阅读说明：本技术 异色满和鸭嘴花碱酮在制备抗菌药物中的应用 (Application of isochroman and vasicine ketone in preparation of antibacterial drugs ) 是由 肖林霞 于 2021-09-26 设计创作，主要内容包括：本发明属于医药科技技术领域,本发明提供了一类结构通式1表示的新型抗菌药物,该化合物结构具有异色满和鸭嘴花碱酮复合抑菌结构单元,R1-R5独立的选自H、OH、OMe、t-Bu、卤素。该类药物实验证明,对革兰阳性菌,尤其是抗耐甲氧西林金黄色葡萄球菌(MRSA)具有很强的抑制作用,可以用于制备有效的抗菌药物。(The invention belongs to the technical field of medicine science and technology, and provides a novel antibacterial drug represented by a structural general formula 1, wherein the structure of the compound has isochroman and vasicine compound antibacterial structural units, and R1-R5 are independently selected from H, OH, OMe, t-Bu and halogen. The drug experiments prove that the compound has strong inhibition effect on gram-positive bacteria, especially on methicillin-resistant staphylococcus aureus (MRSA), and can be used for preparing effective antibacterial drugs.)

1. The application of isochroman and vasicine ketone in preparing antibacterial drugs is characterized in that: comprising isochroman and vasicinone derivatives represented by formula 1, having the following structural formula:

R1-R5 are independently selected from H, OH, OMe, t-Bu, halogen.

2. Use of isochroman and vasicine in the manufacture of an antibacterial medicament according to claim 1, wherein: the isochroman and vasicine ketone derivative is applied to preparing antibacterial drugs.

3. Use of isochroman and vasicine in the manufacture of an antibacterial medicament according to claim 2, wherein: the antibacterial drug is a drug for resisting gram-positive bacteria.

4. Use of isochroman and vasicine in the manufacture of an antibacterial medicament according to claim 2, wherein: the antibacterial drug is a drug for resisting methicillin-resistant staphylococcus aureus (MRSA).

5. A medicament for antimicrobial use, characterized by: the medicament comprises the isochroman and vasicinone derivatives of claim 1 and pharmaceutically acceptable adjuvants.

Technical Field

The invention relates to the technical field of medicine science and technology, in particular to application of isochroman and vasicine ketone in preparation of antibacterial drugs.

Background

Antibacterial drugs are currently the most commonly used class of drugs for the treatment of bacterial infections, and unreasonably serious antibiotic abuse has occurred for many years with the global use of antibiotics. The emergence of multiple drug resistant strains, both gram positive and gram negative, and particularly the emergence of methicillin resistant staphylococcus aureus (mrs), is a serious problem in the current clinical setting.

At present, effective treatment drugs for infections caused by these strains are lacked, and development of new-structure antibacterial drugs free from cross-resistance and more effective is urgently needed.

The vasicine ketone is an important heterocyclic compound, has good biological activities of antibiosis, tumor resistance and the like, and is one of hot spots for developing and researching new medicaments and new pesticides; the isochroman compounds generally have good antibacterial, antiviral, antiproliferative pheromone and central nervous system activity. According to the dominant structure recombination concept, the isochroman and vasicine ketone compound derivative has good research prospect.

Disclosure of Invention

This section is for the purpose of summarizing some aspects of embodiments of the invention and to briefly introduce some preferred embodiments. In this section, as well as in the abstract and the title of the invention of this application, simplifications or omissions may be made to avoid obscuring the purpose of the section, the abstract and the title, and such simplifications or omissions are not intended to limit the scope of the invention.

The invention aims to provide a structure of isochroman and vasicine ketone mixed type antibacterial drugs, the compounds have strong inhibition effect on gram positive bacteria, especially on methicillin-resistant staphylococcus aureus (MRSA), and can be used for preparing effective antibacterial drugs.

To solve the above technical problem, according to an aspect of the present invention, the present invention provides the following technical solutions:

the application of isochroman and vasicine ketone in preparing antibacterial drugs comprises isochroman and vasicine ketone derivatives represented by a general formula 1, and the derivatives have the following structural expression:

R1-R5 are independently selected from H, OH, OMe, t-Bu, halogen.

As a preferred embodiment of the use of isochroman and vasicine in the preparation of antibacterial drugs according to the invention, wherein: the isochroman and vasicine ketone derivative is applied to preparing antibacterial drugs.

As a preferred embodiment of the use of isochroman and vasicine in the preparation of antibacterial drugs according to the invention, wherein: the antibacterial drug is a drug for resisting gram-positive bacteria.

As a preferred embodiment of the use of isochroman and vasicine in the preparation of antibacterial drugs according to the invention, wherein: the antibacterial drug is a drug for resisting methicillin-resistant staphylococcus aureus (MRSA).

As a preferred embodiment of the use of isochroman and vasicine in the preparation of antibacterial drugs according to the invention, wherein: an antibacterial agent comprising the isochroman and vasicidone derivative of claim 1 and pharmaceutically acceptable adjuvants.

