CN115368252B - 4-aminophenol derivative and application thereof - Google Patents

4-aminophenol derivative and application thereof Download PDF

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CN115368252B
CN115368252B CN202211135773.1A CN202211135773A CN115368252B CN 115368252 B CN115368252 B CN 115368252B CN 202211135773 A CN202211135773 A CN 202211135773A CN 115368252 B CN115368252 B CN 115368252B
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纪克攻
赵欣
杨芳
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Northwest A&F University
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Abstract

The invention provides a 4-aminophenol derivative and application thereof, and the structural general formula of the derivative is shown as the following formula (I-1) or formula (I-2):the invention provides a plurality of compounds with tyrosinase inhibitory activity and antibacterial activity by introducing N-aryl para-aminophenol to stabilize the structure, enhancing the derivatization of the compounds and evaluating the antibacterial, antioxidant and tyrosine inhibitory activity of the structure. The invention has the characteristics of simple synthesis of the compound, good antibacterial effect on MRSA (methicillin-resistant staphylococcus aureus), high enzyme inhibition rate and the like, has wide application prospect, and solves the problems that N-monoalkyl substituted p-aminophenol is generally unstable and easy to oxidize and has single derivative structure.

Description

4-aminophenol derivative and application thereof
Technical Field
The invention relates to the technical field of chemical biology, in particular to a 4-aminophenol derivative and application thereof.
Background
Tyrosinase (TYR) is a class of metabolic enzymes in humans that mediate melanin synthesis, and is involved in the pathogenesis of a variety of diseases. The enzyme can cause pigment synthesis disorder dermatoses such as vitiligo or albino when the function of the enzyme is reduced or deleted; in contrast, if the expression level of the enzyme is too high, pigmentation symptoms such as freckle, darkness, chloasma, senile plaque and the like may occur due to vigorous melanin production. With the deep research, tyrosinase inhibitors with complex structures can be used as antibacterial agents, so that the functions of the compounds are further enriched, the compounds have great potential in medical raceways, but the compounds are usually barbiturates, pyrazolines, aloe-emodin and other compounds with complex structures.
Para-aminophenol derivatives are receiving a great deal of attention for their various biological activities, the skeletons are regarded as ampholytes, have good water solubility, and these skeletons are capable of providing hydrogen atoms of phenolic hydroxyl groups to free radicals to prevent chain propagation during oxidation, so that such compounds have good biological activities.
However, research at home and abroad is focused on aliphatic secondary alkylamino phenol compounds, the stability is lacking due to the fact that the electron cloud density of the compounds is high due to the alkyl electron effect, and meanwhile, a special secondary alkylamino phenol structure is one of reasons for poor derivatization, so that further biological activity research on the structure at home and abroad is less.
At present, p-aminophenol derivatives have been studied and developed mainly as colorants, but studies on the development of compounds having both tyrosinase activity and acid enzyme inhibitory activity, antioxidant activity and antibacterial activity have not been reported yet. Therefore, the invention enhances the derivatization of the compound while stabilizing the structure of the aminophenol by introducing the N-aryl, and finally successfully finds a plurality of compounds with good amylase inhibitory activity, antioxidant activity and antibacterial activity from the derivative compounds.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a 4-aminophenol derivative and application thereof. The N-aryl is introduced to stabilize the structure of the aminophenol, the derivatization of the compound is enhanced, and finally, a plurality of compounds with good amino acid enzyme inhibition activity, antioxidation and antibacterial activity are successfully found from the derivative compounds.
In order to achieve the above object, the technical scheme of the present invention is as follows.
A4-aminophenol derivative has a structural general formula shown in the following formula (I-1) or formula (I-2):
in the formulae (I-1) and (I-2), D 1 、D 2 、D 3 Each independently selected from the group consisting of a group of formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) and formula (VIII):
in the formula (II), R 1 Selected from-H, -F, -Cl, -Br, C1-C4 alkyl, nitro, cyano, methoxy, substituted or unsubstituted aryl, substituted or unsubstitutedAny one of a condensed ring aryl group, a substituted or unsubstituted condensed heterocyclic ring, a substituted or unsubstituted arylethynyl group;
R 2 any one selected from C1-C14 alkyl, allyl, substituted or unsubstituted mono-heterocycloalkyl, substituted or unsubstituted fused-heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted fused-ring aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted fused-ring arylalkyl, and substituted or unsubstituted arylaminoalkyl;
in the formulas (III) to (V), X is any one of an oxygen atom, a sulfur atom and a carbon atom.
Further, in formula (II), when R 1 When the aryl is selected from any one of substituted aryl, substituted condensed ring and substituted aryl ethynyl, the substituent is any one of-F, -Cl, -Br, C1-C4 alkyl, nitro, cyano and methoxy;
when R is 2 When the substituent is any one selected from substituted mono-heterocycloalkyl, substituted fused-heterocycloalkyl, substituted aryl, substituted fused-ring aryl, substituted arylalkyl, substituted fused-ring arylalkyl and substituted arylaminoalkyl, the substituent is any one selected from-F, -Cl, -Br, C1-C4 alkyl, nitro, cyano and methoxy.
Further, the group represented by formula (II) is selected from one of the following structural formulas:
further, the group represented by formula (III) is selected from one of the following structural formulas:
further, specifically one of the following compounds:
the invention also provides application of the 4-aminophenol derivative in preparing a tyrosinase inhibitor.
The invention also provides application of the 4-aminophenol derivative in preparing an antibacterial agent for MRSA (methicillin-resistant staphylococcus aureus).
The invention also provides application of the 4-aminophenol derivative in preparing an antioxidant.
The invention has the beneficial effects that:
1. the invention enhances the derivatization of the compound while stabilizing the structure of the aminophenol by introducing the N-aryl, and finally successfully finds a plurality of compounds with good amino acid enzyme inhibition activity, antioxidation and antibacterial activity from the derivative compounds.
2. Aiming at the problems that N-monoalkyl substituted para-aminophenol is generally unstable and easy to oxidize and has single derivative structure, the invention leads the structure to be stable by introducing N-aryl para-aminophenol, enhances the derivatizability of the compound, evaluates the antibacterial, antioxidant and tyrosine inhibitory activity of the structure, and finds a plurality of compounds with tyrosinase inhibitory activity and antibacterial activity at the same time. The invention has the characteristics of simple synthesis of the compound, good antibacterial effect on MRSA (methicillin-resistant staphylococcus aureus), high enzyme inhibition rate and the like, and has wide application prospect.
