CN115784848A - Nor-sorbosone derivative and preparation method and application thereof - Google Patents
Nor-sorbosone derivative and preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- -1 p-propylphenyl Chemical group 0.000 claims abstract description 13
- 229940121375 antifungal agent Drugs 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 201000007336 Cryptococcosis Diseases 0.000 claims abstract description 5
- 241000221204 Cryptococcus neoformans Species 0.000 claims abstract description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 4
- 241000222122 Candida albicans Species 0.000 claims abstract description 3
- 241000222178 Candida tropicalis Species 0.000 claims abstract description 3
- 229940095731 candida albicans Drugs 0.000 claims abstract description 3
- 239000003429 antifungal agent Substances 0.000 claims abstract 2
- 125000005998 bromoethyl group Chemical group 0.000 claims abstract 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- KNPNGMXRGITFLE-UHFFFAOYSA-N methylperoxy(phenyl)borinic acid Chemical compound COOB(O)C1=CC=CC=C1 KNPNGMXRGITFLE-UHFFFAOYSA-N 0.000 claims description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 238000010520 demethylation reaction Methods 0.000 claims description 5
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 5
- QARVLSVVCXYDNA-UHFFFAOYSA-N phenyl bromide Natural products BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 238000005859 coupling reaction Methods 0.000 claims description 4
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- 238000004519 manufacturing process Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 230000017858 demethylation Effects 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
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- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
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- 150000001875 compounds Chemical class 0.000 abstract description 10
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 abstract description 5
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 36
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
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- 238000002844 melting Methods 0.000 description 13
- 230000008018 melting Effects 0.000 description 13
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- 235000010290 biphenyl Nutrition 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 238000012360 testing method Methods 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
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- 230000001580 bacterial effect Effects 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000031888 Mycoses Diseases 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- RULQUTYJXDLRFL-UHFFFAOYSA-N (3,4,5-trimethoxyphenyl)boronic acid Chemical compound COC1=CC(B(O)O)=CC(OC)=C1OC RULQUTYJXDLRFL-UHFFFAOYSA-N 0.000 description 1
- RCVDPBFUMYUKPB-UHFFFAOYSA-N (3,4-dimethoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1OC RCVDPBFUMYUKPB-UHFFFAOYSA-N 0.000 description 1
- 125000005999 2-bromoethyl group Chemical group 0.000 description 1
- ITHHJJXXFDRPNU-UHFFFAOYSA-N 4-(4-butylphenyl)benzene-1,2-diol Chemical class C(CCC)C1=CC=C(C=C1)C1=CC(=C(C=C1)O)O ITHHJJXXFDRPNU-UHFFFAOYSA-N 0.000 description 1
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- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000693079 Maloideae Species 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 235000004789 Rosa xanthina Nutrition 0.000 description 1
- 241000220222 Rosaceae Species 0.000 description 1
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- 150000003851 azoles Chemical class 0.000 description 1
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 238000004440 column chromatography Methods 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N dihydroxy-phenylborane Natural products OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
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- 229910052739 hydrogen Inorganic materials 0.000 description 1
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of pharmaceutical chemistry, and discloses a norkalopanax septentrion derivative shown as a formula I, wherein R is 1 When it is methoxy, R 2 Respectively H, C2-C8 alkyl, OH, bromoethyl, p-propylphenyl and propionitrile; when R is 1 When is H, R 2 Butyl and pentyl, respectively. The preparation method of the noralopecuroide derivative has the advantages of mild reaction conditions, simple route, low toxicity of the used reagent and simple and convenient operation. The norkalopanax delavayi extract derivative has inhibitory action with different degrees on candida albicans, candida tropicalis and cryptococcus neoformans, wherein the activity of a part of compounds is close to or similar to that of a first-line antifungal drug amphotericin B, and the norkalopanax delavayi extract derivative is used as an effective component for preparing a medical and medical antifungal drugPotential for antifungal drugs.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a norsorbosol derivative, a preparation method thereof and application thereof in preparing antifungal medicines.