Compared with the prior art, the invention has the beneficial effects that: the above medicine can be mixed with one or more medicinal carriers or excipients, and made into tablet, capsule, granule or emulsion. In vitro pharmacodynamic experiments prove that: the compounds have strong inhibitory action on gram-positive bacteria, especially on methicillin-resistant staphylococcus aureus (MRSA).

Detailed Description

The present invention will be described in detail with reference to the following embodiments in order to make the aforementioned objects, features and advantages of the invention more comprehensible.

In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described herein, and it will be apparent to those of ordinary skill in the art that the present invention may be practiced without departing from the spirit and scope of the present invention, and therefore the present invention is not limited to the specific embodiments disclosed below.

In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention will be described in further detail below.

The general formula of the medicine structure of the invention is as follows:

R1-R5 are independently selected from H, OH, OMe, t-Bu, halogen; one preferred embodiment is where three of the substituents R1-R5 are hydrogen, one is halogen and the other is OH, for example: r1 is Br, R2, R3 and R5 are H, and R4 is OH. Another preference is given to R1-R5 wherein the three substituents are H, one is halogen and the other is OMe, for example: r1 is F, R2, R3 and R5 are H, and R4 is OMe. The halogen is Br, Cl or F. Most preferably, R1 is Br, R2 is F, R3, R5 are H, and R4 is OH.

The synthesis of the compound takes R1-R5 substituted phenethyl alcohol, anthranilic acid and 3-dimethoxymethyl-2-pyrrolidone as raw materials to carry out condensation reaction, and the specific synthetic route is as follows:

according to the synthesis route, the following structural drugs can be obtained:

the above medicine can be mixed with one or more medicinal carriers or excipients, and made into tablet, capsule, granule or emulsion. In vitro pharmacodynamic experiments prove that: the compounds have strong inhibitory action on gram-positive bacteria, especially on methicillin-resistant staphylococcus aureus (MRSA).

The following are the pharmacological tests and data for some of the compounds of the invention:

the MIC (. mu.g/mL) value of the test compound was determined by the agar dilution method.

1. Preparing an antibacterial drug stock solution: the concentration of the stock solution is more than 10 times of the highest concentration, after the stock solution is prepared, the stock solution is sterilized by a filtration method, and a small amount of the stock solution is subpackaged for standby.

2. Preparation of drug-containing agar: the stock solution was diluted to 10 concentration gradients by half dilution. 1mL of each was added to a series of labeled plates with an inner diameter of 90 mm. Then 19mL of MH agar sterilized at 50 ℃ is added into the plate, and the mixture is cooled after being mixed evenly.

3. Inoculation: inoculating with inoculator one by one on the marked medicated plate, each time the inoculum size is 1-2 μ L (the bacterial content is about 10)⁶CFU/mL). Finally, the growth control plate without the drug is inoculatedTo check the survival status of the test bacteria throughout the test.

4. And (3) incubation: after the inoculum solution was dry, the plate was incubated at 37 ℃ for 18-24 h.

5. And (5) judging a result: the lowest drug concentration at which colony growth is completely inhibited is the MIC value of the drug for the test bacteria. Single colonies grew negligibly.

The test results are shown in Table 1

TABLE 1 antimicrobial Activity assay of some of the compounds of the invention

Wherein the compound 1-7 is a positive drug amoxicillin. From the above data, it can be seen that the compounds of the present invention have certain antibacterial effects, especially strong inhibitory effect against methicillin-resistant staphylococcus aureus (MRSA).

Example 1:

synthesis method of compound 1-1

Adding 1.39g (10mmol) of 4-hydroxybenzene ethanol and 1.59g (10mmol) of 3-dimethoxymethyl-2-pyrrolidone into a 100mL round-bottom double-mouth bottle, adding 35mL of anhydrous dichloromethane and 0.2mL of concentrated hydrochloric acid, performing reflux reaction for 8h, adding 2.15g (10mmol) of 4-bromo-2-aminobenzoic acid, reacting for 3h, adding 10mL of saturated saline, standing, separating, directly concentrating and spin-drying the filtrate, and recrystallizing the mixed solution of ethyl acetate and petroleum ether to obtain 3.47g of the target product with the yield of 84.4%.

¹H-NMR(400M,DMSO-d6):1.71-1.73(m,2H),2.04-2.21(m,2H),2.79-2.83(m,2H),3.13-3.34(m,4H),3.41(m,1H),6.26-6.27(m,1H),7.24-7.37(m,3H),7.88-7.91(m,2H),9.45(s,1H).

Example 2:

synthesis method of compound 1-2

Adding 1.39g (10mmol) of 4-hydroxybenzene ethanol and 1.59g (10mmol) of 3-dimethoxymethyl-2-pyrrolidone into a 100mL round-bottom double-mouth bottle, adding 35mL of anhydrous dichloromethane and 0.2mL of concentrated hydrochloric acid, performing reflux reaction for 8h, adding 1.55g (10mmol) of 4-fluoro-2-aminobenzoic acid, reacting for 3h, adding 10mL of saturated saline, standing, separating, directly concentrating and spin-drying the filtrate, and recrystallizing the mixed solution of ethyl acetate and petroleum ether to obtain 3.01g of the target product with the yield of 86%.

