrroles, echinocandins, 5-fluorocytosine (5-FC) and the like. Polyenes are the first antifungal drugs used in clinical applications, mainly amphotericin B and the like, and inhibit fungal growth by acting on the specific sterol binding on fungal cell membranes to impair the permeability of fungal cell membranes. The medicine has the advantages of wide antifungal spectrum, strong activity and great toxicity, such as hepatotoxicity, nephrotoxicity, transfusion related toxicity, etc. The pyrrole comprises imidazole and triazole, and the ergosterol acting on the fungal cell membrane influences the stability of the cell membrane to break the fungal cell and kill the fungal cell. Imidazoles mainly represent ketoconazole, clotrimazole, miconazole and the like, and are suitable for treating superficial fungal infections. Triazoles mainly represent drugs such as fluconazole, voriconazole, itraconazole and the like, and can be used for treating deep fungal infection. The medicine has certain influence on liver and kidney functions and has other adverse reactions. The action mechanism of the 5-fluorocytosine is to interfere nucleic acid and protein synthesis of fungal cells, so that fungal drug resistance is easy to appear, and the 5-fluorocytosine is not used independently. Echinocandins are relatively new powerful antifungal agents, dissolve and die fungi by destroying the cell walls of the fungi through a non-competitive inhibitor 1, 3-beta-D-glucan synthetase, and have high-efficiency and low-toxicity clinical effects. Representative drugs are caspofungin, micafungin, etc.
The development of antifungal drugs has been progressing slowly in recent decades, and after newer echinocandin caspofungin was discovered in 1970 and started to be applied clinically in 2000, no new antifungal drug has been developed and successfully applied in recent 20 years. Due to the shortage of selectable types and quantity of clinical antifungal medicines, the drug resistance of fungi is more serious, and even the phenomenon that the existing 'super fungi' has drug resistance to the last line-defense medicines of the antifungal medicines such as caspofungin, micafungin and the like is repeated for many times, so that the life health and safety of patients are seriously threatened. Therefore, as soon as possible, more and better novel antifungal drugs are searched, and effective overcoming of the problem of fungal drug resistance is an important task urgently needed to be solved by current technologists.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides an antifungal compound which has good antifungal effect and can be used for preparing antifungal agents.
In order to achieve the technical purpose, the technical scheme of the invention is as follows:
an antifungal compound which is an amino acid carbon ester or a pharmaceutically acceptable salt thereof.
The amino acid carbon ester has the following structural formula:
Figure BDA0002491259940000021
wherein R is1Is one of C5-C17 alkyl or C5-C17 alkenyl; the R is2Is an amino acid side chain group.
Further, said R1Is one of straight chain alkyl with total carbon number of C5-C17 or alkyl with side chain with total carbon number of C5-C17.
Further, said R1Is one of a linear alkylene group having a total carbon number of C5-C17 or a branched alkylene group having a total carbon number of C5-C17.
The preparation method of the antifungal compound, namely the preparation method of the amino acid carbon ester, takes amino acid and carbon alcohol as raw materials, and the antifungal compound is obtained by reflux reaction, and comprises the following specific steps:
step 1, dissolving amino acid in toluene to form amino acid toluene liquid, wherein the concentration of the amino acid in the toluene is 0.5 mol/L;
and 2, adding carbon alcohol and p-toluenesulfonic acid into the amino acid toluene liquid for reflux reaction, performing water azeotropic separation to obtain amino acid carbon ester, wherein the addition amount of the carbon alcohol is consistent with the molar amount of the amino acid, the addition amount of the p-toluenesulfonic acid is consistent with the molar amount of the amino acid, and the reflux reaction is carried out to raise the temperature to the reflux temperature in a slow temperature raising manner.
The step 2 adopts thin layer chromatography for reaction monitoring.
