CN115505018B - Fusidic acid derivative with anti-inflammatory activity and preparation method and application thereof - Google Patents

Fusidic acid derivative with anti-inflammatory activity and preparation method and application thereof Download PDF

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CN115505018B
CN115505018B CN202211211181.3A CN202211211181A CN115505018B CN 115505018 B CN115505018 B CN 115505018B CN 202211211181 A CN202211211181 A CN 202211211181A CN 115505018 B CN115505018 B CN 115505018B
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fusidic acid
acid
alpha
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毕毅
张雷明
龙俊俊
应天昊
张雷
刘亚森
吴金惠
余涛
朱奕霏
李晓丽
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Yantai University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
    • C07J13/007—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 17 (20)
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Abstract

The invention relates to the fields of organic synthesis and pharmaceutical chemistry, in particular to a fusidic acid derivative with anti-inflammatory activity, and a preparation method and application thereof. The fusidic acid derivative has a structure shown in a general formula I, a general formula II and a general formula III:the beneficial effects are that: the invention takes 3,3' -dithiodipropionic acid and phthalic acid as connecting chains to connect hydroxylamine groups at C-3 position of fusidic acid for the first time, and the anti-inflammatory activity is improved compared with that of fusidic acid. According to the invention, phthalic acid is used as a connecting chain to connect a nitrogen-containing heterocycle at the C-3 position of fusidic acid, and the introduction of the nitrogen-containing heterocycle is found for the first time, so that the anti-inflammatory activity of fusidic acid can be improved.

Description

Fusidic acid derivative with anti-inflammatory activity and preparation method and application thereof
Technical Field
The invention relates to the fields of organic synthesis and pharmaceutical chemistry, in particular to a fusidic acid derivative with anti-inflammatory activity, and a preparation method and application thereof.
Background
Inflammation is a complex biological process that regulates immune responses caused by various triggers such as infectious agents, allergens, free radicals, highly refined foods, and sedentary lifestyles. Excessive inflammation and excessive duration may lead to various diseases, which seriously threaten human health, such as arthritis, septicemia, and even cancer. Currently, adverse reactions common to commonly used nonsteroidal anti-inflammatory drugs include central nervous system symptoms (pain, dizziness, tinnitus, etc.), cardiovascular damage (hypertension, edema, myocardial infarction, heart failure, etc.), gastrointestinal symptoms (upper abdominal pain, anorexia, vomiting, ulcers, bleeding, etc.), hematopoietic system changes (thrombocytopenia), liver and kidney insufficiency, asthma, skin rash, etc., limiting their clinical application. Therefore, there is a need to develop anti-inflammatory drugs with novel structures and good therapeutic effects.
Fusidic Acid (FA) is a tetracyclic triterpene separated from fungi, the FA and derivatives thereof have wide pharmacological activities, including antibiosis, antimalarial, antineoplastic, tumor multi-drug resistance reversal, anti-inflammatory, antifungal, antiviral and the like, and are clinically used for systemic and local staphylococcal infections, including methicillin-resistant staphylococcus aureus and coagulase negative staphylococcus infections, such as a Fusidic acid derivative with antineoplastic activity in the prior art CN201811105318.0 and a synthetic preparation method thereof, the F-3-site modified structure is mainly connected with an amino-containing group at the tail end through esterification reaction, and the amino-containing group at the tail end of the C-3-site is important for the Fusidic acid derivative to exert the antineoplastic activity in terms of structure-activity.
Since 1962, the research has been focused on antibacterial aspects, such as the prior art CN201610284210.7, which protects the application of fusidic acid in antibacterial aspects, a fusidic acid modification, and a preparation method and application thereof. Previous studies have shown that fusidic acid has anti-inflammatory activity, but has poor effect, so that further chemical modification is performed, the research in the field is expanded, and the development of novel and effective anti-inflammatory drugs is necessary.
Disclosure of Invention
In view of the above-described deficiencies of the prior art, the present invention provides a fusidic acid derivative having anti-inflammatory activity.