Background
In recent years, with the increase of the number of people suffering from AIDS, malignant tumors, organ transplantation audiences and the like, the morbidity and mortality of deep fungal infection are in an increasing situation, and the situation becomes a very challenging global health problem. The fungal infection is effectively controlled thanks to the wide use of clinical antifungal drugs, but with the long-term wide use of limited types of antifungal drugs and the serious lag of the research of novel anti-infective drugs, the drug resistance problem becomes more and more non-negligible, and particularly, the drug resistance problem of first-line azole and echinocandin drugs is very prominent, so that the clinical application of the novel antifungal drugs is urgently needed.
Natural products play a very important role in drug discovery due to their chemical structure and diversity of biological functions. Noralprostadil is a biphenyl plant antitoxin, is a chemical defense substance generated by plants in the subfamily Maloideae of Rosaceae under biotic or abiotic stress, and has proved to have excellent antimicrobial activity, anti-tumor function, insecticidal function and the like. However, as a class of natural products, the derivatives also have some limitations common to natural products, such as rare content, difficult extraction, and unsatisfactory biological activity, so it is necessary to further modify the derivatives as lead compounds to obtain derivatives with stronger activity and better pharmaceutical property.
Nor-sorbosone derivative with general structural formula (Nor-sorbosone R) 1 =OMe,R 2 =H)
Disclosure of Invention
The invention provides a norkalopanax derivative, a preparation method and application thereof, so as to obtain a compound with high-efficiency antifungal activity.
The purpose of the invention is realized by the following technical scheme:
nor-sorbosone derivatives represented by formula I,
wherein R is 1 When it is methoxy, R 2 The group is selected from any one of the following groups:
R 1 when is H, R 2 The radicals are respectively butyl and pentyl.
The invention also aims to provide a preparation method of the norsorbosone derivative shown in the formula I, which takes the bromobenzene compound shown in the formula II and methoxyphenylboronic acid shown in the formula III as raw materials to obtain a target compound through two steps of Suzuki coupling and demethylation. The synthetic route is as follows:
step (1), coupling reaction: the bromobenzene compounds shown in formulas II and III and methoxyphenylboronic acid are used as raw materials, a mixed solution of 1, 4-dioxane, water =4 (volume ratio) is used as a reaction solvent under the protection of nitrogen, potassium carbonate is used as an alkali in a reaction system, and the reaction is carried out at 90 ℃ in the presence of 0.01 equivalent of palladium acetate and 0.01 equivalent of triphenylphosphine, so as to obtain the methoxybiphenyl compound shown in formula IV.
Step (2), demethylation reaction: taking a methoxyl biphenyl compound shown as a formula IV as a raw material, taking anhydrous dichloromethane as a reaction solvent, and slowly dropwise adding BBr 3 Reacting in ice bath, and quenching with precooled alkali solution to obtain the norkalopanax derivative shown in the formula I.
In the step (1), the molar ratio of the methoxyphenylboronic acid to the substituted bromobenzene is 1.2; the molar ratio of the methoxyphenylboronic acid to the potassium carbonate is 1; the molar ratio of the methoxyphenylboronic acid to the palladium acetate is 1; the molar ratio of the methoxyphenylboronic acid to the triphenylphosphine is 1; the reaction temperature is 90 ℃; after 10 hours of reaction under nitrogen protection, water was added for dilution, extraction was performed with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography after removal of ethyl acetate to obtain intermediate iv.
In the step (2), the intermediate IV and the demethylating reagent BBr 3 The molar ratio of (1) to (4) is 1.2 to react in an ice-water bath; after the reaction is finished, slowly adding pre-cooled 3M NaOH solution to quench the reaction, adding diluted hydrochloric acid to acidify after the solution is recovered to room temperature, removing dichloromethane, extracting with ethyl acetate, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, removing ethyl acetate, and performing column chromatography to obtain the norkalopanax bungeana derivative.
