CN110776432B - Safflower octal mannich base derivative and preparation method and application thereof - Google Patents
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Abstract
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 as follows: (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.
Description
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 drug resistance has become a major challenge in the global public health field and is also a worldwide issue of widespread concern for governments and society of various countries. MRSA is a common gram-positive pathogen in clinic, has strong toxicity, can cause septicemia, necrotizing pneumonia, meningitis, osteomyelitis, endocarditis and the like, and has the 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 safflower is only reported, and although the earlier research of the subject group has found that illicium alcohol safflower has certain antibacterial effect on staphylococcus aureus and MRSA (Liu Ji et al 2017.CN 106822068), no further publication exists on how to develop a new MRSA infection resisting medicine 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 carthamus tinctorius octal alcohol Mannich base derivative comprises the following specific steps: dissolving carthamus tinctorius octal alcohol in 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 compound 1 with dichloromethane (dichloromethane), dropwise adding concentrated hydrochloric acid, removing dichloromethane under reduced pressure 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, wherein the yield is 93%; 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 with the yield of 60 percent, wherein the pure products of the compounds 1 to 7 are the octandiol mannich base derivatives;
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 amine methylation reaction is 100-120 ℃, and the time of the amine methylation reaction is 3-9h;
the concentrated hydrochloric acid is 36-38% by mass;
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 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 compound 1,2,6,7 were between 1-2. Mu.g/mL for both standard Staphylococcus aureus 29213 and MRSA. Therefore, the compound of the invention can be used as a new antibacterial candidate drug, thereby solving the problem of drug-resistant bacteria faced worldwide at present.
Drawings
FIG. 1 is an infrared spectrum (IR) of Compound 6 of the present invention.
FIG. 2 is a NMR 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 sterilization 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.
Example 1:
the preparation method of the pure product of the compound 1 comprises the following steps: dissolving 50.0mg of octandiol safflower with 2mL of toluene, respectively adding 30.6mg of formaldehyde aqueous solution with the mass percent concentration of 37% and 42.4mg of dimethylamine aqueous solution with the mass percent concentration of 40%, respectively reacting for 5h at 110 ℃, dissolving with dichloromethane after the reaction is finished, and separating by using thin layer chromatography to obtain a pure compound 1 with the yield of 93%.
Or dissolving 50.0mg of octandiol safflower with 2mL of toluene, respectively adding 30.6mg of formaldehyde aqueous solution with the mass percentage concentration of 37% and 42.4mg of dimethylamine aqueous solution with the mass percentage concentration of 40%, respectively reacting for 3h, 4h,6h, 7h, 8h or 9h at 100 ℃ or 120 ℃, after the reaction is finished, dissolving with dichloromethane, and separating by using a thin layer chromatography to obtain a pure compound 1 with the yield of 93%;
the chemical structural formula of the pure product of the compound 1 is as follows:
physicochemical properties of the pure product of compound 1:
1) Brown solid, m.p. 171-172 ℃.
2) Infrared spectrogram (IR) characteristics of the compound:
by using potassium bromideTabletting method: 3433cm -1 For the stretching vibration absorption of phenolic hydroxyl, 3074,2923cm -1 Respectively unsaturated and saturated hydrocarbon telescopic vibration absorption of 1637cm -1 1464cm for absorbing carbon-carbon double bond stretching vibration -1 The vibration absorption of the aromatic ring skeleton is realized.
3) NMR spectrum of the compound (A) 1 H NMR,400 MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows: δ 7.13 (s, 2H, -Ar), 7.12 (s, 2H, -Ar), 6.80 (s, 2H, -Ar), 5.92-6.08 (m, 3H, -CH = CH) 2 ),5.03-5.14(m,6H,-CH＝CH 2 ),3.71(s,4H,-CH 2 -N(CH 3 ) 2 ),3.41(d,J＝6.8Hz,2H,-CH 2 -CH＝CH 2 ),3.32(d,J＝6.4Hz,4H,-CH 2 -CH＝CH 2 ),2.33(s,12H,-CH 3 )。
Example 2
The preparation steps of the pure compound 2 are as follows: dissolving 50.0mg of illicium alcohol safflower in 2mL of toluene, adding 30.6mg of aqueous formaldehyde solution with the mass percentage concentration of 37% and 26.8mg of pyrrolidine, reacting for 5 hours at 110 ℃, dissolving with dichloromethane after the reaction is finished, and separating by thin layer chromatography to obtain a pure compound 2 product with the yield of 78%.