Further, the purification steps of the amino acid carbon ester are as follows:
step a, concentrating a reaction mixture subjected to water azeotropic separation in vacuum, and filtering to obtain a residue;
step b, extracting residues by using ethyl acetate, washing by using a sodium carbonate aqueous solution and saline water in sequence, drying an organic layer by using sodium sulfate, and concentrating in vacuum to obtain a crude product, wherein the mass concentration of sodium carbonate in the sodium carbonate aqueous solution is 5%;
step c, the crude product was chromatographed on silica gel with MeOH in silica gel: DCM ═ 1:50 to 1:5 to give the product.
Use of an antifungal compound, i.e., a carbon ester of an amino acid or a pharmaceutically acceptable salt thereof, as an antifungal agent.
An application of antifungal compound in preparing antifungal medicine, i.e. the application of carbon amino acid ester or its pharmaceutically acceptable salt in preparing antifungal medicine.
An antifungal composition comprises an active ingredient which is an antifungal compound and one or more pharmaceutically acceptable auxiliary materials, and specifically comprises amino acid carbon ester or pharmaceutically acceptable salt thereof which is used as an active ingredient and is matched with one or more pharmaceutically acceptable auxiliary materials.
From the above description, it can be seen that the present invention has the following advantages:
1. the antifungal compound has good antifungal effect and can be used for preparing antifungal agents.
2. The invention adopts a slow temperature rise mode to be matched with the reflux reaction, effectively controls the reaction, has good reaction efficiency and reaction stability and effectively reduces side reaction.
3. The invention utilizes the thin-layer chromatography to track the reaction progress, can effectively control the reaction and effectively ensure the high efficiency of the reaction.
Drawings
FIG. 1 is an IR spectrum of lauryl leucine according to example 1 of the present invention;
FIG. 2 is a mass spectrum of lauryl leucine according to example 1 of the present invention;
FIG. 3 is a nuclear magnetic spectrum of lauryl leucine according to example 1 of the present invention;
FIG. 4 is a nuclear magnetic spectrum of octadecyl leucine in example 2 of the present invention;
FIG. 5 is a nuclear magnetic spectrum of octadecyl leucine in example 3 of the present invention.
Detailed Description
An embodiment of the present invention is described in detail with reference to fig. 1 to 3, but the present invention is not limited in any way by the claims.
Leucine:
example 1
An antifungal compound which is lauryl leucine having the formula:
Figure BDA0002491259940000041
the preparation method of the leucine dodecyl ester comprises the following steps:
dodecanol (16.8g, 0.1mol) and p-toluenesulfonic acid (20.9g, 0.1mol) were added to a solution of DL-leucine (13.1g, 0.1mol) in toluene (200mL), slowly warmed to reflux temperature, water azeotropically separated, and the reaction monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo, and the resulting residue was extracted with ethyl acetate (200ml), which was washed with 5% Na2CO3Washed with aqueous solution (3 × 50ml) and then with brine solution in Na2SO4The organic layer was dried and concentrated in vacuo to give the crude product, which was chromatographed on silica gel (MeOH: DCM ═ 1:50) to give yellow, oily leucine dodecyl ester (10g, 33%).
Fig. 1 is an infrared spectrum of leucine dodecyl ester, fig. 2 is a mass spectrum of leucine dodecyl ester, fig. 3 is a nuclear magnetic spectrum of leucine dodecyl ester, and the product is leucine dodecyl ester as can be verified by fig. 1 to fig. 3.
1. Antifungal drug sensitivity detection test
The lauryl leucine ester of this example was tested for antifungal activity in a semi-dilution assay, using caspofungin as a control, which is a commercially available drug.
The detection concentrations were as follows:
name of drug Assay concentration (μ g/mL)
This example 100,50,25,12.5,6.25,3.125,1.56,0.78,0.39,0.195
Caspofungin 100,50,25,12.5,6.25,3.125,1.56,0.78,0.39,0.195
The experimental strains adopt aspergillus fumigatus, spore silk, cryptococcus and rhizopus; positive control bacteria: nearly smooth, krusen.