A fusidic acid derivative having anti-inflammatory activity, the fusidic acid derivative having a structure represented by general formula I, general formula II, general formula III:
wherein:
R 1 represents one of the following structures:
R 2 represents one of the following structures:
R 3 represents one of the following structures:
further, the fusidic acid derivative is at least one of the following compounds:
3 α - [ (3-dithio-O-allylpropionamide) propionyloxy ] -16 β -acetoxy-11 α -hydroxy-4 α,8 α,14 β -trimethyl-18-nor-5 α,10 β -cholesteric- (17Z) -17 (20), 24-diene-21-oic acid benzyl ester;
3 α - [ (3-dithio-N-methyl-N-methoxypropionamide) propionyloxy ] -16 β -acetoxy-11 α -hydroxy-4 α,8 α,14 β -trimethyl-18-nor-5 α,10 β -cholesteric- (17Z) -17 (20), 24-diene-21-oic acid benzyl ester;
3 α - [ (3-dithio-O- (tetrahydro-2H-pyran) propionamide) propionyloxy ] -16 β -acetoxy-11 α -hydroxy-4 α,8 α,14 β -trimethyl-18-nor-5 α,10 β -cholesteric- (17Z) -17 (20), 24-diene-21-oic acid benzyl ester;
3 α - [ (3-dithio-O- (4-nitrophenyl) propionamide) propionyloxy ] -16 β -acetoxy-11 α -hydroxy-4 α,8 α,14 β -trimethyl-18-nor-5 α,10 β -cholesteric- (17Z) -17 (20), 24-diene-21-oic acid benzyl ester;
3 alpha- { [ 3-dithio- [ O- (4-nitrobenzoyl) propionamide ] propionyloxy } -16 beta-acetoxy-11 alpha-hydroxy-4 alpha, 8 alpha, 14 beta-trimethyl-18-nor-5 alpha, 10 beta-cholesteric- (17Z) -17 (20), 24-diene-21-oic acid benzyl ester;
2- (21-fusidic acid benzyl ester-3β -oxy) -2-oxo-benzoylmorpholine;
2- (21-fusidic acid benzyl ester-3β -oxy) -2-oxo-benzoylpiperidine;
2- (21-fusidic acid benzyl ester-3β -oxy) -2-oxo- (N-methoxy) -benzamide;
2- (21-fusidic acid benzyl ester-3β -oxy) -2-oxo- (N-methoxy-N-methyl) -benzamide;
2- (21-fusidic acid benzyl ester-3β -oxy) -2-oxo- (N-tert-butyloxy) -benzamide;
2- (21-fusidic acid benzyl ester-3β -oxy) -2-oxo- (N-allyloxy) -benzamide;
2- (21-fusidic acid benzyl ester-3β -oxy) -2-oxo- (N-4-nitrobenzoyloxy) -benzamide;
21-fusidic acid- (O-allyloxy) amide;
21-fusidic acid-methoxy amide.
The beneficial effects are that: the invention takes 3,3' -dithiodipropionic acid and phthalic acid as connecting chains to connect hydroxylamine groups at C-3 position of fusidic acid for the first time, and the anti-inflammatory activity is improved compared with that of fusidic acid. According to the invention, phthalic acid is used as a connecting chain to connect a nitrogen-containing heterocycle at the C-3 position of fusidic acid, and the introduction of the nitrogen-containing heterocycle is found for the first time, so that the anti-inflammatory activity of fusidic acid can be improved.
The invention also provides a preparation method of the fusidic acid derivative with anti-inflammatory activity. The preparation method comprises the following steps:
when R1 and R2 are respectively hydroxylamine groups or nitrogen-containing heterocycles, the preparation method comprises the following steps:
a, taking fusidic acid as a raw material, and reacting with benzyl bromide under the alkaline condition and the action of a catalyst;
reacting the product obtained in b.a step with 3,3' -dithiodipropionic acid under the catalysis of DMAP and EDCI or reacting with phthalic anhydride under the catalysis of DMAP;
c.b reacting the product obtained in step c.b with different hydroxylamine under the catalysis of HATU and DIEA or with nitrogen-containing heterocycle under the catalysis of EDCI;
when R3 is a hydroxylamine group, the preparation steps include:
a. taking fusidic acid as a raw material, and reacting with different hydroxylamine compounds under the catalysis of DMAP and EDCI.
The invention also provides application of the fusidic acid derivative with anti-inflammatory activity, which is application in preparing anti-inflammatory medicines.
Pharmacological tests prove that the fusidic acid derivative has anti-inflammatory effect and can be applied to the development of novel anti-inflammatory medicaments.
Drawings
FIG. 1 is a graph showing the effect of fusidic acid derivatives according to the present invention on RAW264.7 cell viability.
FIG. 2 is a graph showing the effect of fusidic acid derivatives according to the present invention on NO production by RAW264.7 cells.
Detailed Description
The fusidic acid derivative of the general formula is prepared by synthesis according to the following method:
when R is 1 、R 2 In the case of hydroxylamine groups or nitrogen-containing heterocycles, respectively, the preparation steps include:
a, taking fusidic acid as a raw material, and reacting with benzyl bromide under the alkaline condition and the action of a catalyst;
reacting the product obtained in b.a step with 3,3' -dithiodipropionic acid under the catalysis of DMAP and EDCI or reacting with phthalic anhydride under the catalysis of DMAP;
c.b the product obtained in step c.b is reacted with different hydroxylamine under the catalysis of HATU and DIEA or with nitrogen-containing heterocycle under the catalysis of EDCI.
When R is 3 In the case of hydroxylamine groups, the preparation steps include:
a. taking fusidic acid as a raw material, and reacting with different hydroxylamine compounds under the catalysis of DMAP and EDCI.
The present invention will be described in further detail by way of examples, but the present invention is not limited to the following examples.
Example 1
3 alpha- [ (3-dithio-O-allylpropionamide) propionyloxy ] -16 beta-acetoxy-11 alpha-hydroxy-4 alpha, 8 alpha, 14 beta-trimethyl-18-nor-5 alpha, 10 beta-cholest- (17Z) -17 (20), 24-diene-21-acid benzyl ester, the specific structure is as follows:
a500 mL eggplant-type bottle was used, fusidic acid (10.01 g,0.019 mol) was dissolved in acetone (200 mL), and potassium carbonate (5.36 g,0.039 mol) and benzyl bromide (2.78 mL,0.023 mol) were added with stirring to react at 30℃for 5-7 hours. Suction filtration, concentration, ethyl acetate (50 mL) dilution, 10% hydrochloric acid washing to acidity, water washing, saturated saline water washing, anhydrous sodium sulfate drying, filtration, reduced pressure evaporation of solvent, silica gel column chromatography (V) Chloroform (chloroform) :V Methanol =210:1-190:1) to afford 21-benzyl fusidate as a white solid (8.86 g, 75.4%).