Or dissolving 50.0mg of illicium alcohol safflower in 2mL of toluene, adding 30.6mg of formaldehyde water solution with the mass percentage concentration of 37% and 26.8mg of pyrrolidine, reacting at 100 ℃ or 120 ℃ for 3h, 4h,6h, 7h, 8h or 9h respectively, dissolving with dichloromethane after the reaction is finished, and separating by using thin layer chromatography to obtain a pure compound 2 with the yield of 78%.
The chemical structural formula of the pure compound 2 is as follows:
the physicochemical properties of compound 2 are as follows:
1) Brown solid, m.p. 109-110 ℃.
2) Infrared spectrogram (IR) characteristics of the compound:
by the use of brominePotassium melting tabletting method: 3428cm -1 For the stretching vibration absorption of phenolic hydroxyl groups, 3074,2971 and 2925cm -1 Respectively unsaturated and saturated hydrocarbon telescopic vibration absorption of 1637cm -1 Is 1462cm for absorbing carbon-carbon double bond stretching vibration -1 The vibration absorption of the aromatic ring skeleton is realized.
3) NMR spectrum of the compound (A) 1 H NMR,400 MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows: δ:7.19 (d, J =1.6Hz,2H, -Ar), 7.17 (s, 2H, -Ar), 6.97 (s, 2H, -Ar), 5.99-6.07 (m, 1H, -CH = CH) 2 ),5.92-5.98(m,2H,-CH＝CH 2 ),5.02-5.13(m,6H,-CH＝CH 2 ),4.04(s,4H,N-CH 2 -),3.41(d,J＝6.4Hz,2H,-CH 2 -CH＝CH 2 ),3.34(d,J＝6.4Hz,4H,-CH 2 -CH＝CH 2 ),2.89(s,8H,pyrrolidine),1.79(s,8H,pyrrolidine)。
Example 3
The preparation steps of the pure compound 3 are as follows: dissolving 50.0mg of illicium alcohol safflower in 2mL of toluene, adding 30.6mg of aqueous formaldehyde solution with the mass percentage concentration of 37% and 37.7mg of N-methylpiperazine, reacting for 7 hours at 110 ℃, dissolving with dichloromethane after the reaction is finished, and separating by thin layer chromatography to obtain a pure compound 3 with the yield of 61%.
Or dissolving 50.0mg of illicium alcohol safflower in 2mL of toluene, adding 30.6mg of formaldehyde water solution with the mass percentage concentration of 37% and 37.7mg of N-methylpiperazine, reacting for 3h, 4h, 5h, 6h, 8h or 9h at 100 ℃ or 120 ℃, dissolving with dichloromethane after the reaction is finished, and separating by thin-layer chromatography to obtain the pure compound 3 with the yield of 61%.
The chemical structural formula of the pure compound 3 is as follows:
the physicochemical properties of compound 3 are as follows:
1) Grey solid, melting point 180-181 ℃.
2) Infrared spectrogram (IR) characteristics of the compound:
a potassium bromide tabletting method is adopted: 3431cm -1 2922cm for phenolic hydroxyl group stretching vibration absorption -1 1584cm for saturated hydrocarbon stretching vibration absorption -1 1444cm for absorbing telescopic vibration of carbon-carbon double bonds -1 The vibration absorption of the aromatic ring skeleton is realized.
