CN111662351A - New octreolone type sapogenin derivative and application thereof in preparation of drug-resistant bacteria resistant drugs - Google Patents

New octreolone type sapogenin derivative and application thereof in preparation of drug-resistant bacteria resistant drugs Download PDF

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CN111662351A
CN111662351A CN202010548873.1A CN202010548873A CN111662351A CN 111662351 A CN111662351 A CN 111662351A CN 202010548873 A CN202010548873 A CN 202010548873A CN 111662351 A CN111662351 A CN 111662351A
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dammarane
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diol
fmoc
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毕毅
曹玉成
王恺奕
孟庆国
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Yantai University
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Abstract

The invention disclosesThe new ocrtalone type sapogenin derivative and the application in preparing medicine for resisting drug-resistant bacteria are provided. The preparation method of the oxtriptolone type ginsenoside derivative comprises the following steps: a.20(S) -protopanaxadiol as raw material, acetic anhydride protecting C-3 and C-12 hydroxyl; b. oxidizing m-chloroperoxybenzoic acid to ensure that a tetrahydrofuran ring is formed at the C-24 position; c. removing the protecting groups at C-3 and C-12 positions by sodium hydroxide; d. under the catalysis of DMAP and EDCI, reacting with different Boc-amino acid and Fmoc-Boc-amino acid; e. removing Boc protecting group under the catalysis of trifluoroacetic acid to obtain a crude product, and purifying by column chromatography to obtain a target compound; f. reacting amino with dansyl chloride under the catalysis of DIEA; g. removing Fmoc protection under piperidine catalysis to obtain a crude product, and purifying by column chromatography to obtain the target compound. The oxtriptolone type ginsenoside derivative has a good antibacterial effect, and compared with an oxtriptolone type ginsenoside mother core, the oxtriptolone type ginsenoside derivative has a remarkably enhanced inhibition effect on methicillin-resistant staphylococcus aureus.

Description

New octreolone type sapogenin derivative and application thereof in preparation of drug-resistant bacteria resistant drugs
Technical Field
The invention relates to the field of organic synthesis and pharmaceutical chemistry, in particular to an oxtriptolone type ginsenoside derivative with a novel structure. The invention discloses a preparation method of the oxtriptolone type ginsenoside derivatives, a pharmaceutical composition containing the oxtriptolone type ginsenoside derivatives and application of the oxtriptolone type ginsenoside derivatives in resisting bacterial infection diseases.
Background
The natural product is an important source of lead compounds in drug research and development, and has the characteristics of rich structure types, small toxic and side effects and the like, so that the search of components with antibacterial effects from the natural product becomes a hot direction for research of researchers. The ocotillol-type ginsenoside is dammarane type tetracyclic triterpene saponin with tetrahydrofuran ring on side chain, mainly exists in Panax plant, and has antitumor effect.
The discovery and research of antibacterial drugs play an important role in the treatment of infectious diseases caused by bacteria. However, abuse of antibacterial drugs has prompted bacterial resistance. Staphylococcus aureus is one of the most common pathogenic bacteria of hospital and community acquired infections. In recent years, the development of drug resistant staphylococcus aureus strains such as Methicillin Resistant Staphylococcus Aureus (MRSA) has been caused by the large use of clinical antibiotics. MRSA, commonly referred to as superbacteria, cause infections with high morbidity and mortality, and are clinically difficult to treat. The development of new highly effective drug resistant bacteria drugs (methicillin-resistant staphylococcus aureus (MRSA)) is therefore of great importance for combating increasingly serious bacterial infections.
Disclosure of Invention
The invention provides a new oxtriptolone type sapogenin derivative which has better drug-resistant antibacterial activity, and also provides a preparation method and application of the derivative.
The invention aims to solve the technical problem of searching a new structural type compound with excellent antibacterial activity and further providing an application of the compound in preparing a methicillin-resistant staphylococcus aureus antibacterial drug.
In order to solve the technical problems, the invention provides the following technical scheme:
oxtriptolone type ginsenoside derivative shown in general formula (I) and pharmaceutically acceptable salt thereof,
Figure BDA0002541728210000011
wherein the content of the first and second substances,
R1represents-NH2、-R3NH2、
Figure BDA0002541728210000021
-CH3、H、
Figure BDA0002541728210000022
R2Represents
Figure BDA0002541728210000023
R3Represents (C1-C8) straight-chain or branched alkyl;
R4represents (C1-C3), (C5-C8) straight chain or branched chain alkyl.
Preferably, the compounds and their pharmaceutically acceptable salts, wherein,
R1represents-NH2、-R3NH2、
Figure BDA0002541728210000024
-CH3、H、
Figure BDA0002541728210000025
R2Represents
Figure BDA0002541728210000026
R3Represents (C1-C8) straight-chain or branched alkyl;
R4represents (C1-C3), (C5-C8) straight chain or branched chain alkyl.