A500 mL eggplant-shaped bottle was taken, and 21-fusidic acid benzyl ester (2.4 g,4.0 mmol) was dissolved in anhydrous CH 2 Cl 2 To (200 mL) was added DMAP (730 mg,6.0 mmol), EDCI (1.5 g,8.0 mmol) and 3,3' -dithiodipropionic acid (3.7 g,12.0 mmol), and the reaction was stirred at room temperature for 5 hours. After the reaction is finished, ethyl acetate is added for dilution after concentration, 5% hydrochloric acid solution, water washing, saturated saline water washing, anhydrous sodium sulfate drying, filtration and concentration are sequentially carried out. Silica gel column chromatography (V) Petroleum ether :V Acetic acid ethyl ester =8:1) to give 3 α - (3-dithiopropionic acid) propionyloxy-16 β -acetoxy-11 α -hydroxy-4 α,8 α,14 β -trimethyl-18-nor-5 α,10 β -cholesteric- (17Z) -17 (20), 24-diene-21-acid benzyl ester (2.8 g, 87.1%).
A50 mL eggplant-shaped bottle was taken, 3 alpha- (3-dithiopropionic acid) propionyloxy-16 beta-acetoxy-11 alpha-hydroxy-4 alpha, 8 alpha, 14 beta-trimethyl-18-nor-5 alpha, 10 beta-cholesteric- (17Z) -17 (20), 24-diene-21-oic acid benzyl ester (240 mg,0.3 mmol) was dissolved in anhydrous CH 2 Cl 2 (20 mL) was added HATU (190 mg,0.5 mmol),DIEA (148. Mu.L, 0.9 mmol) and O-allylhydroxylamine hydrochloride (131 mg,1.2 mmol) were reacted for 4 hours with stirring at room temperature. After the reaction, ethyl acetate was added for dilution after concentration, saturated brine was used for washing, and the mixture was dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel column chromatography (V) Petroleum ether :V Acetic acid ethyl ester ＝10:1～V Petroleum ether :V Acetic acid ethyl ester =5:1) to give the product as a pale yellow oil (189 mg, 73.7%). 1 H NMR(400MHz,CDCl 3 )δ7.38–7.29(m,5H,Ar-H),6.00–5.91(m,1H,＝CH),5.88(d,J＝8.5Hz,1H,16-H),5.40–5.25(m,2H,＝CH 2 ),5.21(d,J＝12.2Hz,1H,CHAr),5.06(t,J＝7.2Hz,1H,24-H),4.96(d,J＝2.7Hz,1H,3-H),4.93(d,J＝12.2Hz,1H,CHAr),4.44–4.35(m,2H,-OCH 2 -),4.34(s,1H,11-H),3.03(d,J＝11.8Hz,1H,13-H),2.98–2.94(m,4H,2×-SCH 2 -),2.82–2.71(m,3H,3×-COCH-),2.51–2.41(m,3H,-COCH-,2×22-H),2.30(d,J＝13.1Hz,1H,12-H),2.15(m,4H,15-H,2×23-H,1-H),2.05–1.95(m,1H,5-H),1.93(s,3H,OCOCH 3 ),1.63(s,3H,27-CH 3 ),1.52(s,3H,26-CH 3 ),1.37(s,3H,30-CH 3 ),0.99(s,3H,19-CH 3 ),0.92(s,3H,18-CH 3 ),0.83(d,J＝6.7Hz,3H,28-CH 3 ).
Example 2
3 alpha- [ (3-dithio-N-methyl-N-methoxypropionamide) propionyloxy ] -16 beta-acetoxy-11 alpha-hydroxy-4 alpha, 8 alpha, 14 beta-trimethyl-18-nor-5 alpha, 10 beta-cholest- (17Z) -17 (20), 24-diene-21-oic acid benzyl ester having the specific structure:
according to the synthesis method of example 1, 3 α - (3-dithiopropionic acid) propionyloxy-16 β -acetoxy-11 α -hydroxy-4 α,8 α,14 β -trimethyl-18-nor-5 α,10 β -cholest- (17Z) -17 (20), 24-diene-21-oic acid benzyl ester was used as a starting material and reacted with N, O-dimethylhydroxylamine hydrochloride to give a colorless oily product (178 mg, 70.8%). 1 H NMR(400MHz,CDCl 3 )δ7.37–7.28(m,5H,Ar-H),5.88(d,J＝8.4Hz,1H,16-H),5.21(d,J＝12.2Hz,1H,CHAr),5.11–5.01(m,1H,24-H),4.99–4.86(m,2H,3-H,CHAr),4.31(s,1H,11-H),3.70(s,3H,-OCH 3 ),3.16(s,3H,-NCH 3 ),3.04(d,J＝12.9Hz,1H,13-H),2.98–2.93(m,4H,2×-SCH 2 -),2.88–2.71(m,4H,2×-COCH 2 -),2.53–2.37(m,2H,2×22-H),2.29(d,J＝13.3Hz,1H,12-H),2.22–2.09(m,4H,15-H,2×23-H,1-H),2.04–1.97(m,1H,5-H),1.93(s,3H,OCOCH 3 ),1.63(s,3H,27-CH 3 ),1.52(s,3H,26-CH 3 ),1.37(s,3H,30-CH 3 ),0.98(s,3H,19-CH 3 ),0.91(s,3H,18-CH 3 ),0.83(d,J＝6.7Hz,3H,28-CH 3 ).