Drawings
FIG. 1 is a bar graph of toxicity tests on RAW264.7 cells for different concentrations of compounds 4k,4m,4n,4p,4 ab.
FIG. 2 is the result of the effect of compounds on tyrosinase. Wherein (a) is the effect of various compounds on tyrosinase activity at 16. Mu.M. (b) Is the concentration dependent effect (average) of the compound on the tyrosinase activity of mushrooms.
FIG. 3 is a graph showing the kinetics of tyrosinase oxidation of L-tyrosine in the presence of compound 4 ab. Wherein (a) is a Lineweaver-Burk plot of tyrosinase inhibition by 3-1j at concentrations of 0, 1, 2,4, 8, 16 and 32. Mu.M. (b) Is a plot of slope versus inhibitor (3-1 j) concentration.
FIG. 4 is a bar graph showing the scavenging effect of different concentrations of ascorbic acid, 4k,4m,4n,4p and 4ab on DPPH.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Cu(OTf) 2 Copper (ii) trifluoromethane sulfonate. Schlenk tube, shu Lunke tube. THF, tetrahydrofuran. Buchwald-Hartwig coupling reaction, buchwald-Hartmann reaction. Pd (Pd) 2 (dba) 3 Tris (dibenzylideneacetone) dipalladium. Davephos, 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl. LiN (TMS) 2 Lithium bis- (trimethylsilyl) amide. RuPhos, 2-bicyclo-hexylphosphine-2 ',6' -diisopropyloxybiphenyl. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.
In the following we will take different types of compounds as examples, and provide methods for synthesizing these compounds.
Example 1
The synthesis process of N-aryl para amino phenol derivative includes the steps of using cyclohexenone and N-alkyl aniline as substrate and Cu (OTf) 2 Is catalyst, L is ligand, toluene is solvent and oxygenReacting for 8-60h at 80 ℃ in the atmosphere to obtain the target product N-aryl para-aminophenol derivative, wherein the reaction process is as follows:
the specific operation is as follows: removing water from the Schlenk tube with the magnetons, and sequentially adding MgSO 4 (3.0 eq., desiccant), cu (OTf) 2 (5.0 mol%) and L (10.0 mol%) and then evacuated and replaced with oxygen (three times). Cyclohexenone (3.0 eq.) and N-alkylaniline (0.3 mmol,1.0 eq.) and trifluoroacetic acid (2.5 mol%, pre-formulated as trifluoroacetic acid-toluene solution, ready-to-use) were added sequentially to the reaction tube with a needle tube, and reacted for 8-60h at 80℃depending on the different substrates. After the reaction is completed, filtering the insoluble substances, washing the insoluble substances with ethyl acetate for three times, concentrating the insoluble substances, and performing column chromatography to obtain the target product N-aryl para-aminophenol derivatives. Compounds 1 to 27 and compounds 40 to 58 were prepared by the method of example 1.
Example 2
The synthesis process of N-aryl p-naphthene amino phenol derivative includes using p-bromophenol and secondary amine as substrate and Pd 2 (dba) 3 As a catalyst, davephos (2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl) is used as a ligand, THF is used as a solvent, and the reaction is carried out for 8-12h at 65 ℃ in nitrogen atmosphere to obtain the target product N-aryl p-naphthene amino phenol derivative, wherein the reaction process is as follows:
pd is combined with 2 (dba) 3 (2.0 mol% Pd), davephos (2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl) (2.4 mol%), p-bromophenol (5.0 mmol) and secondary amine (6.0 mmol) were added sequentially to a dehydrated Schlenk flask, and after three nitrogen substitutions LiN (TMS) was slowly added with a syringe in an ice-water bath 2 (1M，LiN(TMS) 2 THF solution, 5.5 mL), at 65℃for 8-12h, cooled to room temperature, and added with 1M HCl(5-10 mL) quenching with saturated NaHCO 3 The mixture is made alkaline, the organic phases are combined by three extractions with ethyl acetate, concentrated after drying, chromatographed on a silica gel column, eluting with ethyl acetate: petroleum ether=1:20 to 1:8. Compounds 32-34 were prepared using the procedure of example 2.
Example 3
The synthesis process of N-aryl p-benzocycloalkanoaminophenol derivative includes using p-bromoanisole and secondary amine as substrate and Pd (OAc) 2 As a catalyst, ruPhos was the ligand, DCM/H 2 O is solvent, and reacts for 8-12h at 110 ℃ in nitrogen atmosphere to obtain the target product N-aryl p-benzocycloalkanamino phenol derivative, wherein the reaction process is as follows:
in a dehydrated round bottom flask was added para-bromoanisole (5.1 mmol), secondary amine (5.0 mmol), pd (OAc) 2 (0.05 mmol), ruPhos (0.10 mmol) and NaO t Bu (6.0 mmol), with nitrogen substitution, was reacted at 110℃for 8-12H and after cooling to room temperature DCM/H2O=1:1 mixture was added. The organic phase is extracted three times and then dried and concentrated, and the eluent is methylene dichloride/methyl tertiary ether.
After dissolving the resulting para-amino ether in water-free DCM (30 mL) and adding to a 100mL round bottom flask (2.2 mmol), 1M BBr was slowly added dropwise at-78deg.C 3 (3 mL,3.0 mmol) and after 3h at room temperature, the mixture was poured into ice water and saturated NaHCO was slowly added dropwise 3 Until the solution is alkaline, the solution is dried after being extracted by DCM, concentrated, and chromatographed on silica gel, wherein the eluent is ethyl acetate: petroleum ether=1:20 to 1:8. Compounds 28, 30 were prepared using the procedure of example 3.
Example 4
The synthesis process of N-aryl p-condensed heterocyclic alkylamino phenol derivative includes using p-bromoanisole and secondary amine as substrate and Pd (OAc) 2 As a catalyst, ruPhos was the ligand, DCM/H 2 O is used as a solvent, and the reaction is carried out for 8 to 12 hours at the temperature of 110 ℃ in the nitrogen atmosphere to obtain the target product NAryl-p-fused heterocycloalkylamino phenol derivatives, the reaction process of which is shown below:
in a dehydrated round bottom flask was added para-bromoanisole (5.1 mmol), secondary amine (5.0 mmol), pd (OAc) 2 (0.05 mmol), ruPhos (0.10 mmol) and NaO t Bu (6.0 mmol), with nitrogen substitution, was reacted at 110℃for 8-12H and after cooling to room temperature DCM/H2O=1:1 mixture was added. The organic phase is extracted three times and then dried and concentrated, and the eluent is methylene dichloride/methyl tertiary ether.