Figure BDA0002491259940000042
Figure BDA0002491259940000051
Wherein:
product of this example (MIC) minimum drug concentration that inhibits fungal growth rate by 100% compared to the positive control wells.
Caspofungin (MIC/MEC), the lowest drug concentration that inhibits bacterial growth by 50% compared to the positive control wells. The growth of the filamentous bacteria is restricted compared to the positive control wells and the lowest drug concentration for colony shrinkage is the lowest effective concentration (MEC).
The data clearly show that the antifungal effect of the leucine dodecyl ester on certain fungi is obviously better than that of caspofungin, so that the leucine dodecyl ester has a good antibacterial effect on the antifungal aspect.
In the embodiment, the leucine dodecyl ester formed by the amino acid and the dodecanol has amphiprotic lipid generated by combining amide bonds, the structure is a main constituent component of a cell membrane and is also an important constituent of a signal molecule, and the leucine dodecyl ester participates in various cell processes and plays important roles, such as endocytosis, cell signal transduction, cell heat stress reaction, apoptosis and the like, plays an important role in the pathogenesis of fungal cells and has a good antifungal effect.
Example 2
An antifungal compound which is octadecyl leucine, and the preparation method of the octadecyl leucine comprises the following steps:
octadecanol (0.1mol) and p-toluenesulfonic acid (0.1mol) were added to a solution of leucine (0.1mol) in toluene (200mL), the temperature was slowly raised to reflux temperature, water azeotroped, and the reaction was monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo, and the resulting residue was extracted with ethyl acetate (200ml), which was washed with 5% Na2CO3Washed with aqueous solution (3 × 50ml) and then with brine solution in Na2SO4The organic layer was dried and concentrated in vacuo to give the crude product, which was chromatographed on silica gel (MeOH: DCM ═ 1:5) to afford octadecyl leucine (39%).
FIG. 4 is a nuclear magnetic spectrum of octadecyl leucine, which can be analyzed simply by FIG. 4, and the product is octadecyl leucine.
Antifungal experiments with octadecyl leucine were carried out using the same experiment as the antifungal test in example 1, and the results show that: octadecyl leucine has good effect in resisting fungi and resisting drugs.
Figure BDA0002491259940000061
Example 3
An antifungal compound which is a hexa-alkyl leucine ester prepared by the following method:
hexanol (0.1mol) and p-toluenesulfonic acid (0.1mol) were added to a solution of leucine (0.1mol) in toluene (200mL), slowly warmed to reflux temperature, water azeotropically separated, and the reaction monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo, and the resulting residue was extracted with ethyl acetate (200ml), which was washed with 5% Na2CO3Washed with aqueous solution (3 × 50ml) and then with brine solution in Na2SO4The organic layer was dried and concentrated in vacuo to give the crude product, which was chromatographed on silica gel (MeOH: DCM ═ 1:20) to give the leucine hexaalkyl ester (36%).
FIG. 5 is a nuclear magnetic spectrum of leucine hexaalkyl ester, which can be analyzed simply by FIG. 5, and the product is leucine hexaalkyl ester.
Antifungal tests with hexa-alkyl leucine using the same tests as the antifungal tests in example 1 showed that: the leucine hexaalkyl ester has good antifungal effect.
Figure BDA0002491259940000062
Example 4
An antifungal compound which is isomeric octadecyl leucine ester, and the preparation method of the isomeric octadecyl leucine ester comprises the following steps:
isomeric octadecanol (0.1mol) and p-toluenesulfonic acid (0.1mol) were added to a solution of leucine (0.1mol) in toluene (200mL), slowly warmed to reflux temperature, water azeotroped, and the reaction was monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo, and the resulting residue was extracted with ethyl acetate (200ml), which was washed with 5% Na2CO3Washed with aqueous solution (3 × 50ml) and then with brine solution in Na2SO4The organic layer is dried on the substrate,concentration in vacuo afforded the crude product, which was chromatographed on silica gel (MeOH: DCM ═ 1:10) to afford the isomeric octadecylleucine esters (36%).