Preferably, some of the compounds of the present invention are:
(20S,24R) -epoxy-3 β -oxy- [2- (N' -Fmoc) -5-aminobutyryl ] -dammarane-12 β, 25-diol;
(20S,24S) -epoxy-3 β -oxy- [2- (N' -Fmoc) -5-aminobutyryl ] -dammarane-12 β, 25-diol;
(20S,24R) -epoxy-3 β -oxy- [2- (N' -Fmoc) -6-aminopentanoyl ] -dammarane-12 β, 25-diol;
(20S,24S) -epoxy-3 β -oxy- [2- (N' -Fmoc) -6-aminopentanoyl ] -dammarane-12 β, 25-diol;
(20S,24R) -epoxy-3 β -oxy- [ 2-amino-5- (5-dimethylamino-1-naphthalenesulfonamide) butanoyl ] -dammarane-12 β, 25-diol;
(20S,24S) -epoxy-3 β -oxy- [ 2-amino-5- (5-dimethylamino-1-naphthalenesulfonamide) butanoyl ] -dammarane-12 β, 25-diol;
(20S,24R) -epoxy-3 β -oxy- [ 2-amino-6- (5-dimethylamino-1-naphthalenesulfonamide) valeryl ] -dammarane-12 β, 25-diol;
(20S,24S) -epoxy-3 β -oxy- [ 2-amino-6- (5-dimethylamino-1-naphthalenesulfonamide) valeryl ] -dammarane-12 β, 25-diol;
(20S,24R) -epoxy-3 β -oxy- [2- (5-dimethylamino-1-naphthalenesulfonamide) -6-aminocaproyl ] -dammarane-12 β, 25-diol;
(20S,24S) -epoxy-3 β -oxy- [2- (5-dimethylamino-1-naphthalenesulfonamide) -6-aminocaproyl ] -dammarane-12 β, 25-diol.
The preparation method of the oxtriptolone type ginsenoside derivative comprises the following steps:
a.20 (S) -protopanaxadiol is used as a raw material, and acetic anhydride protects hydroxyl at C-3 and C-12 positions;
b. oxidizing m-chloroperoxybenzoic acid to ensure that a tetrahydrofuran ring is formed at the C-24 position;
c. removing the protecting groups at C-3 and C-12 positions by sodium hydroxide;
d. under the catalysis of DMAP and EDCI, reacting with different Boc-amino acid and Fmoc-Boc-amino acid;
e. removing Boc protecting group under the catalysis of trifluoroacetic acid to obtain a crude product, and purifying by column chromatography to obtain a target compound;
f. reacting amino with dansyl chloride under the catalysis of DIEA;
g. removing Fmoc protection under piperidine catalysis to obtain a crude product, and purifying by column chromatography to obtain the target compound.
The invention comprises a compound of formula (I) or a salt thereof and a pharmaceutically acceptable carrier for the manufacture of a medicament for the treatment of diseases or conditions in mammals, preferably humans, including sepsis, pneumonia, meningitis, endocarditis, bone and joint infections, burn infections, surgical and wound infections, skin infections, and the like.
The application of the oxtriptolone type ginsenoside derivative shown in the general formula (I) and the medically acceptable salt thereof in preparing antibacterial drugs.
Preferably, the oxtriptolone type ginsenoside derivative shown in the general formula (I) and the medically acceptable salt thereof are applied to the preparation of the methicillin-resistant staphylococcus aureus antibacterial drug.
Drug-resistant staphylococcus aureus strains such as methicillin-resistant staphylococcus aureus (MRSA) have drug resistance to beta-lactam antibiotics, and are resistant to most of aminoglycosides, fluoroquinolones, macrolides and other antibacterial drugs, and even vancomycin-resistant MRSA strains have appeared in some areas. However, the antibacterial activity result of the invention shows that the inhibition effect of the oxtriptolone type ginsenoside derivative obtained by structural modification and reformation on methicillin-resistant staphylococcus aureus is obviously enhanced. The oxtriptolone type ginsenoside derivative has a good antibacterial effect, and compared with an oxtriptolone type ginsenoside parent nucleus, the oxtriptolone type ginsenoside derivative disclosed by the invention has the advantages that the examples 1-10 shown in the invention have good activity on methicillin-resistant staphylococcus aureus, and the MIC value is mainly distributed in the range of 1-16 mu g/mL, so that the oxtriptolone type ginsenoside derivative can be used for preparing antibacterial infection medicines. Therefore, the derivative disclosed by the invention is a novel oxtriptolone type ginsenoside derivative with methicillin-resistant staphylococcus aureus antibacterial activity.
Therefore, the invention provides an oxtriptolone type ginsenoside derivative which has better drug-resistant antibacterial activity and a preparation method thereof. Compared with an ocreten-type ginsenoside mother nucleus, the ocreten-type ginsenoside derivative has better antibacterial activity on methicillin-resistant staphylococcus aureus, and the MIC value is within the range of 1-16 mu g/mL. The invention provides application of a medicament for preparing methicillin-resistant staphylococcus aureus (MRSA) infection diseases or symptoms.
Detailed Description
The present invention will be described in further detail below by way of examples, but the present invention is not limited to only the following examples.