Pharmacological experiments show that the noralopecuroxine derivative has good antifungal activity, and the activity of a part of compounds in the noralopecuroxine derivative is close to or similar to that of a first-line antifungal medicine amphotericin B. Therefore, the invention also aims to provide the application of the norsorbose derivative in preparing antifungal medicaments.
The fungi are Candida albicans, candida tropicalis and Cryptococcus neoformans.
The compound can be used alone or in combination with clinically common antifungal drugs such as azoles, polyenes, echinocandins and pyrimidines.
The beneficial effects of the invention are:
the norkalopanax derivative has the advantages of simple preparation method, easily obtained raw materials, mild reaction conditions, convenient post-treatment and large-scale enrichment. Pharmacological experiments show that the noralopecuroxine derivative has good antifungal activity and stable property, and is expected to be developed into novel antifungal medicaments.
Drawings
FIG. 1 is a general structural formula of noralopecuroxin derivatives according to the present invention;
FIG. 2 shows Compound I prepared in example 2 of the present invention 17 Nuclear magnetic resonance hydrogen spectrum of (3);
FIG. 3 shows Compound I prepared in example 2 of the present invention 17 Nuclear magnetic resonance carbon spectrum of (1).
Detailed Description
The following examples are given to illustrate specific embodiments of the present invention.
Example 1: preparation of intermediate IV
Bromobenzene, 3,4, 5-trimethoxyphenylboronic acid or 3, 4-dimethoxyphenylboronic acid, potassium carbonate, palladium acetate and triphenylphosphine are added into a round-bottom flask according to the molar ratio of 1.2;
TABLE 1 Synthesis of intermediate IV
Example 2: preparation of noralopecuroide derivative I
Dissolving the intermediate IV in dichloromethane, stirring for 3-5 min in an ice water bath, slowly dropwise adding boron tribromide into the solution, wherein the molar ratio of the dropwise added boron tribromide to the intermediate IV is 1.2-4, continuing to react for 10min after the dropwise addition is finished, and monitoring the reaction progress by thin-layer chromatography. After the reaction is finished, slowly dropwise adding a pre-cooled 3M NaOH solution to quench the reaction. And (3) returning to room temperature, dropwise adding dilute hydrochloric acid to adjust the pH value of the solution to be less than 4, performing rotary evaporation to remove dichloromethane, adding water to dilute the solution, extracting the solution with ethyl acetate for three times, combining organic phases, washing the organic phases with saturated saline solution, drying the organic phases with anhydrous sodium sulfate, performing rotary evaporation to remove the ethyl acetate, and performing silica gel column chromatography to purify the organic phases to obtain the norsorbarin derivative I.
TABLE 2 Synthesis of Noralosorbin derivatives
The structure of noralopecuroxin derivatives is characterized as follows:
nor-sorbosone (I) 1 ) White solid; the melting point is 94.5-95.1 ℃; 1 H NMR(400MHz,CD 3 OD)δ7.61(d,J=7.8Hz,2H),7.47–7.43(m,2H),7.35–7.31(m,1H),6.82(s,1H),6.81(s,1H),3.98(s,3H). 13 C NMR(100MHz,CD 3 OD)δ148.5,145.4,141.3,133.6,132.2,128.2(2×C),126.1(3×C),107.2,102.1,55.3.
5-methoxy- [1,1' -biphenyl]-3, 4' -trisphenol (I) 2 ) A grey solid; the melting point is 149.2-150.6 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ9.35(s,1H),8.84(s,1H),8.20(s,1H),7.33(d,J=8.1Hz,2H),6.76(d,J=8.1Hz,2H),6.59(s,1H),6.58(s,1H),3.79(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ156.8,149.1,146.5,133.6,132.0,131.4,127.6(2×C),115.9(2×C),107.2,102.1,56.3.