Example 3
3 alpha- [ (3-dithio-O- (tetrahydro-2H-pyran) propionamide) propionyloxy ] -16 beta-acetoxy-11 alpha-hydroxy-4 alpha, 8 alpha, 14 beta-trimethyl-18-nor-5 alpha, 10 beta-cholesteric- (17Z) -17 (20), 24-diene-21-oic acid benzyl ester having the specific structure:
according to the synthesis method of example 1, 3 α - (3-dithiopropionic acid) propionyloxy-16 β -acetoxy-11 α -hydroxy-4 α,8 α,14 β -trimethyl-18-nor-5 α,10 β -cholest- (17Z) -17 (20), 24-diene-21-oic acid benzyl ester was used as a starting material and reacted with O- (tetrahydropyran-2-yl) hydroxylamine to give a colorless oily product (181 mg, 67.2%). 1 H NMR(400MHz,CDCl 3 )δ7.38–7.28(m,5H,Ar-H),5.89(d,J＝8.3Hz,1H,16-H),5.21(d,J＝12.2Hz,1H,CHAr),5.06(t,J＝7.2Hz,1H,24-H),4.98–4.95(m,1H,3-H),4.92(d,J＝12.2Hz,1H,CHAr),4.33(s,1H,11-H),3.94(s,1H,-OCHO-),3.65–3.55(m,2H,-OCH 2 -),3.04(d,J＝12.4Hz,1H,13-H),2.97(t,J＝7.2Hz,4H,2×-SCH 2 -),2.79–2.75(m,3H,3×-COCH-),2.57–2.38(m,3H,-COCH-,2×22-H),2.30(d,J＝13.1Hz,1H,12-H),2.23–2.09(m,4H,15-H,2×23-H,1-H),2.05–1.96(m,1H,5-H),1.93(s,3H,OCOCH 3 ),1.63(s,3H,27-CH 3 ),1.53(s,3H,26-CH 3 ),1.37(s,3H,30-CH 3 ),0.98(s,3H,19-CH 3 ),0.92(s,3H,18-CH 3 ),0.83(d,J＝6.7Hz,3H,28-CH 3 ).
Example 4
3 alpha- [ (3-dithio-O- (4-nitrophenyl) propionamide) propionyloxy ] -16 beta-acetoxy-11 alpha-hydroxy-4 alpha, 8 alpha, 14 beta-trimethyl-18-nor-5 alpha, 10 beta-cholest- (17Z) -17 (20), 24-diene-21-oic acid benzyl ester having the specific structure:
with reference to the synthetic method of example 1, 3 α - (3-dithiopropionic acid) propionyloxy-16 β -acetoxy-11 α -hydroxy-4 α,8 α,14 β -trimethyl-18-nor-5 α,10 β -cholesteric- (17Z) -17 (20), 24-diene-21-oic acid benzyl ester was reacted with O- (4-nitrophenyl) hydroxylamine to give a yellow oily product (208.7 mg,74.3% yield). 1 H NMR(400MHz,CDCl 3 )δ8.23–8.06(m,2H,2×Ar-H),7.39–7.30(m,5H,5×Ar-H),7.15(d,J＝9.4Hz,2H,2×Ar-H),5.79(d,J＝8.3Hz,1H,16-H),5.21(d,J＝12.2Hz,1H,CHAr),5.06–4.99(m,1H,24-H),4.97–4.90(m,2H,CHAr,3-H),4.34(s,1H,11-H),3.03–2.97(m,3H,3×-SCH-),2.93(d,J＝12.7Hz,1H,13-H),2.79(s,5H,-SCH-,4×-COCH-),2.38(t,J＝8.1Hz,2H,2×22-H),2.26(dt,J＝13.1,2.9Hz,1H,12-H),2.11(dq,J＝13.8,7.9,6.6Hz,4H,15-H,2×23-H,1-H),1.92(s,3H,OCOCH 3 ),1.62(d,J＝1.4Hz,3H,27-CH 3 ),1.50(d,J＝1.4Hz,3H,26-CH 3 ),1.34(s,3H,30-CH 3 ),0.98(s,3H,19-CH 3 ),0.90(s,3H,18-CH 3 ),0.83(d,J＝6.7Hz,3H,28-CH 3 ).
Example 5
3 alpha- { [ 3-dithio- [ O- (4-nitrobenzoyl) propionamide ] propionyloxy } -16 beta-acetoxy-11 alpha-hydroxy-4 alpha, 8 alpha, 14 beta-trimethyl-18-nor-5 alpha, 10 beta-cholesteric- (17Z) -17 (20), 24-diene-21-oic acid benzyl ester having the specific structure:
with reference to the synthetic method of example 1, 3 alpha- (3-dithiopropionic acid) propionyloxy-16 beta-acetoxy-11 alpha-hydroxy-4 alpha, 8 alpha,14 beta-trimethyl-18-nor-5 alpha, 10 beta-cholest- (17Z) -17 (20), 24-diene-21-acid benzyl ester as raw material was reacted with O-p-nitrobenzoyl hydroxylamine to give the product as a pale yellow oil (206.0 mg,71.2% yield). 1 H NMR(400MHz,CDCl 3 )δ8.31–8.22(m,4H,4×Ar-H),7.37–7.29(m,5H,5×Ar-H),5.86(d,J＝8.3Hz,1H,16-H),5.19(d,J＝12.2Hz,1H,CHAr),5.03–4.90(m,3H,24-H,CHAr,3-H),4.35(q,J＝3.2,2.8Hz,1H,11-H),3.01(qd,J＝8.8,8.0,2.3Hz,5H,4×-SCH-,13-H),2.82–2.73(m,4H,4×-COCH-),2.43–2.00(m,8H,1-H,4-H,5-H,12-H,2×22-H,2×23-H),1.92(s,3H,OCOCH 3 ),1.60(d,J＝1.4Hz,3H,27-CH 3 ),1.48(d,J＝1.3Hz,3H,26-CH 3 ),1.38(s,3H,30-CH 3 ),0.99(s,3H,19-CH 3 ),0.91(s,3H,18-CH 3 ),0.84(d,J＝6.7Hz,3H,28-CH 3 ).
