阅读说明：本技术 含有对氨基苯甲酸衍生物与脂肪六元环羧酸衍生物的组合物及其用途 (Composition containing p-aminobenzoic acid derivative and aliphatic six-membered cyclic carboxylic acid derivative and application thereof ) 是由 向飞 曾佑梅 于 2019-12-13 设计创作，主要内容包括：本发明提供了一种含有对氨基苯甲酸衍生物与脂肪六元环羧酸衍生物的组合物,具体化合物的定义见说明书。本发明所述的对氨基苯甲酸衍生物与脂肪六元环衍生物的组合物能通过协同作用而提高毛老虎、天星草、定心荣等植物的提取物对产气荚膜梭菌、厌氧消化链球菌、黏质沙雷氏菌等多种细菌的抑制作用。(The invention provides a composition containing p-aminobenzoic acid derivatives and aliphatic six-membered cyclic carboxylic acid derivatives, and the specific compounds are defined in the specification. The composition of the para aminobenzoic acid derivative and the fat six-membered ring derivative can improve the inhibition effect of the extracts of the plants such as the boston makinoi, the saxifrage, the Xinglong and the like on various bacteria such as clostridium perfringens, anaerobic digestion streptococcus, serratia marcescens and the like through the synergistic effect.)

1. A composition comprising a p-aminobenzoic acid derivative and an aliphatic six-membered cyclic carboxylic acid derivative, wherein the p-aminobenzoic acid derivative is one selected from the group consisting of compounds a1 to a15 shown below:

the aliphatic six-membered ring carboxylic acid derivative is one selected from a compound H1-a compound H29 shown as follows:

2. the composition according to claim 1, wherein the mass ratio of the para-aminobenzoic acid derivative to the aliphatic six-membered cyclic carboxylic acid derivative is 0.01:1 to 100: 1.

3. The composition of claim 1 or 2, wherein said composition further comprises a plant extract.

4. The composition of claim 3, wherein said plant extract is an extract of a plant selected from the group consisting of boston makinoi, saxifrage, naberry, cyrtomium rhizome, kadsura root, cycas leaf, and clematis root.

5. The composition of claim 1 or 2, wherein said composition is formulated as an oral solid dosage form.

6. The composition of claim 5, wherein said oral solid dosage form is one selected from the group consisting of a tablet, a capsule and a capsule.

7. Use of a composition according to claim 1 or 2 for the preparation of a medicament for the treatment of bacterial infectious diseases.

8. Use according to claim 7, characterized in that said bacterial infectious disease is a disease caused by an infection with a bacterium selected from the group consisting of Clostridium perfringens, Streptococcus anaerobiosis, Serratia marcescens, Micrococcus luteus, Aeromonas hydrophila, Staphylococcus caprae, Legionella pneumophila, Streptococcus pratense, Leuconostoc decarboxyloides, Listeria monocytogenes, Aeromonas parvum, Staphylococcus cohnii, stenotrophomonas maltophilia, Citrobacter freundii, Mycobacterium marini, Microbacterium arborescens and Staphylococcus wovensis.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a composition containing a p-aminobenzoic acid derivative and a fatty six-membered cyclic carboxylic acid derivative and application thereof.

Background

Nosocomial infections are a significant problem affecting hospital medical quality. With the continuous development and progress of modern medical technology, a large amount of antibacterial drugs are used, and the drug-resistant strains of clinical pathogenic bacteria are continuously increased. Therefore, the improvement of the antibacterial activity of the existing drugs can help to improve the treatment effect of the patients with bacterial infection.

Wang Zhi Ling et al (journal of oral medicine, 2003(04), 277-280.), Li Yao et al (journal of Sichuan university (medical edition), 2003(03), 491-493), Guo et al (journal of oral medicine, 2002(04), 296-297), Zhou Tong et al (journal of oral medicine, 2002(04), 38-40+ 89), Guo et al (journal of medical university, China, 2002(04), 38-40+ 219), Xiao Rong et al (journal of medical university, 2002 (210-211 + 219)) and Xiao Rong et al (journal of micro-ecology, 2001 (25-26)) examined the effect of aminobenzoic acid on the growth of actinomyces viscosus or Porphyromonas gingivalis in respective studies.