3) NMR spectrum of the compound (A) 1 H NMR,400 MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows: δ:7.13 (s, 2H, -Ar), 7.11 (d, J =1.6Hz,2H, -Ar), 6.78 (d, J =1.6Hz,2H, -Ar), 5.92-6.09 (m, 3H, -CH = CH) 2 ),5.02-5.15(m,6H,-CH＝CH 2 ),3.71(s,4H,N-CH 2 -),3.41(d,J＝6.8Hz,2H,-CH 2 -CH＝CH 2 ),3.32(d,J＝6.4Hz,4H,-CH 2 -CH＝CH 2 ),2.98(t,J＝11.2Hz,8H,piperazine),2.01-2.18(m,8H,piperazine),1.63(s,3H,-CH 3 ),1.60(s,3H,N-CH 3 )。
Example 4
The preparation method of the pure product of the compound 4 comprises the following steps: dissolving 50.0mg of illicium alcohol safflower in 2mL of toluene, adding 30.6mg of aqueous formaldehyde solution with the mass percentage concentration of 37% and 32.1mg of piperidine, reacting for 7 hours at 110 ℃, dissolving with dichloromethane after the reaction is finished, and separating by thin layer chromatography to obtain a pure compound 4 with the yield of 46%.
Or dissolving 50.0mg of illicium alcohol safflower in 2mL of toluene, adding 30.6mg of formaldehyde water solution with the mass percentage concentration of 37% and 32.1mg of piperidine, reacting at 100 ℃ or 120 ℃ for 3h, 4h, 5h, 6h, 8h or 9h respectively, dissolving with dichloromethane after the reaction is finished, and separating by thin layer chromatography to obtain a pure compound 4 with the yield of 46%.
The chemical structural formula of the pure compound 4 is as follows:
the physicochemical properties of compound 4 are as follows:
1) Yellow solid, mp 123-124 ℃.
2) Infrared spectrogram (IR) characteristics of the compound:
a potassium bromide tabletting method is adopted: 3423cm -1 2921cm for phenolic hydroxyl group stretching vibration absorption -1 1637cm for saturated hydrocarbon stretching vibration absorption -1 1455cm for carbon-carbon double bond stretching vibration absorption -1 The vibration absorption of the aromatic ring skeleton is realized.
3) NMR spectrum of the compound (A) 1 H NMR,400 MHz) characteristics:
deuterated chloroform is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows: δ:7.44 (d, J =6.8Hz,4H, -Ar), 7.24-7.32 (m, 6H, -Ar), 7.16 (s, 2H, -Ar), 7.09 (s, 2H, -Ar), 6.73 (d, J =1.6Hz,2H, -Ar), 6.01-6.12 (m, 1H, -CH = CH) 2 ),5.87-5.97(m,2H,-CH＝CH 2 ),4.98-5.17(m,6H,-CH＝CH 2 ),4.51(s,1H,N-CH),4.50(s,1H,N-CH),3.44(d,J＝6.8Hz,2H,-CH 2 -CH＝CH 2 ),3.25(d,J＝6.4Hz,4H,-CH 2 -CH＝CH 2 ),2.70-2.73(m,2H,piperazine),2.09(t,J＝10.0Hz,2H,piperazine),1.92(t,J＝11.2Hz,2H,piperazine),1.56-1.64(m,4H,piperazine),1.36-1.41(m,4H,piperazine),1.14-1.20(m,2H,piperazine),0.86(t,J＝6.0Hz,6H,N-CH 3 )。
Example 5
The preparation steps of the pure compound 5 are as follows: dissolving 50.0mg of illicium alcohol safflower in 2mL of toluene, adding 30.6mg of aqueous formaldehyde solution with the mass percentage concentration of 37% and 32.8mg of morpholine, reacting for 6h at 110 ℃, dissolving with dichloromethane after the reaction is finished, and separating by thin-layer chromatography to obtain a pure compound 5 with the yield of 20%.
Or dissolving 50.0mg of illicium alcohol safflower in 2mL of toluene, adding 30.6mg of formaldehyde water solution with the mass percentage concentration of 37% and 32.8mg of morpholine, reacting at 100 ℃ or 120 ℃ for 3h, 4h, 5h, 7h, 8h or 9h respectively, dissolving with dichloromethane after the reaction is finished, and separating by thin-layer chromatography to obtain a pure compound 5 with the yield of 20%.