Example 6
2- (21-Fuxidate benzyl ester-3 beta-oxygen radical) -2-oxo-benzoyl morpholine, the specific structure is as follows:
a500 mL eggplant-shaped bottle was taken, and 21-fusidic acid benzyl ester (2.4 g,4.0 mmol) was dissolved in anhydrous CH 2 Cl 2 To (200 mL) was added DMAP (730 mg,6.0 mmol) and phthalic anhydride (178 mg,12.0 mmol), and the reaction was stirred at room temperature for 4 hours. After the reaction is finished, ethyl acetate is added for dilution after concentration, 5% hydrochloric acid solution, water washing, saturated saline water washing, anhydrous sodium sulfate drying, filtration and concentration are sequentially carried out. Silica gel column chromatography (V) Petroleum ether :V Acetic acid ethyl ester =8:1) to give 2- (21-benzyl fusidate-3β -oxy) -2-oxo-benzoic acid (2.6 g, 86.1%) as a white solid.
A25 mL eggplant-shaped bottle was taken, 2- (21-fusidic acid benzyl-3β -oxy) -2-oxo-benzoic acid (100 mg, 133. Mu. Mol) was dissolved in anhydrous dichloromethane (8 mL), morpholine (24. Mu.L, 266.0. Mu. Mol), EDCI (42 mg, 220.0. Mu. Mol) was added, and the reaction was stirred at room temperature for 6 hours. After the completion of the reaction, methylene chloride was diluted, washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed on a silica gel column (V Chloroform (chloroform) :V Methanol =150:1) to give a white solid (88.2 mg, 80.6%). 1 H-NMR(CDCl 3 ,400MHz)δ:7.99(d,J＝7.40Hz,1H,Ar-H),7.60-7.52(m,1H,Ar-H),7.48-7.41(m,1H,Ar-H),7.36-7.26(m,6H,Ar-H),5.87(d,J＝8.30Hz,1H,16-H),5.19(m,2H,11-OH and CHAr),5.03(t,J＝7.20Hz,1H,24-H),4.92(d,J＝12.20Hz,1H,CHAr),4.32(s,1H,11-H),4.00-3.08(m,8H,mor-H),3.04(d,J＝11.20Hz,1H,13-H),2.53-2.35(m,2H,2×22-H),2.33-1.92(m,6H,1-H,2×5-H,12-H and2×23-H),1.90(s,3H,OCOCH 3 ),1.89-1.82(m,4H,2×2-H,7-H and 12-H),1.81-1.63(m,4H,1-H,4-H,6-H and 9-H),1.61(s,3H,27-CH 3 ),1.50(s,3H,26-CH 3 ),1.41(s,3H,30-CH 3 ),1.19-1.03(m,2H,6-H and 7-H),1.00(s,3H,19-CH 3 ),0.91(s,3H,18-CH 3 ),0.85(s,3H,28-CH 3 ).
Example 7
2- (21-Fuxidate benzyl ester-3 beta-oxy) -2-oxo-benzoyl piperidine, the specific structure is as follows:
according to the synthesis method of example 6, starting from 2- (21-benzyl fusidate-3. Beta. -oxy) -2-oxo-benzoic acid, it was reacted with piperidine to give a white solid (41 mg, 75.8%). 1 H-NMR(CDCl 3 ,400MHz)δ:8.02(d,J＝7.40Hz,1H,Ar-H),7.60-7.52(m,1H,Ar-H),7.48-7.43(m,1H,Ar-H),7.40-7.30(m,6H,Ar-H),5.91(d,J＝8.30Hz,1H,16-H),5.28-5.18(m,2H,CHAr and 11-OH),5.07(t,J＝7.10Hz,1H,24-H),4.95(d,J＝12.20Hz,1H,CHAr),4.36(s,1H,11-H),4.10-3.90(m,1H,PIP-H),3.55-3.30(m,1H,PIP-H),3.15-3.00(m,2H,PIP-H),2.89(s,1H,13-H),2.71-2.63(m,4H,2×-CH 2 -),2.56-2.42(m,2H,2×22-H),2.37-2.28(m,1H,12-H),2.26-2.00(m,5H,15-H,2×23-H,1-H and 5-H),1.94(s,3H,OCOCH 3 ),1.93-1.76(m,4H,2×2-H,12-H and 7-H),1.64(s,3H,27-CH 3 ),1.63-1.57(m,6H,2×2-H,1-H,4-H,6-H and 7-H),1.53(s,3H,26-CH 3 ),1.45(s,3H,30-CH 3 ),1.27-1.24(m,3H,15-H,6-H and 7-H),1.03(s,3H,19-CH 3 ),0.94(s,3H,18-CH 3 ),0.89(s,3H,28-CH 3 ).
