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Novel fusidic acid derivative as well as synthesis preparation method and application thereof

A technology of fusidic acid and derivatives, which is applied in the field of fusidic acid derivatives, can solve the problems of low resistance barrier and easy occurrence of drug resistance, and achieve the effect of improving antibacterial activity and activity

Active Publication Date: 2018-10-16
YANTAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The drug resistance barrier of fusidic acid is low, and it will not produce drug resistance when used alone in the short term, but long-term monotherapy is prone to drug resistance

Method used

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  • Novel fusidic acid derivative as well as synthesis preparation method and application thereof
  • Novel fusidic acid derivative as well as synthesis preparation method and application thereof
  • Novel fusidic acid derivative as well as synthesis preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] 21-Fusidic acid (N,N'-dicyclohexyl) carbodiimide ester

[0054] Take a 50mL eggplant-shaped bottle, dissolve fusidic acid (150mg, 0.29mmol) in anhydrous dichloromethane (20mL), stir and add N,N'-dicyclohexylcarbodiimide (180mg, 0.87mmol), DMAP (105mg, 0.86mmol), react at room temperature for 9-11 hours. Wash with 10% hydrochloric acid to acidity successively, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter, evaporate the solvent under reduced pressure, silica gel column chromatography (V 氯仿 :V 甲醇 =160:1-140:1), a white solid (175mg, 83.2%) was obtained. 1 H-NMR (CDCl 3,400MHz)δ:5.56(d,J=8.72Hz,1H,16-H),5.00(t,J=5.66Hz,1H,24-H),4.29(s,1H,11-OH),3.67( d,J=2.14Hz,1H,3-OH),3.58-3.63(m,1H,3-H),2.94-3.02(m,J=12.24Hz,1H,13-H),2.50-2.63(m ,1H,-CH-),2.21(m,1H,-NH-),1.90-1.91(m,2H,2×22-H),1.87-1.89(m,2H,12-H and 15-H) ,1.74-1.84(m,4H,1-H,5-H and 2×23-H),1.68(s,3H,OCOCH 3 ),1.65-1.67(m,2H,2-H and 12-H),1.58-1.61(m,2H,2-H and 7-H),1.53(s...

Embodiment 2

[0056] 21-Fusidic acid [1-ethyl-(3-dimethylaminopropyl)] carbodiimide ester

[0057] Referring to the synthesis method of 21-fusidic acid (N,N'-dicyclohexyl) carbodiimide ester, fusidic acid and 1-ethyl-(3-dimethylaminopropyl) carbonyl diimide The imine was reacted to give a yellow solid (126 mg, 52.3%). 1 H-NMR (CDCl 3 ,400MHz)δ:9.14(s,1H,-NH-),5.93(d,J=8.83Hz,1H,16-H),5.06(t,J=6.92Hz,1H,24-H),4.35( s,1H,11-H),3.75(d,J=2.30Hz,1H,3-OH),3.53-3.61(td,J=4.79,10.96Hz,2H,-CH 2 -),3.24-3.38(m,2H,-CH 2 -), 3.03(d, J=11.49Hz, 1H, 13-H), 2.68-2.75(m, 2H, -CH 2 -),2.27(s,6H,2×-CH 3 ),2.18-2.22(m,2H,-CH 2 -),2.08-2.15(m,3H,12-H and 2×22-H),2.00-2.05(m,3H,15-H and2×23-H),1.95-1.96(m,2H,1- H and 5-H),1.91(s,3H,OCOCH 3 ),1.82-1.86(m,2H,2-H and12-H),1.72-1.78(m,2H,2-H,7-H),1.67(s,3H,27-CH 3 ),1.60(s,3H,26-CH 3 ),1.49-1.53(m,3H,1-H,6-H and 9-H),1.38(s,3H,-CH 3 ),1.26(s,3H,30-CH 3 ), 1.17(t, J=7.25Hz, 1H, -CH 2 -),1.04-1.13(m,2H,6-H and 7-H),0.98(s,3H,19-CH 3 ),0.93(s,3H,18-CH 3...

Embodiment 3

[0059] 21-Fusidic acid (6-chloro-benzotriazole-1) ester

[0060] Take a 50mL eggplant-shaped bottle, dissolve fusidic acid (220mg, 0.42mmol) in anhydrous dichloromethane (20mL), stir and add 6-chloro-1-hydroxybenzotriazole (267mg, 1.30mmol), EDCI (245mg, 1.28mmol), react at room temperature for 4-6 hours. Diluted with dichloromethane (20mL), washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to remove solvent under reduced pressure, silica gel column chromatography (V 氯仿 :V 甲醇 =160:1-140:1), a white solid (233 mg, 85.8%) was obtained. 1 H-NMR (CDCl 3 ,400MHz) δ:7.99(d,J=9.36Hz,1H,Ar-H),7.40(d,J=1.76Hz,1H,Ar-H),7.38(d,J=1.93Hz,1H,Ar-H) H), 5.93(d, J=8.42Hz, 1H, 16-H), 5.23(t, J=7.20Hz, 1H, 24-H), 4.42(s, 1H, 11-H), 3.77(d, J=2.3Hz, 1H, 3-OH), 3.23(d, J=10.58Hz, 1H, 13-H), 2.76-2.82(m, 1H, 22-H), 2.62-2.69(m, 1H, 22 -H),2.37-2.44(m,1H,12-H),2.29-2.34(m,2H,2×23-H),2.12-2.22(m,2H,1-H and5-H),2.09( s,1H,15-H),1.84-1.99(m...

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Abstract

The invention relates to the field of organic synthesis and medicine chemicals and in particular relates to fusidic acid derivatives of novel structures. The invention further discloses a preparationmethod of the derivatives, medicinal compositions with the derivatives, and application of the derivatives in bacterium resistance. Pharmacological testing shows that the fusidic acid derivatives provided by the invention have good antibacterial function, and can be used for preparing anti-infection medicines. Compared with fusidic acid, the fusidic acid derivatives have a staphylococcus aureus inhibition rate of 83.65%; the derivatives provided by the invention have good activity upon staphylococcus aureus, the antibacterial inhibition rate is increased to 90.8% from 83.65%, and remarkable activity improvement is achieved; meanwhile, HC (Hydrocarbon Compound) evaluation results of the derivatives show that the derivatives have no cytotoxicity.

Description

technical field [0001] The invention relates to the fields of organic synthesis and medicinal chemistry, in particular to a class of fusidic acid derivatives with novel structures, a pharmaceutical composition containing them, a preparation method thereof and an antibacterial application thereof. technical background [0002] In 1962, the Danish Leo Pharmaceutical Company extracted Fusidic acid (Fusidic acid) for the first time from the fermentation broth of lipococcus fusidi, which belongs to the class of fusidic acid antibiotics. Fusidic acid is a narrow-spectrum antibiotic with strong activity against Gram-positive bacteria, and can also resist a variety of anaerobic bacteria and several other bacteria, especially Staphylococcus aureus, Staphylococcus epidermidis, Clostridium spp. Bacillus is very sensitive; in addition, it is moderately sensitive to Mycobacterium, Legionella pneumophila, and Nocardia. Fusidic acid has good curative effect on various infections caused by...

Claims

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Application Information

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IPC IPC(8): C07J43/00C07J41/00A61K31/58A61K31/575A61P29/00A61P17/00A61P19/02A61P9/00A61P11/00A61P31/04
CPCA61P9/00A61P11/00A61P17/00A61P19/02A61P29/00A61P31/04C07J41/0044C07J41/005C07J43/003Y02P20/55
Inventor 毕毅芦静倪敬轩王炳华
Owner YANTAI UNIV
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