Example 1
(20S,24R) -epoxy-3 beta-oxy- [2- (N' -Fmoc) -5-aminobutyryl ] -dammarane-12 beta, 25-diol
20(S) -Protopanaxadiol (500.0mg, 1.1mmol) was dissolved in chloroform (3.0mL), DMAP (20.0mg, 0.2mmol) was added and stirred, then acetic anhydride (0.4mL, 4.4mmol) was slowly added dropwise and stirred at room temperature for 1 h. Diluting with ethyl acetate (20.0mL), washing with 10% hydrochloric acid until acidic, washing with water, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography (petroleum ether: ethyl acetate: 10:1) to obtain 20(S) -3, 12-diacetyl protopanaxadiol (500.0mg, 85%) as a white solid.
20(S) -3, 12-diacetyl protopanaxadiol (210.0mg, 0.4mmol) was dissolved in anhydrous dichloromethane (6.0mL), a solution of m-chloroperoxybenzoic acid (190.0mg, 0.2mmol, 75%) in dichloromethane (5.0mL) was slowly added dropwise with ice salt bath precooling, and after 0.5h, the reaction was allowed to warm to room temperature and stirred for 2 h. Adding isopropanol (1.0mL), stirring for 1h, adding saturated sodium bicarbonate solution, stirring for 1h, separating, extracting, sequentially washing the organic phase with saturated sodium thiosulfate solution, water and saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography (petroleum ether: ethyl acetate: 8:1) to obtain 20(S) -20, 24-epoxy-3, 12-diacetyl protopanaxadiol (146.0mg, 70.0%) as a white solid.
20(S) -20, 24-epoxy-3, 12-diacetyl protopanaxadiol (130.0mg, 0.2mmol) was dissolved in methanol (8.0mL), potassium hydroxide (85.0mg, 1.5mmol) was added, and the reaction was stirred at 135 ℃ for 2 h. After the reaction solution is cooled to room temperature, a proper amount of water is added, a large amount of white solid is precipitated, and then the mixture is filtered, dried and subjected to column chromatography (petroleum ether: ethyl acetate: 2:1-1:1) to obtain compounds OR { (20S,24R) -epoxy dammarane-3, 12, 25-triol, 66.0mg } and OS { (20S,24S) -epoxy dammarane-3, 12, 25-triol, 50.0mg }.
OR (80.0mg, 0.2mmol) was dissolved in anhydrous dichloromethane (5.0mL), and 4-dimethylaminopyridine (56.0mg, 0.5mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (96.0mg, 0.5mmol) and (R) -4- (Boc-amino) -2- (Fmoc-amino) butanoic acid (110.0mg, 0.3mmol) were added and reacted at room temperature for 3 h. The reaction solution was diluted with dichloromethane, washed with 5% hydrochloric acid, deionized water, saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The dried intermediate was dissolved in anhydrous dichloromethane, and excess trifluoroacetic acid was added to react at room temperature for 1 h. The reaction solution was distilled under reduced pressure and subjected to silica gel column chromatography (chloroform: methanol: 80:1 to 50:1) to obtain a white solid (0.1g, 77.4%).1H-NMR(CDCl3,400MHz)(ppm):8.27(s,2H,-NH2),7.70(d,J＝7.6Hz,2H,Ar-H×2),7.55(d,J＝6.6Hz,2H,Ar-H×2),7.34(t,J＝7.4Hz,2H,Ar-H×2),7.26(t,J＝7.5Hz,2H,Ar-H×2),6.20(d,J＝7.4Hz,1H,-NH-),4.47(d,J＝7.3Hz,1H,-OCH-),4.32(d,J＝6.5Hz,3H,-OCH2-,-NCH-),4.14(t,J＝6.8Hz,1H,-CH-),3.81(t,J＝7.6Hz,1H,-OCH-),3.60–3.47(m,1H,-OCH-),3.04(d,J＝43.0Hz,2H,-NCH2-),2.23(d,J＝55.9Hz,2H,-CH2-),1.26(s,3H,-CH3),1.24(s,3H,-CH3),1.22(s,3H,-CH3),1.09(s,3H,-CH3),0.94(s,3H,-CH3),0.86(s,3H,-CH3),0.82(s,3H,-CH3),0.79(s,3H,-CH3).
Example 2
(20S,24S) -epoxy-3 β -oxy- [2- (N' -Fmoc) -5-aminobutyryl]Dammarane-12 β, 25-diol to OS (80.0mg, 0)2mmol) was dissolved in anhydrous dichloromethane (5.0mL), and 4-dimethylaminopyridine (56.0mg, 0.5mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (96.0mg, 0.5mmol) and (R) -4- (Boc-amino) -2- (Fmoc-amino) butyric acid (110.0g, 0.3mmol) were added and reacted at room temperature for 3 h. The reaction solution was diluted with dichloromethane, washed with 5% hydrochloric acid, deionized water, saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The dried intermediate was dissolved in anhydrous dichloromethane, and excess trifluoroacetic acid was added to react at room temperature for 1 h. The reaction solution was distilled under reduced pressure and subjected to silica gel column chromatography (chloroform: methanol: 80:1-50:1) to obtain a white solid (94.3mg, 70.1%).1H-NMR(CDCl3,400MHz)(ppm):8.24(s,2H,-NH2),7.69(d,J＝7.5Hz,2H,Ar-H×2),7.54(d,J＝5.6Hz,2H,Ar-H×2),7.34(t,J＝7.4Hz,2H,Ar-H×2),7.25(t,J＝7.4Hz,3H,Ar-H×2),6.13(d,J＝7.5Hz,1H,-NH-),4.55–4.43(m,1H,-OCH-),4.40–4.26(m,3H,-OCH2-,-NCH-),4.13(t,J＝6.9Hz,1H,-CH-),3.92–3.79(m,1H,-OCH-),3.50(s,1H,-OCH-),3.02(d,J＝55.7Hz,2H,-NCH2-),2.26(d,J＝41.9Hz,2H,-CH2-),1.24(s,3H,-CH3),1.23(s,3H,-CH3),1.18(s,3H,-CH3),1.10(s,3H,-CH3),0.96(s,3H,-CH3),0.85(s,3H,-CH3),0.84(s,3H,-CH3),0.79(s,3H,-CH3).