After dissolving the resulting para-amino ether in water-free DCM (30 mL) and adding to a 100mL round bottom flask (2.2 mmol), 1M BBr was slowly added dropwise at-78deg.C 3 (3 mL,3.0 mmol) and after 3h at room temperature, the mixture was poured into ice water and saturated NaHCO was slowly added dropwise 3 Until the solution is alkaline, the solution is dried after being extracted by DCM, concentrated, and chromatographed on silica gel, wherein the eluent is ethyl acetate: petroleum ether=1:20 to 1:8. Compounds 29, 59, 61 were prepared using the procedure of example 4.
Example 5
The synthesis process of N-aryl p-condensed heterocyclic alkylamino phenol derivative includes using p-bromoanisole and secondary amine as substrate and Pd (OAc) 2 As a catalyst, ruPhos was the ligand, DCM/H 2 O is used as a solvent, and the reaction is carried out for 8 to 12 hours at the temperature of 110 ℃ in the nitrogen atmosphere to obtain the target product N-aryl p-condensed heterocyclic alkylamino phenol derivative, wherein the reaction process is as follows:
in a dehydrated round bottom flask was added para-bromoanisole (5.1 mmol), secondary amine (5.0 mmol), pd (OAc) 2 (0.05 mmol), ruPhos (0.10 mmol) and NaO t Bu (6.0 mmol), with nitrogen substitution, was reacted at 110℃for 8-12H and after cooling to room temperature DCM/H2O=1:1 mixture was added. Extracting the organic phase three times and dryingConcentrating, and performing column chromatography with dichloromethane/methyl tertiary ether as eluent.
After dissolving the resulting para-amino ether in water-free DCM (30 mL) and adding to a 100mL round bottom flask (2.2 mmol), 1M BBr was slowly added dropwise at-78deg.C 3 (3 mL,3.0 mmol) and after 3h at room temperature, the mixture was poured into ice water and saturated NaHCO was slowly added dropwise 3 Until the solution is alkaline, the solution is dried after being extracted by DCM, concentrated, and chromatographed on silica gel, wherein the eluent is ethyl acetate: petroleum ether=1:20 to 1:8. Compound 60 was prepared using the procedure of example 5.
Example 6
The synthesis process of N-aryl p-condensed heterocyclic alkylamino phenol derivative includes using p-bromoanisole and secondary amine as substrate and Pd (OAc) 2 As a catalyst, ruPhos was the ligand, DCM/H 2 O is used as a solvent, and the reaction is carried out for 8 to 12 hours at the temperature of 110 ℃ in the nitrogen atmosphere to obtain the target product N-aryl p-condensed heterocyclic alkylamino phenol derivative, wherein the reaction process is as follows:
in a dehydrated round bottom flask was added para-bromoanisole (5.1 mmol), secondary amine (5.0 mmol), pd (OAc) 2 (0.05 mmol), ruPhos (0.10 mmol) and NaO t Bu (6.0 mmol), with nitrogen substitution, was reacted at 110℃for 8-12H and after cooling to room temperature DCM/H2O=1:1 mixture was added. The organic phase is extracted three times and then dried and concentrated, and the eluent is methylene dichloride/methyl tertiary ether.
After dissolving the resulting para-amino ether in water-free DCM (30 mL) and adding to a 100mL round bottom flask (2.2 mmol), 1M BBr was slowly added dropwise at-78deg.C 3 (3 mL,3.0 mmol) and after 3h at room temperature, the mixture was poured into ice water and saturated NaHCO was slowly added dropwise 3 Until the solution is alkaline, the solution is dried after being extracted by DCM, concentrated, and chromatographed on silica gel, wherein the eluent is ethyl acetate: petroleum ether=1:20 to 1:8. Compound 31 was prepared using the procedure of example 6.
Example 7
The synthesis process of N-aryl p-condensed heterocyclic alkylamino phenol derivative includes using p-bromoanisole and secondary amine as substrate and Pd (OAc) 2 As a catalyst, ruPhos was the ligand, DCM/H 2 O is used as a solvent, and the reaction is carried out for 8 to 12 hours at the temperature of 110 ℃ in the nitrogen atmosphere to obtain the target product N-aryl p-condensed heterocyclic alkylamino phenol derivative, wherein the reaction process is as follows:
in a dehydrated round bottom flask was added para-bromoanisole (5.1 mmol), secondary amine (5.0 mmol), pd (OAc) 2 (0.05 mmol), ruPhos (0.10 mmol) and NaO t Bu (6.0 mmol), with nitrogen substitution, was reacted at 110℃for 8-12H and after cooling to room temperature DCM/H2O=1:1 mixture was added. The organic phase is extracted three times and then dried and concentrated, and the eluent is methylene dichloride/methyl tertiary ether.
After dissolving the resulting para-amino ether in water-free DCM (30 mL) and adding to a 100mL round bottom flask (2.2 mmol), 1M BBr was slowly added dropwise at-78deg.C 3 (3 mL,3.0 mmol) and after 3h at room temperature, the mixture was poured into ice water and saturated NaHCO was slowly added dropwise 3 Until the solution is alkaline, the solution is dried after being extracted by DCM, concentrated, and chromatographed on silica gel, wherein the eluent is ethyl acetate: petroleum ether=1:20 to 1:8. Compound 62 was prepared using the procedure of example 7.
Example 8
The synthesis process of 2, 4-diamine phenol derivative includes using N-methylaniline and p-amino phenol compound as substrate and Cu (OTf) 2 Is catalyst, ti (OiPr) 4 Toluene is used as an additive, and the reaction is carried out for 7 to 10 hours at room temperature to obtain the target product 2, 4-diamine phenol derivative, wherein the reaction process is shown as follows.
