Safflower octal mannich base derivative and preparation method and application thereof
阅读说明：本技术 红花八角醇曼尼希碱类衍生物及其制备方法和应用 (Safflower octal mannich base derivative and preparation method and application thereof ) 是由 郭勇 柳继锋 姚红 秦上尚 包崇男 于 2019-11-07 设计创作，主要内容包括：本发明涉及红花八角醇曼尼希碱类衍生物及其制备方法和应用,有效解决治疗金黄色葡萄球菌和MRSA的药物出现耐药菌株,需要新的抗金黄色葡萄球菌和MRSA感染药物的问题,结构式：<Image he="480" wi="489" file="DDA0002264487590000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>R为：(1)：<Image he="134" wi="203" file="DDA0002264487590000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(2)：<Image he="147" wi="244" file="DDA0002264487590000013.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(3)：<Image he="197" wi="270" file="DDA0002264487590000014.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(4)：<Image he="166" wi="247" file="DDA0002264487590000015.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(5)：<Image he="151" wi="236" file="DDA0002264487590000016.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(6)：<Image he="210" wi="198" file="DDA0002264487590000017.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(7)：<Image he="190" wi="216" file="DDA0002264487590000018.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>中的一种,红花八角醇用甲苯溶解,加入醛和仲胺反应,二氯甲烷溶解,薄层色谱法分离得化合物1-5纯品；化合物1和化合物2纯品用二氯甲烷溶解,加入浓盐酸,减压除去二氯甲烷,得化合物6和7粗品,在乙醇中重结晶得化合物6和7纯品,本发明衍生物对金黄色葡萄球菌、金黄色葡萄球菌、粪肠球菌、枯草杆菌和MRSA表现出抑菌活性。(The invention relates to a safflower octal mannich base derivative, a preparation method and application thereof, which effectively solve the problems that medicines for treating staphylococcus aureus and MRSA have drug-resistant strains and need new medicines for resisting the infection of the staphylococcus aureus and MRSA, and have the following structural formula: r is: (1): (2)： (3)： (4)： (5)： (6)： (7)： one of the compounds is prepared by dissolving octandiol safflower in toluene, adding aldehyde and secondary amine to react, dissolving with dichloromethane, and separating by thin layer chromatography to obtain 1-5 pure compounds; dissolving the pure products of the compound 1 and the compound 2 by using dichloromethane, adding concentrated hydrochloric acid, decompressing and removing the dichloromethane to obtain crude products of the compound 6 and the compound 7, and recrystallizing in ethanol to obtain pure products of the compound 6 and the compound 7.)
1. A safflower octal mannich base derivative is characterized by being a compound of the following formula 1:
wherein R is:
(1)：
(5)：
2. The safflower octanediol Mannich base derivative of claim 1, wherein the compound of formula 1 is one of the following:
3. the preparation method of the safflower octal Mannich base derivatives of claims 1-2, which is characterized in that the safflower octal is dissolved by toluene, aldehyde and secondary amine are respectively added for amine methylation reaction, after the reaction is finished, dichloromethane is used for dissolution, and then the compound 1-5 pure products are obtained by thin layer chromatography separation; dissolving the pure product of the compound 1 by using dichloromethane, dropwise adding concentrated hydrochloric acid, decompressing and removing the dichloromethane to obtain a crude product of the compound 6, and recrystallizing the crude product of the compound 6 in ethanol to obtain a pure product of the compound 6; dissolving the pure product of the compound 2 by using dichloromethane, dropwise adding concentrated hydrochloric acid, removing the dichloromethane under reduced pressure to obtain a crude product of the compound 7, recrystallizing the crude product of the compound 7 in ethanol to obtain a pure product of the compound 7, wherein the pure product of the compound 1-the pure product of the compound 7 are the octandiol mannich base derivatives.
4. The method for preparing safflower octal mannich base derivatives as claimed in claim 3, wherein the aldehyde is formaldehyde aqueous solution; the secondary amine is any one of dimethylamine aqueous solution, pyrrolidine, N-methyl piperazine, piperidine and morpholine; the weight ratio of the safflower octandiol to the aldehyde to the secondary amine is 1-2: 1: 0.8-1.4; the temperature of the aminomethylation reaction is 100-120 ℃, and the time of the aminomethylation reaction is 3-9 h; the weight ratio of the concentrated hydrochloric acid to the pure product of the compound 1 is 2.5-2.9: 1; the weight ratio of the concentrated hydrochloric acid to the pure product of the compound 2 is 2.5-2.9: 1; the temperature at which methylene chloride is removed under reduced pressure is in the range of 30 to 45 ℃.
5. The method for preparing safflower octal Mannich base derivatives according to claim 4, wherein the formaldehyde aqueous solution is a formaldehyde aqueous solution with a mass percentage concentration of 37%; the dimethylamine aqueous solution is a dimethylamine aqueous solution with the mass percentage concentration of 40 percent; the concentrated hydrochloric acid is 36-38% by mass.
6. The method for preparing safflower octal Mannich base derivatives according to claim 3, wherein 50.0mg of safflower octal alcohol is dissolved in 2mL of toluene, 30.6mg of aqueous formaldehyde solution with the mass percent concentration of 37% and 42.4mg of aqueous dimethylamine solution with the mass percent concentration of 40% are respectively added, the mixture is respectively reacted for 5 hours at 110 ℃, after the reaction is finished, the mixture is dissolved in dichloromethane, and then the pure compound 1 is obtained by thin layer chromatography.
