Patent Description:
The present invention relates to a technical field of biomedicine, and more particularly to an efficient anti-bacterial hydroxy acid ester oligomer.

Anti-bacterial agents refer to substances which keep the growth or reproduction of certain microorganisms (bacteria, fungi, yeasts, algae, viruses, etc.) below a certain level within a certain period of time. Anti-bacterial agents are widely used in textiles, plastics, detergents, medical supplies and other fields.

With the continuous improvement of living standards, the hygienic requirements for textiles and various household plastics are also getting higher and higher. The continuous improvement of natural and environmental protection standards for anti-bacterial products is of great practical importance for developing the health care level of a country and reducing cross-infection in the public environment. Therefore, it is imperative to do research on natural, safe and efficient anti-bacterial agents for bio-based materials.

Chinese patent <CIT> disclosed a poly-<NUM>-hydroxybutyrate oligomer, which is used to prepare anti-bacterial materials. The minimum inhibitory concentration (MIC, unit mg/mL) is as follows:.

The anti-bacterial activity of the above-mentioned oligomers is not high enough to meet the growing performance requirements for anti-bacterial products; and water solubility of the above-mentioned oligomers is not adjustable, resulting in a narrow application range. In addition, the raw materials used in the synthesis process are expensive and are not biological-based material butyrolactone. Toxic catalysts and solvents are also used, resulting in complicated post-treatment processes.

Because bacteria have a highly organized cell membrane structure, they can effectively resist the combination and penetration of foreign invading molecules. Therefore, rational design of the anti-bacterial agents that effectively penetrate and destroy bacterial cell membranes is of great significance. The present invention is based on long-term research, which shows that the use of the synergistic effect of the end groups and chain lengths of hydroxy acid ester oligomers can effectively improve the efficiency of the anti-bacterial agent during penetrating and destroying bacterial cell membranes, thereby achieving high anti-bacterial efficiency, and further achieving controllable water solubility of the anti-bacterial agent.

Based on development demand for natural and eco-friendly anti-bacterial agents, an object of the present invention is to provide an use of anti-bacterial compound in preparation of an anti-bacterial agent.

The compound has a pH value of nearly neutral, and has a general structural formula (I):
<CHM>.

Preferably, the efficient anti-bacterial hydroxy acid ester oligomer has a general structural formula (II) or (III):
<CHM>
<CHM>
<CHM>.

Preferably, in the general structural formula (I), when n=<NUM>-<NUM>, R<NUM> is the C<NUM>-C<NUM> alkyl group, R<NUM> is a C<NUM>-C<NUM> alkyl group, and m=<NUM>-<NUM>, the R-(-)-hydroxy acid ester oligomer is a water-soluble substance. In the general structural formula (I), when n=<NUM>-<NUM>, R<NUM> is the C<NUM>-C<NUM> alkyl group, R<NUM> is a C<NUM>-C<NUM> alkyl group, and m=<NUM>-<NUM>, the R-(-)-hydroxy acid ester oligomer is a water-insoluble substance which is soluble in a variety of organic solvents (such as ethanol, n-butanol, dimethyl sulfoxide, acetone, ether). In the general structural formula (I), when n=<NUM>-<NUM>, R<NUM> is the C<NUM>-C<NUM> alkyl group, R<NUM> is the C<NUM>-C<NUM> alkyl group, and m=<NUM>-<NUM>, the R-(-)-hydroxy acid ester oligomer is a water-insoluble substance which is soluble in a variety of organic solvents (such as ethanol, n-butanol, dimethyl sulfoxide, acetone, ether).

Preferably, the water-soluble substance R-(-)-hydroxy acid ester oligomer has a general structural formula (IV):
<CHM>
wherein n=<NUM>-<NUM>.

Preferably, the water-insoluble substance R-(-)-hydroxy acid ester oligomer having a general structural formula (V):
<CHM>
wherein n=<NUM>-<NUM>.

Beneficial effects of the present invention are as follows.

The technical solutions and effects of the present invention will be further described below in conjunction with the embodiments. Any changes that can be easily obtained by those skilled in the art based on the material combinations and methods shown in these embodiments belong to the protection scope of the present invention.