Adding magneton and Na into the reaction tube for dewatering 2 SO 4 (85 mg,2.0eq.,0.6 mmol) and Cu (OTf) 2 (16 mg,0.045mmol,15 mol%) N-methylaniline (35 mg,0.33mmol,1.1 eq.) and para-aminophenol (0.3 mmol,1.0 eq.) were dissolved in 3mL of dehydrated toluene and then added to the reaction tube, sealed and Ti (OiPr) was slowly added with a needle tube 4 (25.0 mg,30 mol%) at room temperature for 7-10h, quenched with 0.1M HCl (5 mL) after the end of the reaction, extracted with saturated sodium bicarbonate pH>8, drying with anhydrous sodium sulfate, and separating by silica gel column chromatography. Compounds 35 to 39 were prepared by the method of example 8.
The yields and nuclear magnetic spectrum data for the series of compounds prepared by the methods of examples 1-8 are as follows:
compound 1 (4 a): example 1 procedure, blue-black oily liquid, 73% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4)δ＝7.15–7.08(m,2H,Ph),6.96(d,J＝8.8Hz,2H,Ph),6.79(d,J＝8.8Hz,2H,Ph),6.74–6.66(m,3H,Ph),3.17(d,J＝10.4Hz,3H,-CH 3 )。
compound 2 (4 b): example 1 procedure, black oily liquid, 79% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4):δ＝7.08-7.05(m,2H,Ph),6.94(d,J＝10Hz,2H,Ph),6.79(d,J＝5Hz,2H,Ph),6.65–6.61(m,3H,Ph),3.64(q,J＝6.7Hz,2H,CH 2 -N),1.14(t,J＝7.5Hz,3H,CH 3 -CH 2 N)。
compound 3 (4 c): example 1, black oily liquid, 69% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4)δ＝6.99(t,J＝10.0Hz,2H,Ph),6.87(d,J＝8.7Hz,2H,Ph),6.71(d,J＝8.7Hz,2H,Ph),6.59–6.52(m,3H,Ph),3.49(t,J＝10.0Hz,2H,CH 2 -N),1.56–1.46(m,2H,CH 2 ),1.31–1.26(m,2H,CH 2 ),0.84(t,J＝7.4Hz,3H,CH 3 )。
compound 4 (4 d): example 1, pale yellow solid, 53% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4):δ＝7.09(t,J＝7.9Hz,2H,Ph),6.97(d,J＝8.4Hz,2H,Ph),6.81(d,J＝8.5Hz,2H,Ph),6.66(d,J＝8.1Hz,3H,Ph),3.58(t,J＝7.6Hz,2H,CH 2 -N),1.63(t,J＝7.4Hz,2H,CH 2 ),1.32–1.27(m,22H,C 11 H 22 ),0.92(t,J＝6.7Hz,3H,CH 3 )。
compound 5 (4 e): example 1, white solid, 75% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4)δ＝7.31(d,J＝7.17Hz,2H,Ph),7.25(t,J＝7.65Hz,2H,Ph),7.17(t,J＝7.14Hz,1H,Ph),7.07–7.01(m,4H,Ph),6.77(d,J＝8.83Hz,2H,Ph),6.71–6.68(m,2H,Ph),6.65(t,J＝7.29Hz,1H,Ph),4.84(s,2H,CH 2 )。
compound 6 (4 f): the procedure of example 1 was as a pale yellow solid in 81% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4)δ＝7.41(d,J＝1.9Hz,1H,H-furan),7.13–7.09(m,2H,Ph),7.02(d,J＝8.8Hz,2H,Ph),6.79(t,J＝8.6Hz,4H,Ph),6.70(tt,J＝5Hz,1H,H-furan),6.31(dd,J＝3.2,1.9Hz,1H,H-furan),6.17(dd,J＝3.2,1.9Hz,1H,Ph),4.79(s,2H,CH 2 )。
compound 7 (4 g): the procedure of example 1 was as a pale yellow solid, 66% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4):δ＝8.07(d,J＝9.0Hz,1H,naphthalene),7.89(d,J＝7.5Hz,1H,naphthalene),7.74(d,J＝8.2Hz,1H,naphthalene),7.56–7.47(m,3H,Ph),7.35(t,J＝7.7Hz,1H,naphthalene),7.12–7.03(m,4H,Ar),6.78–6.66(m,5H,Ar),5.30(s,2H,CH 2 )。
compound 8 (4 h): example 1, black solid, 47% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4)δ＝7.15–7.05(m,4H,Ph),7.04–6.95(m,2H,Ph),6.91–6.78(m,2H,Ph),6.75–6.65(m,3H,Ph),6.65–6.56(m,3H,Ph),3.81(t,J＝6.9Hz,2H,CH 2 -NH),3.35–3.32(m,2H,CH 2 -N)。
compound 9 (4 i): example 1, black liquid, 70% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4)δ＝7.23–7.16(m,2H,Ph),7.11–7.05(m,2H,Ph),6.63(d,J＝8.9Hz,2H,Ph),6.45(d,J＝8.9Hz,2H,Ph),3.13(s,3H,CH 3 -N),2.08(s,3H,CH 3 )。
compound 10 (4 j): example 1 procedure, black liquid, 81% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4)δ＝7.02(t,J＝7.8Hz,1H,Ph),6.96(d,J＝8.7Hz,2H,Ph),6.80(d,J＝8.8Hz,2H,Ph),6.58–6.50(m,3H,Ph),3.18(s,3H,CH 3 -N),2.22(s,3H,CH 3 )。
compound 11 (4 j): example 1 procedure, brown solid, 91% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4)δ＝6.97(d,J＝8.2Hz,2H,Ph),6.92(d,J＝8.8Hz,2H,Ph),6.77(d,J＝8.8Hz,2H,Ph),6.68(d,J＝8.5Hz,2H,Ph),3.16(s,3H,CH 3 -N),2.23(s,3H,CH 3 )。
compound 12 (4 j): example 1, gray solid, 77% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4)δ＝6.92(d,J＝8.68Hz,2H,Ph),6.87(t,J＝8.80Hz,2H,Ph),6.77(d,J＝8.78Hz,2H,Ph),6.73–6.69(m,2H,Ph),3.16(s,3H,CH 3 -N)。