The chemical structural formula of the pure compound 5 is as follows:
the physicochemical properties of compound 5 are as follows:
1) A pale yellow solid, melting point 128-129 ℃.
2) Infrared spectrogram (IR) characteristics of the compound:
a potassium bromide tabletting method is adopted: 3414cm -1 2922cm for phenolic hydroxyl group stretching vibration absorption -1 1637cm for absorbing the stretching vibration of saturated hydrocarbon -1 1458cm for carbon-carbon double bond stretching vibration absorption -1 The vibration absorption of the aromatic ring skeleton is realized.
3) NMR spectrum of the compound (A) 1 H NMR,400 MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows: δ:7.32 (d, J =7.2Hz,4H, -Ar), 7.15 (s, 2H, -Ar), 7.08-7.12 (m, 6H, -Ar), 6.72 (d, J =1.6Hz,2H, -Ar), 6.01-6.11 (m, 1H, -CH = CH) 2 ),5.87-5.97(m,2H,-CH＝CH 2 ),4.98-5.16(m,6H,-CH＝CH 2 ),4.49(s,1H,N-CH),4.43(s,1H,N-CH),3.43(d,J＝6.4Hz,2H,-CH 2 -CH＝CH 2 ),3.24(d,J＝6.8Hz,4H,-CH 2 -CH＝CH 2 ),2.72-2.74(m,2H,piperazine),2.31(s,3H,Ar-CH 3 ),2.30(s,3H,Ar-CH 3 ),2.09(t,J＝10.0Hz,2H,piperazine),1.91(t,J＝10.8Hz,2H,piperazine),1.56-1.65(m,4H,piperazine),1.36(t,J＝8.4Hz,4H,piperazine),1.14-1.19(m,2H,piperazine),0.86(t,J＝6.0Hz,6H,N-CH 3 )。
Example 6
The preparation method of the pure compound 6 comprises the following steps: dissolving 200.0mg of the pure compound 1 (prepared in example 1) in 5mL of dichloromethane, dropwise adding 76.9mg of concentrated hydrochloric acid with the mass fraction of 37%, and removing dichloromethane at 40 ℃ under reduced pressure to obtain a crude compound 6, wherein the crude compound is recrystallized in ethanol to obtain the pure compound 6 with the yield of 93%.
Or dissolving 200.1mg of pure compound 1 (prepared in example 1) in 5mL of dichloromethane, dropwise adding 80.04mg or 69mg of concentrated hydrochloric acid with a mass fraction of 36% or 38%, and removing dichloromethane at 30 ℃ or 45 ℃ under reduced pressure to obtain crude compound 6, and recrystallizing the crude compound 6 in ethanol to obtain pure compound 6 with a yield of 93%.
The chemical structural formula of the pure compound 6 is as follows:
the physicochemical properties of compound 6 are as follows:
1) White solid, melting point 160-161 ℃.
2) Infrared spectrogram (IR) characteristics of the compound:
a potassium bromide tabletting method is adopted: 3420cm -1 2925cm for phenolic hydroxyl group stretching vibration absorption -1 1637cm for saturated hydrocarbon stretching vibration absorption -1 Is 1465cm for absorbing carbon-carbon double bond stretching vibration -1 The vibration absorption of the aromatic ring skeleton is realized.