Quosdorf S et al have pointed out (molecules.2017Nov 17; 22 (11)) that neuraminidase (neuramidinase) is a key enzyme in the life cycle of influenza virus and is also present in part of bacterial pathogens, and found that aliphatic six-membered cyclic carboxylic acid derivatives having the structure shown below have moderate inhibitory effects (IC) on Vibrio Cholerae Neuraminidase (VCNA)₅₀114 μ M).

Plant extracts are rich in chemical components with various structures and antibacterial activity, and Research results of Iqbal Ahmad et al show that tetracycline and ciprofloxacin can generate synergistic antibacterial action with extracts of various plants such as Acorus calamus and the like (Microbiological Research,162(2007): 264-275). Liwu et al reported that Japanese thistle herb extract and various antibiotics produced synergistic effect on mycobacteria inhibition (Natural products research and development, 2017,29(12): 2087-2091.).

Poplar Oenome et al report (Reptical zone biology, 2019,10(03):226-

Disclosure of Invention

The invention aims to provide a composition containing a para aminobenzoic acid derivative and a fatty six-membered cyclic carboxylic acid derivative and application thereof, wherein the composition can generate a synergistic antibacterial effect with various plants such as cutworms and the like.

In order to achieve the above object, according to one aspect of the present invention, there is provided a composition comprising a p-aminobenzoic acid derivative and an aliphatic six-membered cyclic carboxylic acid derivative, wherein the p-aminobenzoic acid derivative is one selected from the group consisting of compounds a1 to a15 shown below:

the aliphatic six-membered ring carboxylic acid derivative is one selected from a compound H1-a compound H29 shown as follows:

in one aspect, the mass ratio of the para aminobenzoic acid derivative to the aliphatic six-membered cyclic carboxylic acid derivative in the composition of the present invention is preferably 0.01:1 to 100: 1.

In another aspect, the composition of the present invention preferably further comprises a plant extract.

More preferably, the plant extract of the invention is an extract of one plant selected from the group consisting of boston makinoi, saxifrage, naberry, cyrtomium rhizome, panax notoginseng, cycas revolute leaves and radix sileris.

In another aspect, the composition of the present invention can be prepared into oral solid preparation.

More preferably, the oral solid preparation of the present invention is one selected from the group consisting of tablets, capsules and capsules.

In another aspect, the present invention provides the use of a composition as described above for the preparation of a medicament for the treatment of a bacterial infectious disease.

Preferably, the bacterial infectious disease of the present invention is a disease caused by infection with a bacterium selected from the group consisting of clostridium perfringens, streptococcus anaerobicus, serratia marcescens, micrococcus luteus, aeromonas hydrophila, staphylococcus caprae, legionella pneumophila, streptococcus pratense, lecanobacterium decarboxylatum, listeria monocytogenes, aeromonas parvum, staphylococcus cohnii, stenotrophomonas maltophilia, citrobacter freundii, mycobacterium marinus, microbacterium arborescens, and staphylococcus wadskii.

In-vitro test results show that the para aminobenzoic acid derivative and the aliphatic six-membered cyclic carboxylic acid derivative can generate synergistic antibacterial action with extracts of various plants such as the cutworm, the starwort herb, the Xinglong, the cyrtomium rhizome, the panax notoginseng, the cycas leaf, the radix sileris and the like

Detailed Description

The following description of the embodiments is only intended to aid in the understanding of the method of the invention and its core ideas. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention. The following description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.

Preparation example 1 preparation of plant extract

Drying the dried plant material at 40 deg.C by ultrasonic extraction, pulverizing, sieving with 40 mesh sieve, and placing into self-sealing bag. Before the test, 50g of the dried plant powder was weighed and added with different organic solvents for ultrasonic extraction (as shown in table 1), and the extraction was repeated 3 times for 60min each time. Filtering, concentrating to dry, and storing in a refrigerator at 4 deg.C for use.