compound 13 (4 m): example 1 procedure, gray solid, 62% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4)δ＝7.05(q,J＝5.0Hz,1H,Ph),6.99(d,J＝8.7Hz,2H,Ph),6.81(d,J＝8.7Hz,2H,Ph),6.41(dd,J＝8.3,2.4Hz,1H,Ph),6.36–6.28(m,2H,Ph),3.18(d,J＝0.9Hz,3H,CH 3 -N)。
compound 14 (4 n): example 1, as a black oil, 63% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4)δ＝7.45(d,J＝8.0Hz,1H,Ph),7.31(t,J＝7.6Hz,1H,Ph),7.23(d,J＝8.0Hz,1H,Ph),7.17(t,J＝7.6Hz,1H,Ph),6.68(d,J＝8.9Hz,2H,Ph),6.56(d,J＝8.9Hz,2H,Ph),3.19(s,3H,CH 3 -N)。
compound 15 (4 o): example 1, pale yellow solid, 68% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4)δ＝7.08–7.03(m,2H,Ph),6.99–6.94(m,2H,Ph),6.81(d,J＝8.8Hz,2H,Ph),6.64–6.60(m,2H,Ph),3.16(d,J＝4.7Hz,3H,CH 3 -N)。
compound 16 (4 p): example 1 procedure, black solid, 63% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4)δ＝7.66(d,J＝8.0Hz,1H,Ph),7.36(t,J＝7.6Hz,1H,Ph),7.22(d,J＝8.0Hz,1H,Ph),7.11(t,J＝7.6Hz,1H,Ph),6.68(d,J＝8.9Hz,2H,Ph),6.53(d,J＝8.8Hz,2H,Ph),3.18(s,3H,CH 3 -N)。
compound 17 (4 q): example 1, yellow solid, 41% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4,Ph)δ＝8.01(d,J＝9.4Hz,2H,Ph),7.06(d,J＝8.7Hz,2H,Ph),6.88(d,J＝8.8Hz,2H,Ph),6.63(d,J＝9.5Hz,2H,Ph),3.34(s,3H,CH 3 -N)。
compound 18 (4 r): example 1, pale yellow solid, 37% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4)δ＝7.58–7.49(m,2H,Ph),7.16(d,J＝8.4Hz,1H,Ph),7.01(t,J＝7.5Hz,1H,Ph),6.92(d,J＝8.9Hz,2H,Ph),6.78(d,J＝8.8Hz,2H,Ph),3.34(s,3H,CH 3 -N)。
compound 19 (4 s): example 1, black liquid, 71% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4):δ＝7.15(t,J＝8.07,1H,Ph),7.04(dd,J＝10.40,2H,Ph),6.92(t,J＝7.81,1H,Ph),6.62(d,J＝8.95Hz,2H,Ph),6.54(d,J＝8.95Hz,2H,Ph),3.73(s,3H,CH 3 -O),3.11(s,3H,CH 3 -N)。
compound 20 (4 t): example 1, pale yellow solid, 93% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4):δ＝6.82-6.76(m,6H,Ph),6.73-6.69(m,2H,Ph),3.71(s,3H,CH 3 -O),3.12(s,3H,CH 3 -N)。
compound 21 (4 u): the procedure of example 1 was as pale yellow liquid, 74% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4)δ＝7.44(d,J＝7.60Hz,1H,Ph),7.37(t,J＝7.61Hz,1H,Ph),7.29(t,J＝7.51Hz,1H,Ph),7.24(d,J＝7.90Hz,1H,Ph),6.68(d,J＝9.02Hz,2H,Ph),6.58–6.53(m,4H,Ph),6.41(t,J＝2.30Hz,1H,Ph),3.66(s,6H,CH 3 -O),2.87(s,3H,CH 3 -N)。
compound 22 (4 v): the procedure of example 1, black liquid, 63% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4):δ＝7.35(d,J＝7.63,1H,Ph),7.23-7.16(m,2H,Ph),7.01(d,J＝7.7Hz,1H,Ph),6.62-6.59(m,2H,Ph),6.41-6.37(m,2H,Ph),3.20-3.14(m,1H,CH),3.11(s,3H,CH 3 -N),1.13(d,J＝6.9Hz,6H,CH 3 )。
compound 23 (4 w): example 1 procedure, black solid, 71% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4)δ＝6.88–6.78(m,6H,Ph),6.72(d,J＝8.8Hz,2H,Ph),5.99–5.90(m,1H,CH＝C),5.23(dd,J＝17.2,1.9Hz,1H,CH 2 ＝C),5.12(dd,J＝10.3,1.8Hz,1H,CH 2 ＝C),4.23(dt,J＝5.2,1.7Hz,2H,CH 2 -C＝C),3.75(s,3H,CH 3 -O)。
compound 24 (4 x): example 1 procedure, brown liquid, 53% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4)δ＝7.24(d,J＝8.7Hz,1H,Ar),7.02(s,1H,Ar),6.92–6.61(m,10H,Ar),3.84(d,J＝7.6Hz,2H,CH 2 -N),3.76(d,J＝10.9Hz,6H,CH 3 -O),3.01(d,J＝7.9Hz,2H,CH 2 -Indole)。
compound 25 (4 y): the procedure of example 1 was as a pale yellow solid in 72% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4)δ＝7.47–7.42(m,2H,Ph),7.35–7.27(m,3H,Ph),7.10(td,J＝8.1,4.3Hz,1H,Ph),7.03–6.96(m,2H,Ph),6.86–6.79(m,4H,Ph),6.67(dt,J＝6.7,3.2Hz,1H,Ph),3.19(d,J＝5.9Hz,3H,CH 3 -N)。
compound 26 (4 z): example 1 procedure, violet solid, 53% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d4)δ＝7.92–7.83(m,2H,Ar),7.69(d,J＝8.2Hz,1H,Ar),7.48–7.41(m,2H,Ar),7.35(t,J＝7.3Hz,1H,Ar),7.26(d,J＝7.3Hz,1H,Ar),6.62(d,J＝8.9Hz,2H,Ar),6.54(d,J＝9.0Hz,2H,Ar),3.31(s,3H,CH 3 )。
compound 27 (4 aa): example 1, white solid, 88% yield. Nuclear magnetic spectrum data: 1 H NMR(400MHz,Chloroform-d)δ＝7.37–7.15(m,4H,Ph),7.13–6.89(m,8H,Ph),6.77(d,J＝8.1Hz,2H,Ph),4.73(s,1H,OH)。