Antifungal experiments with isomeric octadecylleucine esters were performed using the same experiment as the antifungal assay in example 1 and the results show that: the isomeric octadecyl leucine ester has good effects in the aspects of antifungal and drug resistance.
Example 5
An antifungal compound, wherein the antifungal compound is 3-methylpentyl leucine ester, and the preparation method of the 3-methylpentyl leucine ester is as follows:
3-methyl-1-pentanol (0.1mol) and p-toluenesulfonic acid (0.1mol) were added to a solution of leucine (0.1mol) in toluene (200mL), slowly warmed to reflux temperature, water azeotropically separated, and the reaction was monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo, and the resulting residue was extracted with ethyl acetate (200ml), which was washed with 5% Na2CO3Washed with aqueous solution (3 × 50ml) and then with brine solution in Na2SO4The organic layer was dried and concentrated in vacuo to give the crude product, which was chromatographed on silica gel (MeOH: DCM ═ 1:10) to give 3-methylpentanyl leucine ester (37%).
An antifungal experiment with 3-methylpentyl leucine ester was carried out using the same experiment as for the antifungal detection in example 1, and the results show that: the 3-methyl amyl leucine ester has good antifungal effect.
Example 6
An antifungal compound, wherein the antifungal compound is 3-methyl-4-n-decyl leucine ester, and the preparation method of the 3-methyl amyl leucine ester comprises the following steps:
3-methyl-4-n-decanol (0.1mol) and p-toluenesulfonic acid (0.1mol) were added to a solution of leucine (0.1mol) in toluene (200mL), slowly warmed to reflux temperature, water azeotropically separated, and the reaction monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo, and the resulting residue was extracted with ethyl acetate (200ml), which was washed with 5% Na2CO3Washed with aqueous solution (3 × 50ml) and then with brine solution in Na2SO4The organic layer was dried and concentrated in vacuo to give the crude product, which was chromatographed on silica gel (MeOH: DCM ═ 1:10) to give 3-methyl-4-n-decylalaninate (37%).
An antifungal experiment of 3-methyl-4-n-decylnedraminic acid ester was carried out using the same experiment as the antifungal detection in example 1, and the results show that: the 3-methyl-4-n-decyl leucine ester has good antifungal effect.
Example 7
An antifungal compound, wherein the antifungal compound is 9-octadecene-1-leucine ester, and the preparation method of the 9-octadecene-1-amino acid ester comprises the following steps:
9-octadecen-1-ol (0.1mol) and p-toluenesulfonic acid (0.1mol) were added to a solution of leucine (0.1mol) in toluene (200mL), slowly warmed to reflux temperature, water azeotroped and the reaction monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo, and the resulting residue was extracted with ethyl acetate (200ml), which was washed with 5% Na2CO3Washed with aqueous solution (3 × 50ml) and then with brine solution in Na2SO4The organic layer was dried and concentrated in vacuo to give the crude product, which was chromatographed on silica gel (MeOH: DCM ═ 1:5) to give 9-octadecen-1-leucine ester (35%).
An antifungal experiment of 9-octadecen-1-leucinate was carried out using the same experiment as the antifungal test in example 1, and the results showed that: 9-octadecen-1-leucine has good antifungal effect.
Example 8
An antifungal compound, wherein the antifungal compound is 3-hexene-1-leucine ester, and the preparation method of the 3-hexene-1-leucine ester comprises the following steps:
3-Hexen-1-ol (0.1mol) and p-toluenesulfonic acid (0.1mol) were added to a solution of leucine (0.1mol) in toluene (200mL), slowly warmed to reflux temperature, water azeotroped and the reaction monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo, and the resulting residue was extracted with ethyl acetate (200ml), which was washed with 5% Na2CO3Washed with aqueous solution (3 × 50ml) and then with brine solution in Na2SO4The organic layer was dried and concentrated in vacuo to give the crude product, which was chromatographed on silica gel (MeOH: DCM ═ 1:10) to give 3-hexene-1-leucine ester (38%).