Example 3
(20S,24R) -epoxy-3 beta-oxy- [2- (N' -Fmoc) -6-aminopentanoyl ] -dammarane-12 beta, 25-diol
Reference (20S,24R) -epoxy-3 β -oxy- [2- (N' -Fmoc) -5-aminobutyryl]Synthesis of (E) -dammarane-12 β, 25-diol, OR reacted with N-Fmoc-N' -Boc-L-ornithine to remove the Boc protecting group to give a white solid (95.1mg, 69.9%).1H-NMR(CDCl3,400MHz)(ppm):8.01(s,2H,-NH2),7.69(d,J＝7.5Hz,2H,Ar-H×2),7.54(t,J＝7.0Hz,2H,Ar-H×2),7.32(t,J＝7.5Hz,2H,Ar-H×2),7.24(d,J＝5.7Hz,2H,Ar-H×2),5.84(d,J＝8.0Hz,1H,-NH-),4.50–4.38(m,1H,-OCH-),4.27(d,J＝6.8Hz,3H,-OCH2-,-NCH-),4.12(t,J＝7.0Hz,1H,-CH-),3.86–3.77(m,1H,-OCH-),3.48(dd,J＝10.2,4.1Hz,1H,-OCH-),2.95(s,2H,-NCH2-),1.25(s,3H,-CH3),1.24(s,6H,-CH3×2),1.08(s,3H,-CH3),0.93(s,3H,-CH3),0.83(s,3H,-CH3),0.79(s,3H,-CH3),0.75(s,3H,-CH3).
Example 4
(20S,24S) -epoxy-3 beta-oxy- [2- (N' -Fmoc) -6-aminopentanoyl ] -dammarane-12 beta, 25-diol
Reference (20S,24S) -epoxy-3 β -oxy- [2- (N' -Fmoc) -5-aminobutyryl]Synthesis of (E) -dammarane-12 β, 25-diol, OS reacted with N-Fmoc-N' -Boc-L-ornithine to remove the Boc protecting group to give a white solid (92.0mg, 67.8%).1H-NMR(CDCl3,400MHz)(ppm):8.07(s,2H,-NH2),7.69(d,J＝7.5Hz,2H,Ar-H×2),7.55(t,J＝6.3Hz,2H,Ar-H×2),7.33(t,J＝7.5Hz,2H,Ar-H×2),7.24(t,J＝7.4Hz,2H,Ar-H×2),5.83(d,J＝8.0Hz,1H,-NH-),4.47(t,J＝8.7Hz,1H,-OCH-),4.28(d,J＝6.6Hz,3H,-OCH2-,-NCH-),4.13(t,J＝7.1Hz,1H,-CH-),3.90–3.81(m,1H,-OCH-),3.54–3.44(m,1H,-OCH-),2.97(s,2H,-NCH2-),1.24(s,3H,-CH3),1.19(s,3H,-CH3),1.09(s,3H,-CH3),0.96(s,3H,-CH3),0.85(s,3H,-CH3),0.84(s,3H,-CH3),0.77(s,3H,-CH3),0.76(s,3H,-CH3).
Example 5
(20S,24R) -epoxy-3 beta-oxy- [ 2-amino- (5-dimethylamino-1-naphthalenesulfonamide) butanoyl ] -dammarane-12 beta, 25-diol
The title compound (20S,24R) -epoxy-3 β -oxy- [2- (N' -Fmoc) -5-aminobutyryl ] obtained in example 1 was added]Dissolving dammarane-12 β, 25-diol (60.0mg, 0.1mmol) in anhydrous dichloromethane (5.0mL), adding N, N-diisopropylethylamine (36.0mg, 0.3mmol), dansyl chloride (24.0mg, 0.1mmol), reacting at room temperature for 4h, diluting the reaction solution with dichloromethane, washing with 5% hydrochloric acid, washing with deionized water, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, and concentrating to obtain an intermediate, dissolving the dried intermediate in anhydrous dichloromethane, adding excess piperidine, reacting at room temperature for 2h, distilling the reaction solution under reduced pressure, and performing silica gel column chromatography (chloroform: methanol: 100:1-50:1) to obtain a pale green solid v-5 (44.0mg, 72.2%).1H-NMR(CDCl3,400MHz)(ppm):8.50(dt,J＝8.5,1.0Hz,1H,Ar-H),8.27(d,J＝8.7Hz,1H,Ar-H),8.22(dd,J＝7.3,1.3Hz,1H,Ar-H),7.51(ddd,J＝14.7,8.6,7.4Hz,2H,Ar-H×2),7.16(dd,J＝7.6,0.7Hz,1H,Ar-H),5.60(s,1H,-OH),4.36(dd,J＝10.6,5.9Hz,1H,-OCH-),3.82(dd,J＝8.8,6.5Hz,1H,-OCH-),3.49–3.42(m,1H,-OCH-),3.30(dd,J＝9.6,3.5Hz,1H,-NH2CH-),3.14(dd,J＝11.7,7.4Hz,1H,-NCH2-),3.01–2.91(m,1H,-NCH2-),2.87(s,6H,-CH3×2),1.25(s,3H,-CH3),1.24(s,3H,-CH3),1.07(s,3H,-CH3),0.94(s,3H,-CH3),0.86(s,3H,-CH3),0.81(s,3H,-CH3),0.73(s,3H,-CH3),0.72(s,3H,-CH3).