Adding <NUM> of <NUM>-hydroxybutyrate ethyl ester and <NUM> of zinc acetate (i.e. a mass ratio of <NUM>-hydroxybutyrate ethyl ester is <NUM>%) in a three-necked flask with mechanical stirring, a thermometer and a distillation device, wherein a stirring speed is approximately <NUM> revolutions; under an environment with a trace of nitrogen, increasing a temperature to <NUM> with a speed of <NUM>-<NUM>/min to react for <NUM> hour, then stopping reaction to obtain a <NUM>-HB oligomer; detecting a degree of polymerization by a mass spectrometry, wherein an anti-bacterial experiment refers to GB/T <NUM>-<NUM> Textiles-Evaluation for anti-bacterial activity-Part <NUM>: Shake flask method, a strain used is Escherichia coli ATCC <NUM>.

According to Table <NUM>, catalyst types and reaction temperatures are changed on the basis of the embodiment <NUM>-<NUM>, while other conditions are the same as those of the embodiment <NUM>-<NUM> to obtain the R-(-)-<NUM>-hydroxybutyrate ethyl ester oligomers with different polymerization degrees.

<FIG> is a mass spectrometry result of a water-soluble R-(-)-<NUM>-hydroxybutyrate ethyl ester oligomer according to embodiment <NUM>-<NUM>.

<FIG> is a mass spectrometry result of a water-insoluble R-(-)-<NUM>-hydroxybutyrate ethyl ester oligomer embodiment <NUM>-<NUM>.

Adding 1mol R-(-)-<NUM>-hydroxybutyric acid, 10mol methanol, <NUM> catalyst p-toluenesulfonic acid (a mass ratio of R-(-)-<NUM>-hydroxybutyric acid is <NUM>%, and a water-carrying agent n-hexane with an amount of <NUM>% of the alcohol volume in a three-necked flask; stirring and slowly increasing a temperature to <NUM>, then keeping the temperature and reacting for <NUM>; cooling to a room temperature after reaction is stopped; removing the remaining alcohol and n-hexane by vacuum distillation at <NUM> and 5000Pa; increasing the temperature to <NUM>, and collecting fraction under reduced pressure of <1000Pa, wherein the fraction is <NUM>-hydroxybutyrate methyl ester, and a yield is <NUM>%.

On the basis of the embodiments <NUM>-<NUM>, the embodiments <NUM>-<NUM> to <NUM>-<NUM> change methanol into ethanol, <NUM>-propanol, <NUM>-butanol, <NUM>-pentanol, <NUM>-hexanol, <NUM>-heptanol and <NUM>-octanol respectively, while other conditions are the same as those of the embodiment <NUM>-<NUM>, so as to obtain R-(-)-<NUM>-hydroxybutyrate ethyl ester (yield <NUM>%), R-(- )-<NUM>-hydroxybutyrate propyl ester (yield <NUM>%), R-(-)-<NUM>-hydroxybutyrate butyl ester (yield <NUM>%), R-(-)-<NUM>-hydroxybutyrate pentyl ester (yield <NUM>%), R-(-)-<NUM>-hydroxybutyrate hexyl ester (yield <NUM>%), R-(-)-<NUM>-hydroxybutyrate heptyl ester (yield <NUM>%), and R-(-)-<NUM>-hydroxybutyrate octyl ester (yield <NUM>%), wherein gas phase detection purity is about <NUM>%.

<FIG> is a nuclear magnetic spectrum of R-(-)-<NUM>-hydroxybutyrate hexyl ester.

The R-(-)-<NUM>-hydroxybutyrate ethyl ester oligomer and R-(-)-<NUM>-hydroxybutyrate hexyl ester oligomer prepared in the embodiments <NUM>-<NUM> and <NUM>-<NUM> are tested by Guangdong Detection Center of Microbiology by referring to: <NPL>, results are shown in Table <NUM>. The compounds that have a clogP value within <NUM>-<NUM> fall under the scope of the claims.

On the basis of the embodiment <NUM>-<NUM>, R-(-)-<NUM>-hydroxybutyric acid is changed to R-(-)-<NUM>-hydroxypropionic acid, and methanol is changed to <NUM>-hexanol. Other experimental conditions are the same as those of the embodiment <NUM>-<NUM> to obtain R-(-)-<NUM>-hydroxypropionic hexyl ester.

<FIG> is a nuclear magnetic spectrum of R-(-)-<NUM>-hydroxypropionic hexyl ester.

R-(-)-<NUM>-hydroxybutyric methyl ester NMR experimental data and spectra are assigned as follows: <NUM>H NMR (CDCl<NUM>): <NUM> (m, H), <NUM> (s, <NUM>), <NUM> (q, <NUM>), <NUM> (D, <NUM>).