An antifungal experiment of 3-hexene-1-leucine ester was carried out using the same experiment as the antifungal test in example 1, and the results show that: the 3-hexene-1-leucine ester has good effect on resisting fungi.
Example 9
An antifungal compound, wherein the antifungal compound is 11-hexadecene-1-leucine ester, and the preparation method of the 11-hexadecene-1-leucine ester comprises the following steps:
11-Hexadecenol (0.1mol) and p-toluenesulfonic acid (0.1mol) were added to a solution of leucine (0.1mol) in toluene (200mL), slowly warmed to reflux temperature, water azeotroped, and the reaction was monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo, and the resulting residue was extracted with ethyl acetate (200ml), which was washed with 5% Na2CO3Washed with aqueous solution (3 × 50ml) and then with brine solution in Na2SO4The organic layer was dried and concentrated in vacuo to give the crude product, which was chromatographed on silica gel (MeOH: DCM ═ 1:40) to give 11-hexadecene-1-leucine ester (34%).
An antifungal experiment of 11-hexadecene-1-leucine ester was carried out using the same experiment as the antifungal detection in example 1, and the results show that: the 11-hexadecene-1-leucine ester has good antifungal effect.
Example 10
An antifungal compound which is 6-methyl-3-heptene-2-leucine ester, wherein the preparation method of the 6-methyl-3-heptene-2-leucine ester comprises the following steps:
6-methyl-3-hepten-2-ol (0.1mol) and p-toluenesulfonic acid (0.1mol) were added to a solution of glutamic acid (0.1mol) in toluene (200mL), slowly warmed to reflux temperature, water azeotropically separated, and the reaction was monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo, and the resulting residue was extracted with ethyl acetate (200ml), which was washed with 5% Na2CO3Washed with aqueous solution (3 × 50ml) and then with brine solution in Na2SO4The organic layer was dried and concentrated in vacuo to give the crude product, which was chromatographed on silica gel (MeOH: DCM ═ 1:10) to give 6-methyl-3-heptene-2-leucine ester (37%).
An antifungal experiment of 6-methyl-3-heptene-2-leucine ester was carried out using the same experiment as the antifungal detection in example 1, and the results showed that: the 6-methyl-3-heptylene-2-leucine ester has good antifungal effect.
Other amino acids:
example 11
An antifungal compound which is dodecyl valine, prepared by the following steps:
dodecanol (0.1mol) and p-toluenesulfonic acid (0.1mol) were added to a solution of valine (0.1mol) in toluene (200mL), slowly warmed to reflux temperature, water azeotroped, and the reaction was monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo, and the resulting residue was extracted with ethyl acetate (200ml), which was washed with 5% Na2CO3Washed with aqueous solution (3 × 50ml) and then with brine solution in Na2SO4The organic layer was dried and concentrated in vacuo to give the crude product, which was chromatographed on silica gel (MeOH: DCM ═ 1:5) to afford valine dodecyl ester (38%).
The antifungal test with dodecyl valine was carried out using the same test as the antifungal test in example 1, and the results show that: the valine dodecyl ester has good antifungal effect.
Figure BDA0002491259940000101
Example 12
An antifungal compound, wherein the antifungal compound is 6-heptene-3-glutamate, and the preparation method of the 6-heptene-3-glutamate comprises the following steps:
6-hepten-3-ol (0.1mol) and p-toluenesulfonic acid (0.1mol) were added to a solution of glutamic acid (0.1mol) in toluene (200mL), slowly warmed to reflux temperature, water azeotropically separated, and the reaction monitored by thin layer chromatography. The reaction mixture isConcentrated in vacuo, the residue was extracted with ethyl acetate (200ml), and extracted with 5% Na2CO3Washed with aqueous solution (3 × 50ml) and then with brine solution in Na2SO4The organic layer was dried and concentrated in vacuo to give the crude product, which was chromatographed on silica gel (MeOH: DCM ═ 1:10) to give 6-heptene-3-glutamate (38%).