3) NMR spectrum of the compound (A) 1 H NMR,400 MHz) characteristics:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows: δ 10.23 (s, 2H, HCl), 7.28 (d, J =2.0Hz,2H, -Ar), 7.07 (d, J =2.0Hz,2H, -Ar), 7.00 (s, 2H, -Ar), 5.93-6.03 (m, 3H, -CH = CH) 2 ),5.02-5.15(m,6H,-CH＝CH 2 ),4.27-4.28(m,4H,-CH 2 -N(CH 3 ) 2 ),3.30-3.37(m,6H,-CH 2 -CH＝CH 2 ),2.74(s,6H,-CH 3 ),2.73(s,6H,-CH 3 )。
Example 7
The preparation method of the pure compound 7 comprises the following steps: dissolving 97.6mg of compound 2 (pure compound 2) with 3mL of dichloromethane, dropwise adding 34.1mg of concentrated hydrochloric acid with the mass fraction of 37%, and removing the dichloromethane at 40 ℃ under reduced pressure to obtain a crude compound 7, wherein the crude compound 7 is recrystallized in ethanol to obtain a pure compound 7 with the yield of 60%.
Or dissolving 97.6mg of compound 2 (pure compound 2) with 3mL of dichloromethane, dropwise adding 39.04mg or 34mg of concentrated hydrochloric acid with the mass fraction of 36% or 38%, and removing dichloromethane at 30 ℃ or 45 ℃ under reduced pressure to obtain a crude compound 7, and recrystallizing the crude compound 7 in ethanol to obtain the pure compound 7 with the yield of 60%.
The chemical structural formula of the pure compound 7 is as follows:
the physicochemical properties of compound 7 are as follows:
1) White solid, melting point 153-154 ℃.
2) Infrared spectrogram (IR) characteristics of the compound:
a potassium bromide tabletting method is adopted: 3386cm -1 2974cm for phenolic hydroxyl group stretching vibration absorption -1 1637cm for saturated hydrocarbon stretching vibration absorption -1 Is used for absorbing carbon-carbon double bond stretching vibration, 1478,1462cm -1 The vibration absorption of the aromatic ring skeleton is realized.
3) NMR spectrum of the compound (A) 1 H NMR,400 MHz) characteristics:
using deuterated chloroform as a solvent and TMS as an internal standard, wherein the attribution of each peak is as follows: Δ:11.20 (s, 2H, HCl), 7.30 (s, 2H, -Ar), 7.21 (s, 2H, -Ar), 7.14 (s, 2H, -Ar), 5.94-6.04 (m, 3H, -CH = CH) 2 ),5.06-5.15(m,6H,-CH＝CH 2 ),4.39(s,4H,-CH 2 -pyrrolidine),3.63(s,4H,pyrrolidine),3.37-3.42(m,6H,-CH 2 -CH＝CH 2 ),2.97(s,4H,pyrrolidine),1.96-2.05(m,8H,pyrrolidine)。
Application example 1: in vitro antimicrobial Activity assay
1. Test bacteria:
staphylococcus aureus (Staphylococcus aureus ATCC 29213); MRSA 1-10 (clinical isolate)
2. Sample and reagent:
the samples were: the safflower octandiol, the vancomycin and the compound 1-7 pure products (the compound 1-7 for short) prepared by the embodiment of the invention.
3. The test method comprises the following steps:
according to the American national clinical laboratory standard, the in vitro antibacterial activity of the compounds of octagonal safflower and 1-7 of the invention (the mannich base derivatives 1-7 of octagonal safflower and 1-7 of the invention are both the compounds 1-7 of the invention) and the standard drug vancomycin is tested on a 96-well plate by a double dilution method, and the OD value of each well is measured at 600nm by visual observation and an enzyme-labeled analyzer. The MIC value was determined by visual observation of the drug concentration in the well.
TABLE one in vitro antibacterial activity (mug/mL) of the safflower octandiol Mannich base derivatives 1-7 of the invention
Note: van-vancomycin, MEM-meropenem; aureus (ATCC 29213); enterococcus faecalis (ATCC 29212); subtilis is Bacillus subtilis; m.luteus, micrococcus luteus; coli (ATCC 25922); and S. maltophilia, namely stenotrophomonas maltophilia.
As shown in the table I, the carthamus tinctorius octal alcohol Mannich base derivative compounds 3 and 4 prepared by the invention have certain bacteriostatic activity on staphylococcus aureus, enterococcus faecalis and bacillus subtilis, and the Minimum Inhibitory Concentration (MIC) is 8-64 mu g/mL. Most prominently, the compound 1,2,6 and 7 has better activity on four selected gram-positive bacteria and certain activity on gram-negative bacteria escherichia coli, and embodies potential broad-spectrum antibacterial property. Therefore, the safflower octal mannich base derivative prepared by the invention can be used for preparing potential natural product bacteriostats.