4 '-Ethyl-5-methoxy- [1,1' -biphenyl]3, 4-biphenol (I) 3 ) Brown solid; the melting point is 78.1-79.3 ℃; 1 H NMR(400MHz,CDCl 3 )δ7.46(d,J=8.1Hz,2H),7.25(d,J=8.1Hz,2H),6.85(s,1H),6.69(s,1H),3.94(s,3H),2.69(q,J=7.6Hz,2H),1.28(t,J=7.6Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ147.1,144.9,143.1,139.7,133.6,131.8,128.2(2×C),126.8(2×C),107.6,101.8,56.2,28.5,15.6.
4 '-propyl-5-methoxy- [1,1' -biphenyl]-3, 4-Diols (I) 4 ) Brown-yellow solid; the melting point is 62.5-63.9 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ8.93(s,1H),8.32(s,1H),7.44(d,J=7.7Hz,2H),7.18(d,J=7.7Hz,2H),6.68(s,2H),3.81(s,3H),2.54(t,J=6.2Hz,2H),1.62~1.53(m,2H),0.88(t,J=7.3Hz,3H). 13 C NMR(100MHz,DM SO-d 6 )δ149.2,146.5,140.8,138.6,134.2,131.2,129.1(2×C),126.4(2×C),107.7,102.5,56.4,37.2,24.5,14.1.
4 '-butyl-5-methoxy- [1,1' -biphenyl]-3, 4-Diols (I) 5 ) A tan solid; the melting point is 63.9-65.2 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ8.92(s,1H),8.32(s,1H),7.44(d,J=7.7Hz,2H),7.18(d,J=7.7Hz,2H),6.68(s,2H),3.81(s,3H),2.56(t,J=7.7Hz,2H),1.57–1.50(m,2H),1.34–1.34(m,2H),0.88(t,J=7.4Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ149.2,146.5,141.0,138.5,134.2,131.2,129.1(2×C),126.4(2×C),107.7,102.5,56.3,34.8,33.6,22.2,14.2.
4'- (1-propionitrile) -5-methoxy- [1,1' -biphenyl]-3, 4-Diols (I) 6 ) Yellow solid; the melting point is 104.3-105.7 ℃; 1 H NMR(400MH z,CDCl 3 )δ7.49(d,J=7.8Hz,2H),7.27(d,J=7.8Hz,2H),6.83(s,1H),6.68(s,1H),3.93(s,3H),2.98(t,J=7.4Hz,2H),2.65(t,J=7.4Hz,2H). 13 C NMR(100MHz,CDCl 3 )δ147.2,144.1,140.1,136.7,132.9,132.2,128.6(2×C),127.3(2×C),119.2,107.7,102.2,56.3,31.2,19.4.
4'- (2-bromoethyl) -5-methoxy- [1,1' -biphenyl]3, 4-biphenol (I) 7 ) Light yellow solid; the melting point is 128.1-128.8 ℃; 1 H NMR(400
MHz,CDCl 3 )δ7.49(d,J=7.6Hz,2H),7.25(d,J=7.6Hz,2H),6.85(s,1H),6.70(s,1H),3.94(s,3
H),3.60(t,J=7.7Hz,2H),3.20(t,J=7.7Hz,2H). 13 C NMR(100MHz,CDCl 3 )δ147.1,144.1,139.8,
137.6,133.1,132.0,129.0(2×C),127.0(2×C),107.7,102.2,56.4,39.0,32.9.
4 '-hexyl-5-methoxy- [1,1' -biphenyl]-3, 4-Diols (I) 8 ) Brown liquid; 1 H NMR(400MHz,CDCl 3 )δ7.45(d,J=7.7Hz,2H),7.22(d,J=7.7Hz,2H),6.85(s,1H),6.70(s,1H),3.94(s,3H),2.64(t,J=7.7Hz,2H),1.68–1.61(m,2H),1.39–1.31(m,6H),0.90(t,J=6.0Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ148.3,144.7,142.4,138.9,134.2,131.8,129.5(2×C),127.5(2×C),107.6,103.4,56.2,37.2,32.9,31.0,29.0,22.6,14.1.