An antifungal experiment of 6-heptene-3-glutamate was carried out using the same experiment as the antifungal detection in example 1, and the results show that: 6-heptene-3-glutamate has good antifungal effect.
Example 13
An antifungal compound which is a pentyl threonine ester prepared by the following method:
n-pentanol (0.1mol) and p-toluenesulfonic acid (0.1mol) were added to a toluene (200mL) solution of threonine (0.1mol), slowly warmed to reflux temperature, water azeotropically separated, and the reaction was monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo, and the resulting residue was extracted with ethyl acetate (200ml), which was washed with 5% Na2CO3Washed with aqueous solution (3 × 50ml) and then with brine solution in Na2SO4The organic layer was dried and concentrated in vacuo to give the crude product, which was chromatographed on silica gel (MeOH: DCM ═ 1:10) to give the pentanyl threonine ester (37%).
The antifungal test of the pentyl threonine esters was carried out using the same test as the antifungal test in example 1, and the results show that: the amyl threonine esters all have good antifungal effects.
Example 14
An antifungal compound, wherein the antifungal compound is 3-hexadecylserine, and the preparation method of the 3-hexadecylserine comprises the following steps:
3-Hexadecanol (0.1mol) and p-toluenesulfonic acid (0.1mol) were added to a solution of serine (0.1mol) in toluene (200mL), slowly warmed to reflux temperature, water azeotroped and the reaction monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo, and the resulting residue was extracted with ethyl acetate (200ml), which was washed with 5% Na2CO3Washed with aqueous solution (3 × 50ml) and then with brine solution in Na2SO4The organic layer was dried and concentrated in vacuo to give the crude product, which was chromatographed on silica gel (MeOH: DCM ═ 1:40) to give 3-hexadecylserine (38%).
The antifungal experiment with 3-hexadecylserine was carried out using the same experiment as the antifungal test in example 1, and the results show that: 3-hexadecylserine has good antifungal effect.
Example 15
An antifungal compound, wherein the antifungal compound is 4-pentene-1-arginine ester, and the preparation method of the 4-pentene-1-arginine ester is as follows:
4-penten-1-ol (0.1mol) and p-toluenesulfonic acid (0.1mol) were added to a solution of arginine (0.1mol) in toluene (200mL), slowly warmed to reflux temperature, water azeotroped and the reaction monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo, and the resulting residue was extracted with ethyl acetate (200ml), which was washed with 5% Na2CO3Washed with aqueous solution (3 × 50ml) and then with brine solution in Na2SO4The organic layer was dried and concentrated in vacuo to give the crude product, which was chromatographed on silica gel (MeOH: DCM ═ 1:40) to give 4-penten-1-arginate (34%).
The antifungal test of 4-penten-1-arginine ester was carried out using the same test as the antifungal test in example 1, and the results showed that: 4-penten-1-arginine ester has good antifungal effect.
Example 16
An antifungal compound which is 2, 6-dimethylheptene-5-serine ester, wherein the preparation method of the 2, 6-dimethylheptene-5-serine ester comprises the following steps:
2, 6-dimethyl-5-heptenol (0.1mol) and p-toluenesulfonic acid (0.1mol) were added to a solution of threonine (0.1mol) in toluene (200mL), slowly warmed to reflux temperature, water azeotropically separated, and the reaction monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo, and the resulting residue was extracted with ethyl acetate (200ml), which was washed with 5% Na2CO3Washed with aqueous solution (3 × 50ml) and then with brine solution in Na2SO4The organic layer was dried and concentrated in vacuo to give the crude product, which was chromatographed on silica gel (MeOH: DCM ═ 1:15) to give 2, 6-dimethylheptene-5-serine ester (39%).