Example 8
2- (21-Fuxidate benzyl ester-3 beta-oxygen radical) -2-oxo- (N-methoxy) -benzamide has the following specific structural formula:
according to the synthesis method of example 1, starting from 2- (21-benzyl fusidate-3β -oxy) -2-oxo-benzoic acid, reaction with N-methoxy hydroxylamine hydrochloride gave a white solid (124.9 mg,82.3% yield). 1 H NMR(400MHz,CDCl 3 )δ7.99(d,J＝41.5Hz,1H,-CONH-),7.62–7.22(m,9H,9×Ar-H),5.87(d,J＝8.4Hz,1H,16-H),5.19(d,J＝12.2Hz,2H,3-H,-CHAr),5.10–5.03(m,1H,24-H),4.93(d,J＝12.2Hz,1H,CHAr),4.40(d,J＝36.0Hz,1H,11-H),3.82(s,1H,-OCH 3a ),3.34(s,1H,-OCH 3b ),3.09(d,J＝12.1Hz,1H,13-H),2.54–1.96(m,9H,2×22-H,12-H,15-H,2×23-H,1-H,4-H,5-H),1.91(s,3H,OCOCH 3 ),1.63(d,J＝1.4Hz,3H,27-CH 3 ),1.52(d,J＝1.3Hz,3H,26-CH 3 ),1.45(s,3H,30-CH 3 ),1.01(s,3H,19-CH 3 ),0.92(s,3H,18-CH 3 ),0.85–0.79(m,3H,28-CH 3 ).
Example 9
2- (21-Fuxidate benzyl ester-3 beta-oxygen radical) -2-oxo- (N-methoxy-N-methyl) -benzamide has the specific structure as follows:
according to the synthesis method of example 1, 2- (21-fusidic acid benzyl ester-3β -oxy) -2-oxo-benzoic acid was used as a starting material, and reacted with dimethylol amine hydrochloride to give a white solid (125.4 mg,81.2% yield). 1 H NMR(400MHz,CDCl 3 )δ7.97(d,J＝7.7Hz,1H,-CONH-),7.60–7.28(m,9H,9×Ar-H),5.90(d,J＝8.3Hz,1H,16-H),5.25–5.17(m,2H,3-H,-CHAr),5.06(ddd,J＝8.7,5.2,1.5Hz,1H,24-H),4.94(d,J＝12.2Hz,1H,-CHAr),4.35(q,J＝2.5Hz,1H,11-H),3.21(dd,J＝99.3,13.8Hz,7H,-NCH 3 ,-OCH 3 ,13-H),2.54–1.97(m,9H,2×22-H,12-H,15-H,2×23-H,1-H,4-H,5-H),1.92(s,3H,OCOCH 3 ),1.63(d,J＝1.4Hz,3H,27-CH 3 ),1.52(d,J＝1.3Hz,3H,26-CH 3 ),1.43(s,3H,30-CH 3 ),1.02(s,3H,19-CH 3 ),0.93(s,3H,18-CH 3 ),0.87(d,J＝6.7Hz,3H,28-CH 3 ).
Example 10
2- (21-Fuxidate benzyl ester-3 beta-oxy) -2-oxo- (N-tertiary butyl oxy) -benzamide has a specific structure as follows:
according to the synthesis method of example 1, starting from 2- (21-benzyl fusidate-3β -oxy) -2-oxo-benzoic acid, reaction with N-tert-butylhydroxylamine hydrochloride gave a white solid (132.8 mg,83.1% yield). 1 H NMR(400MHz,CDCl 3 )δ7.56–7.23(m,9H,9×Ar-H),5.87(d,J＝8.3Hz,1H,16-H),5.31–5.17(m,2H,3-H,-CHAr),5.07(tt,J＝7.3,1.6Hz,1H,24-H),4.93(d,J＝12.3Hz,1H,-CHAr),4.39(s,1H,11-H),3.13(s,1H,13-H),2.55–1.96(m,9H,2×22-H,12-H,15-H,2×23-H,1-H,4-H,5-H),1.91(s,3H,OCOCH 3 ),1.64(d,J＝1.4Hz,3H,27-CH 3 ),1.55–1.53(m,3H,26-CH 3 ),1.37–1.23(m,9H,30-CH 3 ,-(CH 3 ) 2 ),1.02(s,3H,-CH 3 ),0.92(s,3H,19-CH 3 ),0.88–0.80(m,6H,18-CH 3 ,28-CH 3 ).
Example 11
2- (21-Fuxidate benzyl ester-3 beta-oxy) -2-oxo- (N-allyloxy) -benzamide has a specific structure as follows:
reference to the synthesis of example 1, starting from 2- (21-benzyl fusidate-3. Beta. -oxy) -2-oxo-benzoic acidO-allylhydroxylamine hydrochloride reacted to give a white solid (127.4 mg,81.3% yield). 1 H NMR(400MHz,CDCl 3 )δ7.99(d,J＝48.8Hz,1H,-CONH-),7.58–7.26(m,9H,9×Ar-H),5.87(d,J＝8.4Hz,2H,16-H,-CH＝),5.36–4.87(m,6H,＝CH 2 ,-CH 2 Ar,24-H,3-H),4.42(d,J＝51.5Hz,2H,-OCH 2 -),3.96(s,1H,11-H),3.14–3.06(m,1H,13-H),2.55–1.96(m,9H,,2×22-H,12-H,15-H,2×23-H,1-H,4-H,5-H),1.92(s,3H,OCOCH 3 ),1.64–1.62(m,3H,27-CH 3 ),1.53(d,J＝1.3Hz,3H,26-CH 3 ),1.46(s,3H,30-CH 3 ),1.01(s,3H,19-CH 3 ),0.92(s,3H,18-CH 3 ),0.83(d,J＝6.2Hz,3H,28-CH 3 ).