4 '-cyclohexyl-5-methoxy- [1,1' -biphenyl]3, 4-biphenol (I) 9 ) Light yellow solid; the melting point is 115.6-116.2 ℃; 1 H NMR(400MHz,CDCl 3 )δ7.46(d,J=7.8Hz,2H),7.25(d,J=7.8Hz,2H),6.85(s,1H),6.69(s,1H),3.93(s,3H),2.55–2.51(m,1H),1.92–1.85(m,4H),1.78–1.75(m,1H),1.50–1.36(m,4H),1.32–1.23(m,1H). 13 C NMR(100MHz,CDCl 3 )δ147.0,146.9,144.0,138.6,133.6,131.8,127.2(2×C),126.7(2×C),107.6,102.2,56.2,44.2,34.5(2×C),26.9(2×C),26.2.
4 '-tert-butyl-5-methoxy- [1,1' -biphenyl]3, 4-biphenol (I) 10 ) Brown-yellow solid; the melting point is 91.9-92.8 ℃; 1 H NMR(400MHz,CDCl 3 )δ7.49(d,J=8.2Hz,2H),7.45(d,J=8.2Hz,2H),6.88(s,1H),6.72(s,1H),3.94(s,3H),1.37(s,9H). 13 C NMR(100MHz,CDCl 3 )δ150.8,147.2,144.1,138.2,134.9,132.4,127.0(2×C),125.6(2×C),108.2,102.3,67.8,34.5,31.4(3×C).
4 '-isopropyl-5-methoxy- [1,1' -biphenyl]3, 4-biphenol (I) 11 ) Yellow solid; the melting point is 90.6-91.3 ℃; 1 H NMR(400MHz,CDCl 3 )δ7.47(d,J=8.1Hz,2H),7.28(d,J=8.1Hz,2H),6.86(s,1H),6.70(s,1H),3.94(s,3H),3.01–2.90(m,1H),1.30(d,J=6.9Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ148.8,146.6,144.0,138.7,134.6,131.8,126.8(4×C),108.7,104.1,56.2,34.3,24.0(2×C).
4 '-pentyl-5-methoxy- [1,1' -biphenyl]3, 4-biphenol (I) 12 ) Brown liquid; 1 H NMR(400MHz,CDCl 3 )δ7.44(d,J=8.2Hz,2H),7.22(d,J=8.2Hz,2H),6.84(s,1H),6.69(s,1H),3.94(s,3H),2.63(t,J=7.9Hz,2H),1.68–1.61(m,2H),1.37–1.33(m,4H),0.91(t,J=6.7Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ147.5,144.9,141.8,138.8,135.2,131.8,128.7(2×C),126.2(2×C),107.6,103.2,56.2,36.9,32.0,31.2,23.0,13.5.
4 '-octyl-5-methoxy- [1,1' -biphenyl]3, 4-biphenol (I) 13 ) A yellow brown liquid; 1 H NMR(400MHz,CDCl 3 )δ7.47(d,J=7.7Hz,2H),7.24(d,J=7.7Hz,2H),6.89(s,1H),6.72(s,1H),3.93(s,3H),2.66(t,J=7.8Hz,2H),1.71–1.63(m,2H),1.43–1.16(m,10H),0.93(t,J=6.5Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ147.2,144.2,141.8,138.4,133.6,131.9,128.8(2×C),126.7(2×C),107.7,102.3,56.3,35.6,32.0,31.6,29.6,29.4,29.3,22.7,14.2.
4'- (4-propylphenyl) -5-methoxy- [1,1' -biphenyl]3, 4-biphenol (I) 14 ) Yellow solid; the melting point is 135.3-136.2 ℃; 1 H NMR(400MHz,CDCl 3 )δ7.64(d,J=8.1Hz,2H),7.60(d,J=8.1Hz,2H),7.56(d,J=7.7Hz,2H),7.28(d,J=7.7Hz,2H),6.92(s,1H),6.75(s,1H),3.96(s,3H),2.65(t,J=7.6Hz,2H),1.75–1.65(m,2H),1.00(t,J=7.4Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ147.2,144.1,141.9,139.8,139.7,138.1,133.1,132.1,128.9(2×C),127.7(2×C),127.1(2×C),126.8(2×C),107.0,103.0,56.3,37.7,24.6,13.9.