Example 6
(20S,24S) -epoxy-3 β -oxy- [ 2-amino- (5-dimethylamino-1-naphthalenesulfonamide) butanoyl][ DAMAALE-12 β, 25-DIOL referring to the synthesis procedure of example 5, (20S,24S) -epoxy-3 β -oxy- [2- (N' -Fmoc) -5-aminobutyryl group, the title compound obtained in example 2, was synthesized]Reaction of-dammarane-12 β, 25-diol with dansyl chloride followed by removal of the Fmoc protecting group gave V-6 as a pale green solid (42.1mg, 69.6%).1H-NMR(CDCl3,400MHz)(ppm):8.51(d,J＝8.4Hz,1H,Ar-H),8.27(d,J＝8.6Hz,1H,Ar-H),8.22(d,J＝7.3Hz,1H,Ar-H),7.56(s,1H,Ar-H),7.52–7.47(m,1H,Ar-H),7.17(d,J＝7.5Hz,1H,Ar-H),5.75(s,1H,-OH),4.38(dd,J＝10.8,5.8Hz,1H,-OCH-),3.85(dd,J＝10.9,5.3Hz,1H,-OCH-),3.50(td,J＝9.8,4.7Hz,1H,-OCH-),3.30(dd,J＝9.7,3.5Hz,1H,-NH2CH-),3.20–3.12(m,1H,-NCH2-),2.97(dd,J＝8.9,4.2Hz,1H,-NCH2-),2.87(s,6H,-CH3×2),1.26(s,3H,-CH3),1.23(s,3H,-CH3),1.08(s,3H,-CH3),0.98(s,3H,-CH3),0.88(s,3H,-CH3),0.86(s,3H,-CH3),0.75(s,3H,-CH3),0.74(s,3H,-CH3).
Example 7
(20S,24R) -epoxy-3 beta-oxy- [ 2-amino- (5-dimethylamino-1-naphthalenesulfonamide) pentanoyl ] -dammarane-12 beta, 25-diol
Example 3 was obtained by reference to the synthesis of example 5The target compound of (20S,24R) -epoxy-3 β -oxy- [2- (N' -Fmoc) -6-aminoornityl]Reaction of dammarane-12 β, 25-diol with dansyl chloride followed by removal of the Fmoc protecting group gave V-7 as a pale green solid (40.0mg, 65.1%).1H-NMR(CDCl3,400MHz)(ppm):8.50(d,J＝8.5Hz,1H,Ar-H),8.29(d,J＝8.7Hz,1H,Ar-H),8.21(dd,J＝7.3,1.3Hz,1H,Ar-H),7.55–7.50(m,1H,Ar-H),7.51–7.46(m,1H,Ar-H),7.15(d,J＝7.5Hz,1H,Ar-H),5.57(s,1H.-OH),4.47–4.39(m,1H,-OCH-),3.82(dd,J＝8.8,6.6Hz,1H,-OCH-),3.49(td,J＝10.5,4.6Hz,1H,-OCH-),3.21(dd,J＝8.6,4.1Hz,1H,-NH2CH-),2.99–2.91(m,1H,-NCH2-),2.86(s,6H,-CH3×2),2.81(ddd,J＝12.7,7.5,5.4Hz,1H,-NCH2-),1.25(s,3H,-CH3),1.24(s,3H,-CH3),1.07(s,3H,-CH3),0.96(s,3H,-CH3),0.87(s,3H,-CH3),0.84(s,3H,-CH3),0.77(s,3H,-CH3),0.74(s,3H,-CH3).