Example 12
2- (21-Fusarium acid benzyl ester-3 beta-oxy) -2-oxo- (N-4-nitrobenzoyloxy) -benzamide has the specific structure shown in the specification:
according to the synthesis method of example 1, starting from 2- (21-benzyl fusidate-3β -oxy) -2-oxo-benzoic acid, reaction with O- (tetrahydropyran-2-yl) hydroxylamine gave a white solid (113.9 mg,68.9% yield). 1 H NMR(400MHz,CDCl 3 )δ8.21–7.94(m,1H,-CONH-),7.61–7.24(m,9H,9×Ar-H),5.88(d,J＝8.4Hz,1H,16-H),5.40–4.89(m,5H,-CH-,-CH 2 -Ar,3-H,24-H),4.45–4.34(m,1H,11-H),3.99–3.39(m,2H,-OCH 2 -),3.11(d,J＝12.1Hz,1H,13-H),2.49–1.97(m,9H,2×22-H,12-H,15-H,2×23-H,1-H,4-H,5-H),1.93(s,3H,OCOCH 3 ),1.63(s,3H,27-CH 3 ),1.52(s,3H,26-CH 3 ),1.28–1.25(m,3H,30-CH 3 ),0.93(d,J＝3.9Hz,3H,19-CH 3 ),0.90–0.83(m,6H,18-CH 3 ,28-CH 3 ).
Example 13
21-fusidic acid- (O-allylhydroxylamine) amide having the specific structure shown in the following formula:
taking 50mL eggplant-shaped bottle, dissolving fusidic acid (100 mg,0.2 mmol) in anhydrous CH 2 Cl 2 To (20 mL) was added DMAP (73.3 mg,0.6 mmol), EDCI (115 mg,0.6 mmol) and O-allylhydroxylamine hydrochloride (131 mg,1.2 mmol), and the reaction was stirred at room temperature for 5 hours. After the reaction is finished, ethyl acetate is added for dilution after concentration, 5% hydrochloric acid solution, water washing, saturated saline water washing, anhydrous sodium sulfate drying, filtration and concentration are sequentially carried out. Silica gel column chromatography (V) Petroleum ether :V Acetic acid ethyl ester =3:1) to give a white solid (87.0 mg, 80.2%). 1 H NMR(400MHz,CDCl 3 )δ8.12(s,1H,-CONH-),5.95(ddt,J＝16.8,10.3,6.3Hz,1H,＝CH),5.63(d,J＝8.5Hz,1H,16-H),5.35(dq,J＝17.3,1.4Hz,1H,＝CH),5.30(dq,J＝10.3,1.1Hz,1H,＝CH),5.08(tt,J＝7.1,1.5Hz,1H,24-H),4.42–4.30(m,3H,-OCH 2 -,11-H),3.75(d,J＝2.5Hz,1H,3-H),2.97(d,J＝12.2Hz,1H,13-H),2.43(d,J＝2.2Hz,1H,22-H),2.34–2.09(m,7H,22-H,12-H,15-H,2×23-H,1-H,5-H),2.05(s,3H,-OCOCH 3 ),1.68(d,J＝1.4Hz,3H,27-CH 3 ),1.61(d,J＝1.3Hz,3H,26-CH 3 ),1.37(s,3H,30-CH 3 ),0.97(s,3H,19-CH 3 ),0.94–0.89(m,6H,18-CH 3 ,28-CH 3 ).
Example 14
The specific structure of the 21-fusidic acid-methoxyamide is as follows:
referring to the synthesis of example 13, starting from fusidic acid, reaction with methoxyamine hydrochloride gave a white solid (81.1 mg, 76.8%). 1 H NMR(400MHz,CDCl 3 )δ8.35(s,1H,-CONH-),5.66(d,J＝8.5Hz,1H,16-H),5.09(ddd,J＝8.4,6.9,1.3Hz,1H,24-H),4.34(q,J＝2.7Hz,1H,11-H),3.72(s,4H,-OCH 3 ,3-H),2.98(d,J＝10.3Hz,1H,13-H),2.46(dd,J＝15.5,6.2Hz,1H,22-H),2.36–2.10(m,7H,22-H,12-H,15-H,2×23-H,1-H,5-H),2.04(s,3H,-OCOCH 3 ),1.69(s,3H,27-CH 3 ),1.61(s,3H,26-CH 3 ),1.37(s,3H,30-CH 3 ),0.97(s,3H,19-CH 3 ),0.91(d,J＝6.7Hz,6H,18-CH 3 ,28-CH 3 ).
The following are the results of pharmacological experiments on the compounds of the present invention.