4 '-heptyl-5-methoxy- [1,1' -biphenyl]-3, 4-Diols (I) 15 ) Brown liquid; 1 H NMR(400MHz,CDCl 3 )δ7.45(d,J=7.7Hz,2H),7.22(d,J=7.7Hz,2H),6.85(s,1H),6.69(s,1H),3.94(s,3H),2.63(t,J=7.7Hz,2H),1.68–1.61(m,2H),1.36~1.25(m,8H),0.89(t,J=6.0Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ147.1,144.0,141.8,138.4,133.6,131.8,128.7(2×C),126.7(2×C),107.6,102.2,56.2,35.6,31.8,31.5,29.3,29.2,22.7,14.1.
4 '-butyl- [1,1' -biphenyl]-3, 4-Diols (I) 16 ) A gray solid; the melting point is 142.8 to 144.1 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ8.96(s,1H),8.95(s,1H),7.39(d,J=8.2Hz,2H),7.17(d,J=8.2Hz,2H),6.99(s,1H),6.88(d,J=8.1Hz,1H),6.78(d,J=8.1Hz,1H),2.55(t,J=7.7Hz,2H),1.57–1.50(m,2H),1.34–1.25(m,2H),0.88(t,J=7.2Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ146.0,145.4,140.8,138.3,132.0,129.1(2×C),126.2(2×C),117.8,116.4,114.2,34.8,33.6,22.2,14.2.
4 '-pentyl- [1,1' -biphenyl]-3, 4-Diols (I) 17 ) White solid; the melting point is 145.2-147.0 ℃; 1 H NMR(400MHz,CDCl 3 )δ7.43(d,J=7.9Hz,2H),7.22(d,J=7.9Hz,2H),7.11(d,J=2.1Hz,1H),7.05(dd,J=8.3,2.1Hz,1H),6.92(d,J=8.3Hz,1H),2.63(t,J=7.8Hz,2H),1.68–1.61(m,2H),1.39–1.32(m,4H),0.91(t,J=6.6Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ143.6,142.8,141.7,137.9,134.8,128.8(2×C),126.6(2×C),119.7,115.7,114.1,35.5,31.5,31.2,22.5,14.0.
example 3: antifungal Activity test
Dilution of Compound I by minimal Broth 1 —Ⅰ 17 Antifungal activity tests were performed with amphotericin B (AMB) as a positive control drug.
The first step is as follows: activating the strain. Transferring the strain stored at low temperature to SDA (glucose peptone agar medium) culture medium by plate-streaking method, and standing in 35 deg.C constant temperature incubator. After three days, the cells were transferred again for use.
The second step is that: preparing a test drug mother solution. Respectively weighing a certain amount of norkalopanax derivative, dissolving with DMSO to obtain solution of 10240 μ g/mL, and storing at-20 deg.C.
The third step: and preparing working bacteria liquid. Scraping the activated strain by using an inoculating loop, transferring the strain into an SDB culture solution, carrying out shaking culture at 37 ℃ for 24h to obtain turbid bacterial suspension, adjusting the absorbance of the bacterial suspension at 620nm to 0.10-0.13 by using an ultraviolet spectrophotometer, adding 100 mu L of the turbid bacterial suspension into 100mL of sterile SDB culture solution, and shaking the turbid bacterial suspension uniformly for later use.