Example 8
(20S,24S) -epoxy-3 β -oxy- [ 2-amino- (5-dimethylamino-1-naphthalenesulfonamide) pentanoyl][ 12- (N '-Fmoc) -6-Aminoornyl ] -dammarane-12 β, 25-diol the title compound (20S,24S) -epoxy-3 β -oxy- [2- (N' -Fmoc) -6-aminoornityl ] obtained in example 4 was synthesized according to the procedure of example 5]Reaction of dammarane-12 β, 25-diol with dansyl chloride followed by removal of the Fmoc protecting group gave V-8 as a pale green solid (39.1mg, 63.4%).1H-NMR(CDCl3,400MHz)(ppm):8.51(d,J＝10.6Hz,1H,Ar-H),8.29(d,J＝8.7Hz,1H,Ar-H),8.24–8.19(m,1H,Ar-H),7.58–7.52(m,1H,Ar-H),7.53–7.47(m,1H,Ar-H),7.16(d,J＝8.3Hz,1H,Ar-H),5.75(s,1H,-OH),4.44(dd,J＝9.3,7.2Hz,1H,-OCH-),3.86(dd,J＝10.8,5.4Hz,1H,-OCH-),3.51(td,J＝10.3,4.8Hz,1H,-OCH-),3.23(dd,J＝8.7,4.1Hz,1H,-NH2CH-),3.01–2.91(m,1H,-NCH2-),2.87(s,6H,-CH3×2),2.80(ddd,J＝12.7,7.6,5.3Hz,1H,-NCH2-),1.26(s,3H,-CH3),1.23(s,3H,-CH3),1.08(s,3H,-CH3),0.99(s,3H,-CH3),0.89(s,3H,-CH3),0.88(s,3H,-CH3),0.79(s,3H,-CH3),0.75(s,3H,-CH3).
Example 9
(20S,24R) -epoxy-3 beta-oxy- [2- (5-dimethylamino-1-naphthalenesulfonamide) -6-aminocaproyl ] -dammarane-12 beta, 25-diol
Referring to example 1, OR (80.0mg, 0.2mmol) was dissolved in anhydrous dichloromethane (5.0mL), and 4-dimethylaminopyridine (56.0mg, 0.5mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (96.1mg, 0.5mmol) and N-Boc-N' -Fmoc-L-lysine (116.0mg, 0.3mmol) were added and reacted at room temperature for 3 h. The reaction solution was diluted with dichloromethane, washed with 5% hydrochloric acid, deionized water, saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to give yellow intermediate X1. Dissolving the dried intermediate X1 in anhydrous dichloromethane, adding excess trifluoroacetic acid (1.0ml, 13.4mmol), reacting at room temperature for 1h, and distilling the reaction solution under reduced pressure to obtain yellow intermediate X2. The dried intermediate X2 was dissolved in anhydrous dichloromethane (5.0ml), N-diisopropylethylamine (36.0mg, 0.3mmol), dansyl chloride (24.2mg, 0.1mmol) were added and reacted at room temperature for 4h, after which the Fmoc protecting group was removed and column chromatography on silica gel gave V-9 as a pale green solid (80.1mg, 57.4%).1H-NMR(CDCl3,400MHz)(ppm):8.51(d,J＝8.5Hz,1H,Ar-H),8.29(d,J＝8.7Hz,1H,Ar-H),8.21(d,J＝7.3Hz,1H,Ar-H),7.60–7.52(m,1H,Ar-H),7.52–7.44(m,1H,Ar-H),7.16(d,J＝6.8Hz,1H,Ar-H),4.15(dd,J＝11.8,4.5Hz,1H,-OCH-),3.86–3.78(m,2H,-OCH-,COCH-),3.53–3.41(m,1H,-OCH-),2.85(s,6H,-CH3×2),1.26(s,3H,-CH3),1.24(s,3H,-CH3),1.08(s,3H,-CH3),0.93(s,3H,-CH3),0.83(s,3H,-CH3),0.77(s,3H,-CH3),0.67(s,3H,-CH3),0.66(s,3H,-CH3).
Example 10
(20S,24S) -epoxy-3 beta-oxy- [2- (5-dimethylamino-1-naphthalenesulfonamide) -6-aminocaproyl ] -dammarane-12 beta, 25-diol
OS (80.0mg, 0.2mmol) was dissolved in anhydrous dichloromethane (5.0mL), 4-dimethylaminopyridine (56.0mg, 0.5mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (96.0mg, 0.5mmol) and N-Boc-N' -Fmoc-L-lysine (116.2mg, 0.3mmol) were added and reacted at room temperature for 3 h. The reaction solution was diluted with dichloromethane, washed with 5% hydrochloric acid, deionized water, saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain a white intermediate X3. Dissolving the dried intermediate X3 in anhydrous dichloromethane, adding excessive trifluoroacetic acid (1.0ml, 13.4mmol), reacting at room temperature for 1h, and distilling the reaction solution under reduced pressure to obtain white intermediate X4. Dissolving dried intermediate X4 in anhydrous dichloromethane (5.0ml), adding N, N-diisopropylethylamine (36.1mg, 0.3mmol) and dansyl chloride (24.0mg, 0.1mmol) for reaction, removing Fmoc protecting group, and performing silica gel column chromatography to obtain light green solid V-10 (80.1mg, 57.4%)
1H-NMR(CDCl3,400MHz)(ppm):8.48(d,J＝8.5Hz,1H,Ar-H),8.32(d,J＝8.7Hz,1H,Ar-H),8.20(dd,J＝7.3,1.1Hz,1H,Ar-H),7.58–7.52(m,1H,Ar-H),7.45(dd,J＝8.5,7.4Hz,1H,Ar-H),7.14(d,J＝7.5Hz,1H,Ar-H),5.72(s,1H,-OH),4.11(dd,J＝11.8,4.4Hz,1H,-OCH-),3.90–3.77(m,2H,-OCH-,COCH-),3.46(td,J＝10.1,4.5Hz,1H,-OCH-),2.83(s,6H,-CH3×2),1.24(s,3H,-CH3),1.21(s,3H,-CH3),1.08(s,3H,-CH3),0.94(s,3H,-CH3),0.83(s,3H,-CH3),0.77(s,3H,-CH3),0.62(s,3H,-CH3),0.61(s,3H,-CH3).