1. Experimental method
1.1 MTT method for detecting cell viability
RAW264.7 cells in logarithmic phase were collected and the cell density was adjusted to 5X 10 per 100. Mu.L 4 The suspension of individual cells was inoculated into a 96-well plate and placed in a cell incubator (37 ℃,5% CO) 2 ) And incubating for 24 hours; FA dissolved in DMSO and examples 1-14 were added to cells, respectively, to give a final concentration of 40. Mu.M, and the control group was added with a corresponding volume of DMSO. Incubate in cell incubator for 24h. Each group is provided with 5 parallel complex holes; after 24h, 20. Mu.L of MTT solution was added at 5mg/mL per well and the mixture was further placed in an incubator (37 ℃,5% CO) 2 ) Incubating for 4 hours; taking out the pore plate from the incubator to terminate the reaction, and carefully sucking the culture solution in the pore; 150 mu LDMSO is added into each hole, a shaking table is placed for shaking for 10min at a low speed, so that crystals are fully dissolved, and OD value is detected at 570 nm.
1.2 Griess assay for detecting NO levels
RAW264.7 cells in logarithmic phase were collected and the cell density was adjusted to 5X 10 per 100. Mu.L 4 The suspension of individual cells was inoculated into a 96-well plate and placed in a cell incubator (37 ℃,5% CO) 2 ) And incubating for 24 hours; various compounds having a cell viability of 90% or more were selected, 100. Mu.L of each compound was added to a 96-well plate so that the final concentration of the compound was 5. Mu.M, 5. Mu.M of FA dissolved in DMSO and examples 1 to 14100. Mu.L were added to the 96-well plate, and a dexamethasone group (50 nM) was set as a positive control group. CO 2 Culturing for 2h at constant temperature; LPS (1. Mu.g/mL) was added to stimulate cells, and LPS and CO were added to the other groups except the control group 2 Culturing at constant temperature for 24h; transferring the cell culture supernatant after 24h of culture to a new 96-well plate, wherein 100 mu L of the supernatant is used for each well; uniformly mixing GriessA and GriessB in equal volume, adding 100 μl (A, B mixed solution) into each hole, and shaking in a shaker for 10min; OD was measured at 540 nm.
2 experimental results
FIG. 1 is a graph showing the effect of compounds on RAW264.7 cell viability, control: - - -; FA (examples 1-14): FA (examples 1-14) 40. Mu.M.
FIG. 2 is a graph showing the effect of compounds on NO production by RAW264.7 cells, compared to control ### P<0.001; compared with the model group *** P<0.001; n=5. Control group: - - -; model group: LPS; dexamethasone: lps+dexamethasone; FA (examples 1-14): LPS+FA (examples 1-14).
As shown in FIG. 1, the MTT assay results demonstrate that examples 1-14 have no significant effect on cell viability at 40. Mu.M.
As shown in fig. 2, the inflammatory factor NO levels were significantly increased in the model group compared to the control group; compared with the model group, the examples 1-14 can obviously inhibit the level of the inflammatory factor NO at 5 mu M, and the inhibition activity is superior to FA, thus indicating that the examples 1-14 have good anti-inflammatory activity. Among them, example 1 had the strongest anti-inflammatory activity, and had an anti-inflammatory effect stronger than that of dexamethasone, a positive control drug, and showed a 78.66% inhibition of NO at a concentration of 5. Mu.M.
Fusidic acid is a marketed antibacterial drug with general anti-inflammatory activity, and has an inhibition of NO of 2.18% at 2.5 μm and 14.95% at 5 μm. The invention takes 3,3' -dithiodipropionic acid and phthalic acid as connecting chains to connect hydroxylamine groups at C-3 of fusidic acid for the first time, has structural modification conforming to the activity structure-activity relationship, and obtains examples 1-5 and examples 8-12, and the anti-inflammatory activity is improved compared with that of fusidic acid. In the invention, phthalic acid is used as a connecting chain to connect a nitrogen-containing heterocycle at the C-3 position of the fusidic acid, and the introduction of the nitrogen-containing heterocycle can be found to improve the anti-inflammatory activity of the fusidic acid for the first time, for example, the inhibition rate of the fusidic acid on NO at 5 mu M is 44.50% and 30.83% respectively in the examples 6 and 7. The anti-inflammatory activity of the hydroxylamine group introduced at the C-21 position of fusidic acid was improved, and the inhibition rates of example 13 and example 14 on NO at 5. Mu.M were 21.32% and 18.26%, respectively. The anti-inflammatory activity of example 1 was strongest, with a 78.66% inhibition of NO at a concentration of 5 μm.
The experiment shows that the invention uses nitrogen-containing heterocycle or hydroxylamine to modify the C-3 or C-21 position of the fusidic acid to obtain the fusidic acid derivative with improved anti-inflammatory activity.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various equivalent changes can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the equivalent changes belong to the protection scope of the present invention. In addition, the specific features described in the above embodiments may be combined in any suitable manner without contradiction. The various possible combinations of the invention are not described in detail in order to avoid unnecessary repetition. Moreover, any combination of the various embodiments of the invention can be made without departing from the spirit of the invention, which should also be considered as disclosed herein.

Claims (1)

1. Application of fusidic acid derivatives with anti-inflammatory activity in preparing anti-inflammatory drugs;
the fusidic acid derivative has a structure shown in a general formula I, a general formula II and a general formula III:
；
wherein:
R 1 represents one of the following structures:
；
R 2 represents one of the following structures:
；
R 3 represents one of the following structures:
。
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