The fourth step: and (5) manufacturing a drug sensitive plate. After the mother solution of the test drug is returned to the room temperature, 100 mu L of the mother solution is diluted by 10 times by using sterile water, 200 mu L of the mother solution is respectively added into the first row of a 96-well plate after the mother solution is uniformly blown, and other drugs are sequentially operated. Adding 100 mu L of 10% DMSO-containing sterile water into all the wells in the 2 nd to 12 th rows, taking 100 mu L of the liquid medicine in the wells in the first row into the wells in the second row, uniformly blowing, repeating the operation, sequentially diluting to the 10 th row, taking 100 mu L, and discarding. 100. Mu.L of the working medium solution was added to each of columns 1 to 11, and 100. Mu.L of the sterile SDB culture solution was added to column 12. At this time, the volume of the solution in each well of the 96-well plate is 200. Mu.L, and the solution contains 5% DMSO, and the concentrations of the test drugs in the 1 st to 10 th columns are 512, 256, 128, 64, 32, 16,8,4,2 and 1. Mu.g/mL in this order.
The fifth step: and (4) incubating. And (3) culturing the prepared drug sensitive plate at the constant temperature of 35 ℃, culturing candida for 48 hours, and culturing cryptococcus neoformans for 72 hours.
And a sixth step: and (6) recording the result. After the culture was completed, the minimum concentration of the test drug in the well clear without fungal growth was recorded as the minimum inhibitory concentration MIC by visual observation, and each experiment was repeated three times. If the MIC is less than or equal to 1 mu g/mL, the concentration is properly reduced and the test is continued.
TABLE 3 MIC (μ g/mL) of noralopecuroxin derivatives against different pathogenic fungi.
As can be seen from Table 3, most of the noralopecuroxine derivatives of the present invention exhibited moderate to excellent antibacterial activity against three tested fungi, wherein compound I 12 、I 16 And I 17 More active, especially Compound I 17 The cryptococcus neoformans has the same inhibitory activity with the positive control AMB, is expected to become a new antifungal medicine, and is worthy of further research.
While the present invention has been described in detail with reference to the embodiments, the present invention should not be construed as limited by the scope of the claims. Various modifications and changes may be made by those skilled in the art without inventive step within the scope of the appended claims.
Claims (7)
2. A process for the preparation of noralopecuroxine derivatives according to claim 1, characterized by the following synthetic route:
wherein R is 1 When it is methoxy, R 2 Respectively H, C2-C8 alkyl, OH, bromoethyl, p-propylphenyl and propionitrile; r is 1 When is H, R 2 N-butyl and n-propyl, respectively.
3. A method for producing a noralopecuroxine derivative according to claim 2, characterized by comprising:
step (1), coupling reaction: in the presence of 0.01 equivalent of palladium acetate and 0.02 equivalent of triphenylphosphine in nitrogen atmosphere, taking a mixed solution of 1, 4-dioxane, water =4 and 1 as a reaction solvent, and taking potassium carbonate as an alkali in a reaction system, wherein bromobenzene compounds shown as a formula II and a formula III and methoxyphenylboronic acid are subjected to coupling reaction to generate an intermediate IV;
step (2), demethylation reaction: using anhydrous dichloromethane as solvent, intermediate IV and demethylating reagent BBr 3 Reacting, hydrolyzing in alkaline solution to obtain the norkalopanax derivative.
4. A method for producing a noralopecuroxine derivative according to claim 3, wherein in the step (1), the molar ratio of said methoxyphenylboronic acid to bromobenzene compound is 1; the molar ratio of the methoxyphenylboronic acid to the potassium carbonate is 1; the molar ratio of the methoxyphenylboronic acid to the palladium acetate is 1; the molar ratio of the methoxyphenylboronic acid to the triphenylphosphine is 1; the coupling reaction temperature is 90 ℃;
in the step (2), the intermediate IV and the demethylating reagent BBr 3 The molar ratio of (A) to (B) is 1.2-4; the demethylation reaction is carried out in ice-water bath; the demethylation post-treatment is quenched with a pre-cooled alkaline solution.
5. A pharmaceutical composition characterized by comprising the noralopecuroxin derivative according to claim 1 as an active ingredient.
6. Use of the noralopecuropine derivative of claim 1 or the pharmaceutical composition of claim 5 for the preparation of an antifungal agent.
7. Use according to claim 6, characterized in that the fungi are Candida albicans, candida tropicalis and Cryptococcus neoformans.
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