Pharmacological tests prove that the oxtriptolone type ginsenoside derivative has a good antibacterial effect and can be used for preparing anti-infective medicaments.
The following are the results of pharmacological experiments with some of the compounds of the invention.
1 instruments and devices:
water-proof constant temperature incubator: model GNP-9080, Shanghai sperm macro laboratory Equipment Co., Ltd
An enzyme-labeling instrument: model 800TS, Serial No. 17101018, BioTek instruments, Inc
An electronic balance: model PL203, MettlerToledo group
An electronic balance: model DT1000, Normal commercial weighing apparatus factory
Vertical pressure steam sterilizer: model LDZX-75KBS, Shanghai Shenan medical instruments factory
2 cell lines and reagents:
dimethyl sulfoxide (DMSO)
Sodium chloride injection
MH broth (MHB)
MH (A) Medium
Selecting bacteria: methicillin-resistant Staphylococcus aureus MRSA18-19, MRSA18-20, ATCC 29213.
MH (MH A) medium streaking, incubating at 35-37 deg.C for 24 hr, picking single colony, and adjusting to about 0.5 McLeod unit by McLeod turbidimetry8CFU/ml), and then 100-fold dilution of the suspension with MHB medium to a final concentration of about 106CFU/ml。
3, experimental method:
a two-fold dilution of the broth in trace amounts recommended by the national Committee for standardization of clinical laboratories (ClinicaldLaboratyStandardsInstituteCLSI) was used.
The concentration of the experimental drug is set to be within the range of 128-0.008 mu g/ml by two-fold dilution, and the concentration is properly adjusted according to the actual situation.
Dissolving a certain amount of tested medicine with DMSO as an aid, diluting with MHB culture medium to obtain tested medicine solution with the concentration of 256 mu g/ml, adding 200 mu l of each tested medicine solution into the first hole of a 96-hole plate, adding 100 mu l of MHB culture medium into each of the other holes, diluting to 0.08 mu g/ml in a double way, sucking 100 mu l of liquid out of the tail hole, discarding to obtain a hole plate with the medicine concentration of 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03, 0.015 and 0.008 mu g/ml in a double way, adding 100 mu l of diluted corresponding bacterial liquid into each hole, and mixing uniformly to obtain the bacterial liquid with the final concentration of 5 × 105CFU/ml. A test drug control group, a bacteria control group (100. mu.l of bacteria solution + 100. mu.l of MHB culture medium), a vehicle bacteria control group (100. mu.l of bacteria solution + 100. mu.l of DMSOMHB culture medium) and a vehicle culture medium blank control group (200. mu.l of 1% DMSOMHB culture medium) are also arranged. And (3) placing the hole plate in an incubator for 20 hours at 35-37 ℃, measuring the A600 value of each hole by using a microplate reader, judging whether bacteria grow in each hole or not, and determining the MIC value of each hole.
4, experimental results:
the experiment selects 18-19 and 18-20 methicillin-resistant staphylococcus aureus (MRSA) as clinical separated pathogenic bacteria collected in 2018 Chengdu area. MRSA18-19 and MRSA18-20 are identified by a VITEK-60 automatic microorganism identifier and then identified by a conventional laboratory method. ATCC29213 is an outsourced instruction strain with certificate of identification.
The results of the activity measurements are shown in Table 1.
TABLE 1 in vitro antibacterial Activity of oxtriptolone type ginsenoside derivatives
Figure BDA0002541728210000091
The antibacterial activity result shows that the inhibition rates of the 24(R) -configuration ocotillol type ginsenoside OR of the oxcotion trombone type ginsenoside derivative on methicillin-resistant staphylococcus aureus MRSA18-19, MRSA18-20 and ATCC29213 are all more than 128 mu g/mL. Examples 1, 3, 5, 7 and 9 are derivatives having OR as the parent nucleus, and their MIC values are in the range of 2 to 64. mu.g/mL. Among them, example 3 had the strongest inhibitory activity against MRSA18-20, and had a MIC of 2 μ g/mL, which was significantly stronger than that of the parent OR. The inhibition rate of 24(S) -configuration ocotillol type ginsenoside OS on methicillin-resistant staphylococcus aureus MRSA18-19, MRSA18-20 and ATCC29213 is 64 mu g/mL. In the examples obtained by using OS as the mother nucleus, the inhibition rates of example 2 to MRSA18-19, MRSA18-20 and ATCC29213 were all 1. mu.g/mL, and the inhibition effect to drug-resistant bacteria was significantly stronger than that of the mother nucleus.