compound 28 (4 ab): example 3 procedure, brown solid, 65% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d 4 )δ7.01(d,J＝8.8Hz,2H,Ph),6.80(d,J＝8.7Hz,2H,Ph),6.75-6.70(m,1H,Ph),6.61-6.54(m,2H,Ph),6.53-6.46(m,1H,Ph),4.19(t,2H,CH 2 -O),3.51(t,2H,CH 2 -N)。
compound 29 (4 ac): example 4 procedure, white solid, 83% yield. NuclearMagnetic spectrum data: 1 H NMR(500MHz,Methanol-d 4 )δ＝7.09(d,J＝8.7Hz,2H,Ph),6.99(d,J＝8.6Hz,2H,Ph),6.88(dd,J＝7.4,1.6Hz,2H,Ph),6.72(m,4H,Ph),6.14(dd,J＝8.2,1.3Hz,2H,Ph)。
compound 30 (4 ad): example 3 procedure, white solid, 72% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d 4 )δ6.97(d,J＝8.8Hz,2H,Ph),6.88(d,J＝9.0Hz,1H,Ph),6.78(d,J＝8.7Hz,2H,Ph),6.74(t,J＝8.5Hz,1H,Ph),6.50(t,J＝7.3Hz,1H,Ph),6.32(d,J＝9.3Hz,1H,Ph),3.47-3.39(m,2H,CH 2 -N),2.74(t,J＝6.4Hz,2H,CH 2 -Ph),1.98-1.84(m,2H,CH 2 )。
compound 31 (4 ae): example 6 procedure, red solid, 79% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d 4 )δ＝6.97–6.91(m,3H,Ph),6.87–6.80(m,1H,Ph),6.77–6.70(m,2H,Ph),6.65(d,J＝7.9Hz,1H,Ph),6.53(t,J＝7.3Hz,1H,Ph),3.56(t,J＝8.4Hz,2H,CH 2 -N),2.83(t,J＝8.4Hz,2H,CH 2 -Ph)。
compound 32 (7 a): example 2, red solid, 90% yield. Nuclear magnetic spectrum data: 1 H NMR(400MHz,Methanol-d 4 )δ6.86-6.81(m,2H,Ph),6.76-6.66(m,2H,Ph),3.79(t,J＝4.0Hz,4H,C2),2.97(t,J＝4.0Hz,4H,C3)。
compound 33 (7 b): example 2, gray solid, 88% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d 4 )δ6.85(d,J＝9.0Hz,2H,Ph),6.67(d,J＝8.8Hz,2H,Ph),2.91(t,4H,C1),1.74-1.63(m,4H,C2),1.56-1.43(m,2H,C3)。
compound 34 (7 c): example 2, white solid, 82% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d 4 )δ7.35(d,J＝8.3Hz,2H,Ph),7.03(d,J＝8.4Hz,2H,Ph),3.96-3.47(m,4H,C2),3.16(d,J＝6.8Hz,4H,C3)。
compound 35 (10 a): example 8 method, black liquid, 71% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Chloroform-d)δ6.94(d,J＝8.8Hz,1H,Ph),6.85-6.77(m,3H,Ph),6.72-6.66(m,3H,Ph),5.81(s,1H,OH),3.76(s,3H,CH 3 -O),3.14(s,3H,CH 3 -N),3.00-2.91(m,4H,C2),1.69(m,J＝5.8Hz,C3),1.51(t,J＝6.0Hz,2H,C4)。
compound 36 (10 b): example 8 procedure, black liquid, 62% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Chloroform-d)δ7.23(t,J＝7.8Hz,2H,Ph),6.99(d,J＝8.9Hz,1H,Ph),6.86-6.81(m,2H,Ph),6.72(d,J＝8.2Hz,2H,Ph),6.68(d,J＝2.8Hz,1H,Ph),5.71(s,1H,OH),3.82(t,J＝4.7Hz,4H,C2),3.20(s,3H,CH 3- N),3.01(t,J＝4.7Hz,4H,C3)。
compound 38 (10 c): example 8 procedure, black liquid, 78% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Chloroform-d)δ6.96(d,J＝8.7Hz,1H,Ph),6.84-6.75(m,3H,Ph),6.73-6.61(m,3H,Ph),5.87(s,1H,OH),3.81(d,J＝4.6Hz,4H,C2),3.75(s,3H,CH 3 -O),3.14(s,3H,CH 3 -N),2.99(t,J＝4.8Hz,4H,C3)。
compound 37 (10 d): example 8, red liquid, 47% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Chloroform-d)δ6.98(d,J＝8.8Hz,1H,Ph),6.91(t,J＝8.7Hz,2H,Ph),6.81(dd,J＝8.9,2.9Hz,1H,Ph),6.70-6.60(m,3H,Ph),5.78(s,1H,OH),3.98-3.53(m,4H,C2),3.16(s,3H,CH 3 -N),3.06-2.92(m,4H,C3)。
compound 39 (10 e): example 8, yellow solid, 61% yield. Nuclear magnetic spectrum data: 1 H NMR(500MHz,Methanol-d 4 )δ7.05(d,J＝9.1Hz,2H,Ph),6.88(d,J＝8.9Hz,1H,Ph),6.80(dd,J＝8.9,2.9Hz,1H,Ph),6.69(d,J＝3.0Hz,1H,Ph),6.56(d,J＝9.1Hz,2H,Ph),3.81-3.67(m,4H,C2),3.15(s,3H,CH 3 -N),2.99-2.83(m,4H,C3)。
decylaminophenol: white solid, yield 98%. Nuclear magnetic spectrum data: 1 H NMR(400MHz,Chloroform-d)δ6.66(d,J＝8.2Hz,2H,Ph),6.54(d,J＝8.2Hz,2H,Ph),4.37(br,2H,OH&NH),3.04(t,J＝7.2Hz,2H,C1),1.59(t,J＝7.3Hz,2H,C2),1.43–1.19(m,14H,C3-C9),0.89(t,J＝6.7Hz,3H,C10)。
some of the compounds prepared in the above examples were subjected to in vitro antibacterial tests, MTT cell activity assays, tyrosinase inhibition tests, kinetic analysis of tyrosinase inhibition, and antioxidant tests.
1. In vitro antibacterial test
We performed in vitro antimicrobial tests on some of the compounds provided in the above examples of the present invention.
The method comprises the following steps: MIC was determined according to the method of the national clinical laboratory standards committee.