An antifungal experiment of 2, 6-dimethylheptene-5-serine ester was carried out using the same experiment as the antifungal detection in example 1, and the results show that: the 2, 6-dimethylheptene-5-serine ester has good antifungal effect.
Example 17
An antifungal compound which is undecenyl alanine ester, and the preparation method of the undecenyl alanine ester is as follows:
undecylenol (0.1mol) and p-toluenesulfonic acid (0.1mol) were added to a solution of alanine (0.1mol) in toluene (200mL), slowly warmed to reflux temperature, water azeotropically separated, and the reaction was monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo, and the resulting residue was extracted with ethyl acetate (200ml), which was washed with 5% Na2CO3Washed with aqueous solution (3 × 50ml) and then with brine solution in Na2SO4The organic layer was dried and concentrated in vacuo to give the crude product, which was chromatographed on silica gel (MeOH: DCM ═ 1:10) to give undecenylalanine ester (37%).
Antifungal experiments with undecenylalanine esters were carried out using the same experiments as for the antifungal detection in example 1 and the results show that: the undecylenyl alanine ester has good antifungal effect.
It should be understood that the detailed description of the invention is merely illustrative of the invention and is not intended to limit the invention to the specific embodiments described. It will be appreciated by those skilled in the art that the present invention may be modified or substituted equally as well to achieve the same technical result; as long as the use requirements are met, the method is within the protection scope of the invention.

Claims (7)

1. An antifungal compound characterized by: the antifungal compound is an amino acid carbon ester or a pharmaceutically acceptable salt thereof.
2. The antifungal compound of claim 1, wherein: the amino acid carbon ester has the following structural formula:
Figure FDA0002491259930000011
wherein R is1Is one of C5-C17 alkyl or C5-C17 alkenyl; the R is2Is an amino acid side chain group.
3. A process for the preparation of an antifungal compound, characterized in that: taking amino acid and carbon alcohol as raw materials, and carrying out reflux reaction to obtain amino acid carbon ester; the preparation method comprises the following specific steps:
step 1, dissolving amino acid in toluene to form amino acid toluene liquid, wherein the concentration of the amino acid in the toluene is 0.5 mol/L;
step 2, adding carbon alcohol and p-toluenesulfonic acid into amino acid toluene liquid for reflux reaction, and performing water azeotropic separation to obtain amino acid carbon ester, wherein the addition amount of the carbon alcohol is consistent with the molar amount of the amino acid, the addition amount of the p-toluenesulfonic acid is consistent with the molar amount of the amino acid, and the reflux reaction is performed by raising the temperature to the reflux temperature in a slow temperature raising manner; the reaction was monitored by thin layer chromatography.
4. A process for the preparation of antifungal compounds as claimed in claim 3, characterized in that: the purification steps of the amino acid carbon ester are as follows:
step a, concentrating a reaction mixture subjected to water azeotropic separation in vacuum, and filtering to obtain a residue;
step b, extracting residues by using ethyl acetate, washing by using a sodium carbonate aqueous solution and saline water in sequence, drying an organic layer by using sodium sulfate, and concentrating in vacuum to obtain a crude product, wherein the mass concentration of sodium carbonate in the sodium carbonate aqueous solution is 5%;
step c, the crude product was chromatographed on silica gel with MeOH in silica gel: DCM ═ 1:50 to 1:5 to give the product.
5. Use of an antifungal compound according to any one of claims 2 to 4 as an antifungal agent, i.e. as an antifungal agent, an amino acid carbon ester or a pharmaceutically acceptable salt thereof.
6. Use of an antifungal compound according to any one of claims 2 to 4 in the preparation of an antifungal medicament, i.e., the use of a carbon ester of an amino acid or a pharmaceutically acceptable salt thereof in the preparation of an antifungal medicament.
7. Use of an antifungal compound according to any one of claims 2 to 4, an antifungal composition comprising as active ingredient an antifungal compound together with one or more pharmaceutically acceptable excipients.
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