Currently, drug-resistant staphylococcus aureus strains such as methicillin-resistant staphylococcus aureus (MRSA) are resistant to β -lactam antibiotics and resistant to many antibacterial drugs such as aminoglycosides, fluoroquinolones, macrolides, and the like. Moreover, the MRSA drug resistance develops rapidly, and compared with the quality control strain commonly used in a laboratory, the clinically isolated pathogenic bacteria often have stronger drug resistance. However, the antibacterial activity result of the invention shows that the inhibition effect of the oxtriptolone type ginsenoside derivative obtained after structural modification and reformation on methicillin-resistant staphylococcus aureus is obviously enhanced.
Although the preferred embodiments of the present invention have been described in detail, the present invention is not limited to the details of the embodiments, and various equivalent modifications can be made within the technical spirit of the present invention, and the scope of the present invention is also within the scope of the present invention. It should be noted that the various features described in the above embodiments may be combined in any suitable manner without departing from the scope of the invention. The invention is not described in detail in order to avoid unnecessary repetition. In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.

Claims (6)

1. The oxtriptolone type ginsenoside derivative shown in the general formula (I) and the medically acceptable salt thereof are characterized in that the structural formula is as follows
Figure FDA0002541728200000011
Wherein the content of the first and second substances,
R1represents-NH2、-R3NH2、
Figure FDA0002541728200000012
-CH3、H、
Figure FDA0002541728200000013
R2Represents
Figure FDA0002541728200000014
R3Represents (C1-C8) straight-chain or branched alkyl;
R4represents (C1-C3), (C5-C8) straight chain or branched chain alkyl.
2. The derivative and the pharmaceutically acceptable salt thereof according to claim 1,
R1represents-NH2、-R3NH2、
Figure FDA0002541728200000015
-CH3、H、
Figure FDA0002541728200000016
R2Represents
Figure FDA0002541728200000017
R3Represents (C1-C8) straight-chain or branched alkyl;
R4represents (C1-C3), (C5-C8) straight chain or branched chain alkyl.
3. The derivative and the pharmaceutically acceptable salt thereof according to claim 2,
(20S,24R) -epoxy-3 β -oxy- [2- (N' -Fmoc) -5-aminobutyryl ] -dammarane-12 β, 25-diol;
(20S,24S) -epoxy-3 β -oxy- [2- (N' -Fmoc) -5-aminobutyryl ] -dammarane-12 β, 25-diol;
(20S,24R) -epoxy-3 β -oxy- [2- (N' -Fmoc) -6-aminopentanoyl ] -dammarane-12 β, 25-diol;
(20S,24S) -epoxy-3 β -oxy- [2- (N' -Fmoc) -6-aminopentanoyl ] -dammarane-12 β, 25-diol;
(20S,24R) -epoxy-3 β -oxy- [ 2-amino-5- (5-dimethylamino-1-naphthalenesulfonamide) butanoyl ] -dammarane-12 β, 25-diol;
(20S,24S) -epoxy-3 β -oxy- [ 2-amino-5- (5-dimethylamino-1-naphthalenesulfonamide) butanoyl ] -dammarane-12 β, 25-diol;
(20S,24R) -epoxy-3 β -oxy- [ 2-amino-6- (5-dimethylamino-1-naphthalenesulfonamide) valeryl ] -dammarane-12 β, 25-diol;
(20S,24S) -epoxy-3 β -oxy- [ 2-amino-6- (5-dimethylamino-1-naphthalenesulfonamide) valeryl ] -dammarane-12 β, 25-diol;
(20S,24R) -epoxy-3 β -oxy- [2- (5-dimethylamino-1-naphthalenesulfonamide) -6-aminocaproyl ] -dammarane-12 β, 25-diol;
(20S,24S) -epoxy-3 β -oxy- [2- (5-dimethylamino-1-naphthalenesulfonamide) -6-aminocaproyl ] -dammarane-12 β, 25-diol.
4. Use of ocotillol-type ginsenoside derivatives of general formula (I) according to claim 1, 2 or 3 and pharmaceutically acceptable salts thereof for the preparation of antibacterial agents.
5. The use according to claim 4, characterized in that the oxtriptolone type ginsenoside derivative shown in the general formula (I) and the medically acceptable salt thereof are used for preparing the methicillin-resistant staphylococcus aureus antibacterial medicament.
6. A method for preparing an oxtriptolone-type ginsenoside derivative represented by the general formula (I) as claimed in claim 1, 2 or 3, which comprises the steps of:
a.20 (S) -protopanaxadiol is used as a raw material, and acetic anhydride protects hydroxyl at C-3 and C-12 positions;
b. oxidizing m-chloroperoxybenzoic acid to ensure that a tetrahydrofuran ring is formed at the C-24 position;
c. removing the protecting groups at C-3 and C-12 positions by sodium hydroxide;
d. under the catalysis of DMAP and EDCI, reacting with different Boc-amino acid and Fmoc-Boc-amino acid;
e. removing Boc protecting group under the catalysis of trifluoroacetic acid to obtain a crude product, and purifying by column chromatography to obtain a target compound;
f. reacting amino with dansyl chloride under the catalysis of DIEA;
g. removing Fmoc protection under piperidine catalysis to obtain a crude product, and purifying by column chromatography to obtain the target compound.
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