R-(-)-<NUM>-hydroxybutyrate ethyl ester NMR experimental data and spectra are assigned as follows: <NUM>H NMR (CDCl<NUM>): <NUM> (m, H), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (M, <NUM>).

R-(-)-<NUM>-hydroxybutyrate propyl ester NMR experimental data and spectra are assigned as follows: <NUM>H NMR (<NUM>, Chloroform-d) δ <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, <NUM>), <NUM> (t, <NUM>).

R-(-)-<NUM>-hydroxybutyrate butyl ester NMR experimental data and spectra are assigned as follows: <NUM>H NMR (<NUM>, Chloroform-d) δ <NUM>-<NUM> (m, <NUM>), <NUM> (ddt, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (tdd, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>).

R-(-)-<NUM>-hydroxybutyrate pentyl ester NMR experimental data and spectra are assigned as follows: <NUM>H NMR (CDCl<NUM>): <NUM> (m, H), <NUM> (t, <NUM>), <NUM> (m, <NUM>), <NUM> (M, <NUM>), <NUM> (m, <NUM>), <NUM> (d, <NUM>), <NUM> (m, <NUM>).

R-(-)<NUM>-hydroxybutyrate hexyl ester NMR experimental data and spectra are assigned as follows: <NUM>H NMR (<NUM>, Chloroform-d) δ <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>), <NUM>-<NUM> (m, <NUM>).

R-(-)-<NUM>-hydroxybutyrate heptyl ester NMR experimental data and spectra are assigned as follows: <NUM>H NMR (<NUM>, Chloroform-d) δ <NUM> (dqd, <NUM>), <NUM> (t, <NUM>), <NUM> (dd, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, <NUM>), <NUM> (t, <NUM>).

R-(-)-<NUM>-hydroxybutyrate octyl ester NMR experimental data and spectra are assigned as follows: <NUM>H NMR (<NUM>, Chloroform-d) δ <NUM> (t, <NUM>), <NUM> (t, <NUM>), <NUM> (dd, <NUM>), <NUM> (dd, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>).

R-(-)-<NUM>-hydroxybutyric acid in the embodiment <NUM>-<NUM> is changed to R-(-)-lactic acid, and methanol is changed to <NUM>-hexanol. Other conditions are the same as those of the embodiment <NUM>-<NUM> to obtain R-(-)-lactate hexyl ester, wherein a yield is <NUM>%, and a gas phase detection purity is about <NUM>%.

On the basis of the embodiment <NUM>-<NUM>, the embodiments <NUM>-<NUM> and <NUM>-<NUM> change <NUM>-hexanol to ethanol and <NUM>-heptanol respectively, and other conditions are the same as those in the embodiment <NUM>-<NUM> to obtain R-(-)-lactate ethyl ester and R-(-)-lactate heptyl ester, wherein gas phase detection purity is about <NUM>%.

On the basis of Embodiment <NUM>-<NUM>, R-(-)-lactic acid is changed to R-(-)-<NUM>-hydroxypropionic acid to obtain R-(-)-<NUM>-hydroxypropionic hexyl ester, wherein a gas phase detection purity is about <NUM>%.

R-(-)-<NUM>-hydroxypropionic hexyl ester NMR experimental data and spectra are assigned as follows: <NUM>H NMR (CDCl<NUM>): <NUM> (m, H), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>).

Anti-bacterial tests and clogP theoretical calculation are performed on the products of the embodiment <NUM> and the embodiment <NUM>, as shown in Table <NUM>. The compounds that have a clogP value within <NUM>-<NUM> fall under the scope of the claims.

It can be seen from Table <NUM> that the clogP value of the hydroxy acid ester oligomers prepared by the present invention increases regularly with the chain length of the ester groups, but when the clogP value is about <NUM>, the anti-bacterial effect is the highest (MIC is <NUM>/mL). Therefore, when clogP=<NUM>, the molecular size of R-(-)-hydroxy acid ester is the most suitable, which means it can be inserted into the cell membrane, destroy the stable structure of the cell membrane phospholipid bilayer, thereby achieving high anti-bacterial efficiency.

Claim 1:
Use of an anti-bacterial compound in the preparation of an anti-bacterial agent, wherein the compound has a general structural formula (I):
<CHM>
characterized in that n is a natural number of <NUM>-<NUM>; Ri is a C<NUM>-C<NUM> alkyl group; R<NUM> is a C<NUM>-C<NUM> alkyl group; m is a natural number of <NUM>-<NUM>, and
the compound has a clogP value within <NUM>-<NUM>.