¹H-NMR(400M,DMSO-d6):1.70-1.72(m,2H),2.07-2.26(m,2H),2.73-2.80(m,2H),3.15-3.31(m,4H),3.44(m,1H),6.27-6.29(m,1H),7.21-7.36(m,3H),7.84-7.90(m,2H),9.47(s,1H).

Example 3:

synthesis method of compound 1-3

Adding 1.39g (10mmol) of 4-hydroxybenzene ethanol and 1.59g (10mmol) of 3-dimethoxymethyl-2-pyrrolidone into a 100mL round-bottom double-mouth bottle, adding 35mL of anhydrous dichloromethane and 0.2mL of concentrated hydrochloric acid, performing reflux reaction for 8h, adding 2.33g (10mmol) of 4-bromo-5-fluoro-2-aminobenzoic acid, reacting for 3h, adding 10mL of saturated saline solution, standing, separating liquid, directly concentrating and spin-drying the filtrate, and recrystallizing the mixed solution of ethyl acetate and petroleum ether to obtain 3.41g of the target product with the yield of 79.4%.

¹H-NMR(400M,DMSO-d6):1.69-1.72(m,2H),2.12-2.26(m,2H),2.74-2.80(m,2H),3.17-3.31(m,4H),3.54(m,1H),6.16-6.21(m,1H),7.04-7.27(m,2H),7.68-7.81(m,2H),9.38(s,1H).

Example 4:

synthesis method of compounds 1-4

Adding 1.51g (10mmol) of 4-methoxyphenethanol and 1.59g (10mmol) of 3-dimethoxymethyl-2-pyrrolidone into a 100mL round-bottom double-mouth bottle, adding 35mL of anhydrous dichloromethane and 0.2mL of concentrated hydrochloric acid, performing reflux reaction for 8h, adding 2.33g (10mmol) of 4-bromo-5-fluoro-2-aminobenzoic acid, reacting for 3h, adding 10mL of saturated saline solution, standing, separating liquid, directly concentrating and spin-drying the filtrate, and recrystallizing the mixed solution of ethyl acetate and petroleum ether to obtain 3.09g of a target product with the yield of 69.7%.

¹H-NMR(400M,DMSO-d6):1.71-1.76(m,2H),2.10-2.22(m,2H),2.70-2.79(m,2H),3.19-3.31(m,4H),3.45(s,3H),3.55(m,1H),6.18-6.20(m,1H),7.26-7.34(m,3H),7.80-7.89(m,1H).

Example 5:

synthesis method of compounds 1-5

Adding 1.53g (10mmol) of 4-methoxyphenethanol and 1.59g (10mmol) of 3-dimethoxymethyl-2-pyrrolidone into a 100mL round-bottom double-mouth bottle, adding 35mL of anhydrous dichloromethane and 0.2mL of concentrated hydrochloric acid, performing reflux reaction for 8h, adding 1.37g (10mmol) of 2-aminobenzoic acid, reacting for 3h, adding 10mL of saturated saline solution, standing, separating, directly concentrating and spin-drying the filtrate, and recrystallizing the mixed solution of ethyl acetate and petroleum ether to obtain 2.59g of a target product with the yield of 74.6%.

¹H-NMR(400M,DMSO-d6):1.68-1.74(m,2H),2.11-2.24(m,2H),2.68-2.75(m,2H),3.18-3.31(m,4H),3.44(s,3H),3.56(m,1H),6.19-6.23(m,2H),7.19-7.21(m,4H),7.73-7.81(m,1H).

Example 6:

synthesis method of compounds 1-6

Adding 1.23g (10mmol) of phenethyl alcohol and 1.59g (10mmol) of 3-dimethoxymethyl-2-pyrrolidone into a 100mL round bottom double-neck bottle, adding 35mL of anhydrous dichloromethane and 0.2mL of concentrated hydrochloric acid, carrying out reflux reaction for 8h, adding 1.73g (10mmol) of 4, 5-difluoro-2-aminobenzoic acid, reacting for 3h, adding 10mL of saturated saline, standing, carrying out liquid separation, directly concentrating and spin-drying the filtrate, and recrystallizing the mixed solution of ethyl acetate and petroleum ether to obtain 2.79g of a target product with the yield of 79.1%.

¹H-NMR(400M,DMSO-d6):1.73-1.75(m,2H),2.08-2.17(m,2H),2.54-2.63(m,2H),3.11-3.23(m,4H),3.49(m,1H),6.34-6.38(m,2H),7.25-7.31(m,3H),7.69-7.74(m,1H).。

While the invention has been described above with reference to an embodiment, various modifications may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In particular, the various features of the disclosed embodiments of the invention may be used in any combination, provided that no structural conflict exists, and the combinations are not exhaustively described in this specification merely for the sake of brevity and resource conservation. Therefore, it is intended that the invention not be limited to the particular embodiments disclosed, but that the invention will include all embodiments falling within the scope of the appended claims.