As test bacteria, 3 gram-positive bacteria and 3 gram-negative bacteria were selected. Bacillus cereus and escherichia coli were purchased from the chinese common microbiological bacterial deposit management center. MRSA (Staphylococcus aureus ATCC 43300) and Bacillus subtilis are offered by the university of North Western agriculture and forestry science and technology, chemical and pharmaceutical college. Cabbage soft rot and konjak soft rot are provided by the plant protection college of the university of agriculture and forestry science and technology in north of west. MIC was defined as the minimum inhibitory concentration, with each compound producing a significant inhibition of bacterial growth (incubation at 37 ℃ for 12-14 h). The concentration of each bacterial suspension was adjusted to 1X 10 6 CFU/mL. All compounds were thoroughly dried before weighing. Initially, the compound was dissolved in dimethyl sulfoxide (DMSO) to prepare a stock solution. Test compounds and control drugs were then prepared in liquid luria Bertan medium. The required concentrations were 128, 64, 32, 16, 8, 4, 2, 1, 0.5 and 0.25. Mu.g/mL (dimethyl sulfoxide)<0.5%). Ciprofloxacin and gentamicin were selected as positive controls (k.p. rakesh et al 2020. [1] )。
The experiment uses a double dilution method to determine the minimum inhibitory concentration (MIC value) of 40 test compounds. 3mL of sterilized LB culture solution is added into a 5mL centrifuge tube under the aseptic condition, a small amount of bacteria to be tested is selected by a sterilized inoculating needle and added into the culture solution, and the culture solution is cultivated in a constant temperature incubator at 37.5 ℃ for 12 hours after the mouth is sealed. 100. Mu.L of the sterilized culture medium was taken and absorbance was measured at 600nm, and LB medium without the test bacteria was used as a blank, corresponding to a concentration of 1X 10 according to 0.1OD600 8 CFU/mL, and diluting the bacterial liquid 100 times to 1X 10 6 CFU/mL. MIC assays were performed using 96-well (U-bottom, 12×8) microwell dilution plates. The compound was first prepared as 51200. Mu.g/mL of DMSO solution for use, 5. Mu.L of the solution was aspirated, and 1995. Mu.L of sterile water was added to prepare a stock solution having an initial concentration of 128. Mu.g/mL. 1 is added to each of the 2 nd to 8 th wells200 mu L of mother solution is added into the 1 st hole of 00 mu L of sterile water, 100 mu L of solution in the 1 st hole is removed to the 2 nd hole by a liquid-transferring gun after being uniformly mixed, the 2-8 holes are subjected to double dilution by pushing, and finally 100 mu L of mixed solution is sucked out from the 8 th hole, so that a concentration gradient of 128-1 mu g/mL can be obtained. 100 mu L of bacterial liquid is added to each of 1-8 and 10 holes, so that a concentration gradient of 64-0.5 mu g/mL can be obtained in the 1-8 holes. 10. 100. Mu.L of sterile water was added to 11 wells, 100. Mu.L of LB medium was added to 11 wells, and 200. Mu.L of sterile water was added to 12 wells as a blank.
Shaking the solution in the micropores uniformly, and culturing in a constant temperature incubator at 37 ℃; using gentamicin and ciprofloxacin as positive controls, each treatment was repeated three times (the initial concentration of the positive control and the concentration of the drug solution were 64. Mu.g/mL). The compounds initially tested for MICs at 0.5. Mu.g/mL were further tested for their lowest inhibitory concentration values over the 0.5-0.015. Mu.g/mL concentration interval using the same procedure. And observing the result after culturing for 12-16 hours, wherein sediment exists in the hole with hypha growth, and the concentration of the liquid medicine in the hole with sterile silk growth is the MIC value of the sample.
Test bacteria: bacillus cereus 1.1846, bacillus subtilis Bacillus subtilis,1.88, methicillin-resistant staphylococcus aureus Staphylococcus aureus,1.89, escherichia coli 1.1574, cabbage soft rot fungus (Erwinia carotovora. A) and konjak soft rot fungus (Erwinia carotovora. B). Positive control drug: ciprofloxacin and gentamicin.
TABLE 1 antibacterial Activity data
a Mrsa=methcillin-resistant Staphylococcus aureus (methicillin-resistant staphylococcus aureus), b.cereus=bacillus cereus (Bacillus cereus), b.subtilis=bacillusBacillus subtilis, E.coli=Escherichia coli.
b Erwinia carotovora subsp. Carotovora isolated from seed cell (erwinia carotovora subsp. Isolated from cabbage).
c Erwinia carotovora subsp. Carotovora isolated from konjac (a strain isolated from konjak).
d DAP = p-decylaminol (p-decylaminophenol).
e Cip=ciprofloxacin (ciprofloxacin), gent=gentamicin (gentamicin).
As shown in Table 1, most of the compounds prepared in examples 1 to 8 of the present invention have antibacterial activity against gram-positive bacteria (especially methicillin-resistant Staphylococcus aureus) and have lower antibacterial activity against gram-negative bacteria. Wherein, the structural general formula of the compound with the antibacterial activity to MRSA is shown as the following formulas A1 and A2:
in the formulae A1 and A2, R 1 Selected from the group consisting of-Me, -Et, -F, -Cl, -Br, -OMe, -iPr, -CN, -NO 2 Any one of them; r is R 2 Selected from-Ph or H; x is selected from any one of C, O, S, N; n=0 or 1.
Of the above compounds, compounds 4k,4m,4n,4p and 4ab are the most potent compounds against MRSA, with a minimum MIC value of 0.5. Mu.g/mL, approaching that of the positive control drug (MIC Cip ＝0.25μg/mL；MIC Gen =0.25 μg/mL). Compounds 4k,4o and 4ab showed some bacillus cereus inhibitory activity despite the MIC value being higher than the positive control, with a MIC value of 16 μg/mL; compound 4m showed better activity (mic=8 μg/mL) against bacillus subtilis, showing potential derivatization prospects; all compounds were less active against gram negative bacteria with a minimum MIC value of 64 μg/mL.
2. MTT cell Activity assay
We performed MTT cell activity assays on some of the compounds prepared in examples 1-8 of the present invention.
Among them, the MTT cell activity data of the compounds represented by the formulas A1 and A2 are substantially the same, and therefore, only MTT cell activity of the compounds (4 k,4m,4n,4p,4 ab) will be described below.