TABLE II anti-MRSA activity (μ g/mL) of the octandiol derivatives 1-7 of the present invention
Note: van-vancomycin; MRSA 1-10 clinical isolate of Methicillin-resistant Staphylococcus aureus (Methicillin-resistant Staphylococcus aureus) 1-10.
As shown in the table II, the carthamus flower octal Mannich base derivatives 3 and 4 prepared by the invention have better inhibitory activity to clinically isolated MRSA, and the MIC value is 4-64 mug/mL; compound 5 also exhibited some bacteriostatic activity against clinically isolated MRSA, with MIC > 64. Mu.g/mL. The best performance is that the MIC value of the compound 1,2,6,7 to MRSA is basically 1-2 mug/mL, the effect is close to that of the positive drug vancomycin, and the compound has better antibacterial activity. Therefore, the safflower octal mannich base derivative prepared by the invention can be used for preparing potential natural product bacteriostats.
Application example 2: time sterilization kinetics experiment:
1. test bacteria:
staphylococcus aureus (Staphylococcus aureus ATCC 29213); MRSA 4 (clinical isolate)
2. Sample and reagent:
the samples were: vancomycin and compound 6 prepared in the examples of the present invention.
3. The test method comprises the following steps:
staphylococcus aureus was shaken overnight at 225rpm and 37 ℃ in a shaking table, diluted 10000 times in MHB medium, and then shaken at 225rpm and 37 ℃ for 2.5h (early logarithmic growth phase) and 5h (middle logarithmic growth phase), and then the drug to be tested was added at concentrations of 6. Mu.g/mL and 8. Mu.g/mL, vancomycin was used as a positive control, and a blank group without drug addition was set. After adding drugs, 0h,0.5h,1h,2h,4h and 6h, centrifuging each group at 3500rpm for 3min at 4 ℃ at each time point by taking 100 mu L of each group into a 96-well plate, removing supernatant, adding 100 mu L of 1 XPBS solution for resuspending, diluting the groups by using 1 XPBS solution in ten-fold gradient, dropping 10 mu L of diluted bacteria liquid onto MH agar plates, performing parallel control at three drops of each concentration, culturing overnight in a constant-temperature incubator at 37 ℃, counting the number of colonies next day, and counting the unit log 10 CFU/mL, plotted, and the results are shown in FIG. three.
The result shows that the compound 6 of S.aurens, MRSA 4,6 mug/mL and 8 mug/mL in the early logarithmic growth stage can achieve complete elimination within 1h, and the effect is obviously better than that of the positive drug vancomycin. The compound 6 shows excellent bactericidal effect on MRSA 4 in the middle stage of growth, bacteria can be completely eliminated within 4h, and vancomycin only has certain bacteriostatic effect. For s.aurens in the middle of logarithmic growth, neither compound 6 nor vancomycin killed the bacteria completely within 8h, but at the same concentration (8 μ g/mL), compound 6 achieved a superior bactericidal effect than the positive control drug vancomycin. Therefore, the carthamus flower octal alcohol Mannich base derivatives prepared by the invention can be used for preparing potential natural product antibacterial candidate drugs.
Claims (10)
1. A safflower octal mannich base derivative is characterized by being a compound of the following formula 1:
wherein R is:
(1)：
(2)：
(3)：
(4)：
(5)：
(6)：
(7)：
one kind of (1).
2. The mannich base derivatives of octadienol as claimed in 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 amine methylation reaction is 100-120 ℃, and the time of the amine methylation reaction is 3-9h; 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 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.
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| WO2008102086A2 (en) * | 2007-01-19 | 2008-08-28 | Europe Finances | Use of compositions containing at least one lignane and/or neolignane for modulating testosterone levels |
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