TABLE 1 organic solution of ultrasonic extraction of different plant extracts

Plant material	Solvent for extraction	Extract number
			Mao LaoTiger	Methanol	PE1
All-grass of Szechwan-Yunnan Sambucus	Methanol	PE2
			Good heart-nourishing	Isopropanol (I-propanol)	PE3
Rhizoma Osmundae	Ethanol	PE4
			Root of Teng pseudo-ginseng	Isopropanol (I-propanol)	PE5
Folium Ferri Suffruticosae	Acetone (II)	PE6
			Medicine for treating bone fracture	Chloroform	PE7

Test example 1 Effect of a mixture of para-aminobenzoic acid derivative and aliphatic six-membered cyclic carboxylic acid derivative on antibacterial Activity of plant extract

The inhibition of various bacteria by the test substances ① - ③ shown below is determined by a method disclosed by Lemna hexandra et al (food and fermentation industry, 2017,43(02): 232-238.).

(1) Test article

Test ① reaction of p-aminobenzoic acid derivative (compound AX, X is selected from 1-15) withAliphatic six-membered cyclic carboxylic acid derivative (compound HY, Y is selected from 1-29) in specific mass ratio (R)₁) The resulting mixture was designated "AX-HY".

Test ② plant extract (PEZ, Z is selected from 1-7) obtained in preparation example 1.

Test object ③ test object ① and test object ② in a mass ratio (R)₂) The resulting mixture was designated AX-HY-PEZ.

(2) Test method

① preparing test sample solution by taking a certain amount of test substance, using DMF as solvent, and adopting a specific multiple continuous dilution method to prepare test sample solution with 6 concentrations.

② bacterial suspension is prepared by inoculating activated strain to liquid culture medium (no agar), shake-culturing, calculating bacterial colony number by plate dilution method, and adjusting bacterial suspension concentration to 10 with sterile physiological saline⁷CFU/mL。

③ agar-hole diffusion method for determining antibacterial activity comprises cooling the sterilized culture medium to 50 deg.C, adding 6mL of bacterial suspension, mixing, pouring into a culture dish with diameter of 9cm, standing for 45min, uniformly perforating (diameter of 7mm) on the cured culture medium with an aseptic perforator, marking, adding 40 μ L of sample solution into each hole, DMF as blank control, culturing at 37 deg.C for 18h, measuring and recording the diameter (mm) of the zone of inhibition, repeating for 3 times, averaging to obtain the result, and calculating the Inhibition Ratio (IR) of the strain to be tested according to the following formula.

For each of the test substance ① and test substance ②, the total concentration of AX-HY in IR was plotted against the logarithm (log (c)) of the test concentration (ng/mL) of PEZ, and the concentration of each test substance at which the inhibition of specific fa occurred was calculated from the linear regression equation and was designated as IC_fa(A)And IC_fa(PEZ)For test substance ③, the concentration of AX-HY in test substance ③ at the time of the inhibition of a specific fa was calculated from the linear regression equation by plotting IR against the logarithm of the concentration of AX-HY therein (ng/mL), and this was designated as IC_fa(mixA)。

The Combination Index (CI) at which a specific fa inhibitory rate is produced is calculated according to the following formula.

When CI <1, it means that there is synergism, the smaller the CI, the stronger the synergism.

TABLE 2.1 inhibition of Clostridium perfringens by test substances

TABLE 2.2 inhibitory Effect of test substances on anaerobic digestion of Streptococcus

TABLE 2.3 inhibition of Serratia marcescens by the test substances

TABLE 2.4 inhibitory Effect of test substances on Micrococcus luteus

TABLE 2.5 inhibition of Aeromonas hydrophila by test substances

TABLE 2.6 inhibition of Staphylococcus capriae by test substances

TABLE 2.7 inhibition of Legionella pneumophila by test substances

TABLE 2.8 inhibition of S.praelii by test substances

TABLE 2.9 inhibition of non-decarboxylating bacteria by the test substances

TABLE 2.10 inhibitory Effect of the test substances on Listeria monocytogenes

TABLE 2.11 test substance inhibition of Aeromonas veronii

TABLE 2.12 inhibitory Effect of the test substances on Staphylococcus cohnii

TABLE 2.13 inhibitory Effect of the test substances on stenotrophomonas maltophilia

TABLE 2.14 inhibition of Citrobacter freundii by test substances

TABLE 2.15 test substances for the inhibition of Mycobacterium marinum

TABLE 2.16 inhibitory Effect of the test substances on Microbacterium arborescens

TABLE 2.17 inhibitory Effect of the test substances on Staphylococcus Wauteri