7. The preparation method of the safflower octal Mannich base derivatives according to claim 3, wherein 50.0mg of safflower octal is dissolved in 2mL of toluene, 30.6mg of formaldehyde solution with the mass percent concentration of 37% and 26.8mg of tetrahydropyrrole are added, the mixture is reacted for 5 hours at 110 ℃, after the reaction is finished, the mixture is dissolved in dichloromethane, and then the compound 2 pure product is obtained by thin layer chromatography separation.
8. Use of the safflower octandiol Mannich base derivatives having the structures shown in the formulas 1-3 and 1-4 in claim 2 in preparing medicaments for resisting staphylococcus aureus, enterococcus faecalis, bacillus subtilis and MRSA infection.
9. Use of the safflower octanediol Mannich base derivatives having the structures of formulas 1 to 5 as claimed in claim 2 for the preparation of a medicament for the treatment of MRSA infection.
10. Use of the safflower octanediol Mannich base derivatives having the structures of formulas 1-1, 1-2, 1-6 and 1-7 as claimed in claim 2 in the preparation of medicaments against Staphylococcus aureus 29213 and MRSA infections.
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a safflower octal mannich base derivative and a preparation method and application thereof.
Background
Currently, bacterial resistance has become a major challenge in the global public health field and is also a worldwide issue of widespread concern to governments and society of various countries. MRSA is a common gram-positive pathogen in clinical use, has a strong toxicity, can cause septicemia, necrotizing pneumonia, meningitis, osteomyelitis, endocarditis, and the like, and has characteristics of high morbidity and high mortality (Vanbelkum a, et al, 2009.infection, Genetics and Evolution,9(1): 32). The national bacterial drug resistance monitoring network (CARSS) monitoring data shows that the national average separation rate of the Chinese methicillin-resistant staphylococcus aureus (MRSA) strains in 2017 is 32.2%. At present, the drugs for clinically treating MRSA mainly comprise vancomycin, teicoplanin, linezolid, daptomycin and the like, but the drug resistance of bacteria develops rapidly, so that drug-resistant strains of the drugs gradually appear clinically. Therefore, the development of new drugs for resisting MRSA infection is a problem to be solved urgently in clinic.
The octandiol (dunnianol) is a Sesqui-neolignan compound (Sesqui-neolignans) derived from natural plants, and is structurally characterized by being polymerized from three phenylpropanoid compounds. Illicinol was first found isolated from Illicium sativum (Kouno I, et al.1991.chemical and Pharmaceutical Bulletin,39(10): 2606).
However, the activity of illicium alcohol carthami is only reported, and although the earlier research of the subject group has found that illicium carthami alcohol has certain antibacterial effect on staphylococcus aureus and MRSA (Liu Shenfeng et al, 2017, CN 106822068), no further publication exists on how to develop a new MRSA infection resistant medicament so as to obtain a novel antibacterial agent with better activity.
Disclosure of Invention
In view of the above situation, in order to overcome the defects of the prior art, the invention aims to provide the octacosanol mannich base derivative and the preparation method and the application thereof, which can effectively solve the problems that the existing medicines for treating staphylococcus aureus and MRSA have drug-resistant strains and new medicines for resisting the infection of the staphylococcus aureus and MRSA need to be developed.
The technical scheme of the invention is that the safflower octal mannich base derivative has a chemical structural formula as follows:
wherein R is:
the preparation method of the safflower octal mannich base derivative comprises the following specific steps: dissolving safflower octal with toluene, respectively adding aldehyde and secondary amine (secondary amine), performing aminomethylation reaction, dissolving with dichloromethane after the reaction is finished, and separating by thin-layer chromatography to obtain a compound 1-5 pure product with a yield of 20% -93%; dissolving the pure product of the
the aldehyde is formaldehyde aqueous solution;
the formaldehyde aqueous solution is a formaldehyde aqueous solution (formaldehydes) with the mass percentage concentration of 37%;
the secondary amine is any one of dimethylamine aqueous solution, pyrrolidine, N-methyl piperazine, piperidine and morpholine;
the dimethylamine aqueous solution is a dimethylamine aqueous solution with the mass percentage concentration of 40 percent;
the weight ratio of the safflower octandiol to the aldehyde to the secondary amine is 1-2: 1: 0.8-1.4;
the temperature of the aminomethylation reaction is 100-120 ℃, and the time of the aminomethylation reaction is 3-9 h;
the concentrated hydrochloric acid is 36-38% by mass;
the weight ratio of the concentrated hydrochloric acid to the pure product of the
the weight ratio of the concentrated hydrochloric acid to the pure product of the compound 2 is 2.5-2.9: 1;
the temperature for removing the dichloromethane under reduced pressure is 30-45 ℃.
The prepared partial safflower octal Mannich base derivatives have good activity on staphylococcus aureus, for example, the compounds 3 and 4 have bacteriostatic activity on staphylococcus aureus, enterococcus faecalis and bacillus subtilis, and the Minimum Inhibitory Concentration (MIC) is 8-64 mu g/mL. Compound 5 also showed bacteriostatic activity against clinically isolated MRSA with MIC > 64. mu.g/mL. Most notably, the MIC results for
Drawings
FIG. 1 is an infrared spectrum (IR) of Compound 6 of the present invention.
FIG. 2 is a nuclear magnetic resonance spectrum of Compound 6 of the present invention.
FIG. 3 shows the bactericidal rate (a) of Compound 6 of the present invention against Staphylococcus aureus cultured for 3 hours; the bactericidal rate of compound 6 against MRSA 4 cultured for 2.5h (b); the sterilization rate (c) of compound 6 against staphylococcus aureus cultured for 5 h; the bactericidal rate (d) of compound 6 against MRSA 4 cultured for 5 h.
Detailed Description
The following examples are provided to explain the present invention in detail.