The method comprises the following steps: cell viability of test compounds (4 k,4m,4n,4p,4 ab) according to Duan [2] The assay was performed as described by et al (J.Duan et al 2016. [2] ). Compounds with anti-MRSA activity (concentrations of 0.5, 1, 2,4, 8, 16 and 32 μg/mL) were tested against the RAW264.7 cell line, each with 3 replicates of the in vitro cell activity test to determine potential toxic effects. Control cells were added dimethyl sulfoxide alone at a concentration equal to that in the drug-treated cell samples. 5% CO at 37℃for compounds with different concentrations and cells 2 Is cultured in 96-well plates for 12h. The medium was removed and 0.5mg/mL MTT was added for 4h. The medium was removed. DMSO (100 μl) was then added to each well. Shaking for 15min to dissolve purple formazan crystals. Finally, the plate was selected for testing at a wavelength of 570 nm. Blank groups served as control groups. Data were analyzed by GraphPad Prism 6.0. The formula for cell viability was (absorbance of treated cells/absorbance of untreated cells) ×100%.
Test cells: RAW264.7 cells
The biological activity was further assessed using the MTT method and the toxicity of compounds 4k,4m,4n,4p,4ab to RAW264.7 cells was shown in figure 1.
As can be seen from the results in fig. 1, the MTT method detects cytotoxicity of 4k,4m,4n,4p and 4ab (error bars represent standard deviation values of absorbance values) in the RAW264.7 cell line by Student's t-test, p <0.05, p <0.01 or p <0.001 compared to the control group
After 24h of incubation of the compounds with cells, the cell viability of 4k,4m,4n,4p,4ab was over 95% at a concentration of 0.5 μg/mL. While compounds 4k,4m,4n showed excellent survival (105%, 103% and 103%) for RAW264.7 cells at an effective antibacterial dose (0.5 μg/mL). Compounds 4k,4m,4n,4p and 4ab were non-toxic to RAW264.7 cells at a concentration of 8. Mu.g/mL. Experimental results indicate that all compounds tested were less toxic to cells at the effective concentrations.
3. Tyrosinase inhibition assay
We performed tyrosinase inhibition assays on some of the compounds provided in the above examples of the invention.
The compounds having an inhibitory effect on tyrosinase activity are represented by the following formulas A3 and A4:
in the formulae A3 and A4, R 3 Selected from any one of Me, F, cl, br.
The inhibitory effect of the compounds represented by formulas A3 and A4 on tyrosinase activity is substantially the same, and therefore, only the inhibitory effect of the compounds (4 k,4m,4n,4p,4 ab) on tyrosinase activity will be described below.
The method comprises the following steps: mushroom tyrosinase (EC 1.14.18.1) (Sigma Chemical Co.) enzyme inhibition assay using L-tyrosine as substrate (V.N. Takahashi et al 2014) [3] ). Stock solutions of test compounds 4k,4m,4n,4p and 4ab and kojic acid were prepared in DMSO (40 mM) and then diluted to the desired concentrations with phosphate buffer (ph=6.8). First, 10 μl of mushroom tyrosinase (0.5 mg/mL) was mixed with 160 μl of phosphate buffer (50 mm, ph=6.8) in 96-well microwell plates, and then 10 μl of test compound was added. After the mixture was pre-incubated at 28℃for 20min, 20. Mu.L of L-tyrosine solution (0.5 mM) was added to each well and monitored at 475nm for 10min. The final concentration of all test compounds was 16 μm. Three replicates per well, DMSO without test compound was used as a control. The final concentration of DMSO in the test solution was less than 2.0%. The inhibition was calculated according to the following equation:
inhibition (%) =100× (test compound)/control
The inhibitory effect of each compound was expressed as the concentration (IC 50) required for inhibition of the enzyme activity by 50%.
Test enzyme: mushroom tyrosinase (EC 1.14.18.1)
To verify the relationship between the anti-MRSA activity and tyrosinase inhibitory activity of N-aryl-para-aminophenol, we selected compounds 4k,4m,4N,4p and 4ab with good bacteriostatic activity to complete the experiment. We used mushroom tyrosinase as inhibited enzyme, kojic Acid (KA) as positive control, all compounds were treated at a final concentration of 16 μm (m.d. aytemir et al 2019 [4] ). When L-tyrosine is used as a reaction substrate, all compounds exhibit a significantly good anti-tyrosinase activity.
FIG. 2 is the result of the effect of compounds on tyrosinase. Wherein (a) is the effect of various compounds on tyrosinase activity at 16. Mu.M. Results represent mean ± SD of each group. By Student's t-test, p <0.05, < p <0.01 or < p <0.001 compared to control group. (b) Is the concentration dependent effect (average) of the compound on the tyrosinase activity of mushrooms.
As can be seen from the results of FIG. 2, 4k,4m,4n,4p,4ab and KA inhibited tyrosinase activity by 47%, 39%, 44%, 49%, 53% and 26%, respectively, as compared to the control group. We also studied the effect of different concentrations of 4k,4m,4n,4p and 4ab on mushroom tyrosinase activity and calculated the IC50 values for the 5 compounds. These compounds all showed higher activity than KA. The IC50 values of compounds 4k,4M,4n,4p and 4ab were 3.95. Mu.M, 2.65. Mu.M, 2.56. Mu.M, 3.35. Mu.M and 2.53. Mu.M, respectively. These results indicate that such compounds with high tyrosinase inhibitory activity also have good anti-MRSA activity, of which 4ab is the most potent inhibitor of mushroom tyrosinase activity.
4. Kinetic analysis of tyrosinase inhibition
We performed a kinetic analysis of tyrosinase inhibition on some of the compounds provided in the above examples of the invention.
The method comprises the following steps: in the inhibition kinetics of compound 4ab, we selected the concentrations as: 0.1, 2,4, 8, 16 and 32 μm. Substrate L-tyrosine concentrations were 0, 0.062, 0.125, 0.25, 0.5, 1, 2 and 4mM, with tyrosinase concentrations of 0.5mg/mL in all kinetic studies. Pre-incubation and measurement time in mushroom tyrosinase inhibition assay protocolThe same method as in (a). Inhibition type pass rate (1/V) and substrate concentration (1/[ S)]) The inverse Lineweavere-Burk plot of (C) was analyzed. Dissociation constant K i Determined from a conic plot of slope versus inhibitor concentration.
The most effective inhibition mechanism of compound 4ab was analyzed using the linehaver-Burk double reciprocal method. In the presence of different inhibitor concentrations, the kinetics of the enzyme was studied by plotting 1/V versus 1/[ S ] to yield a series of lines transverse to the X-axis in the second quadrant, as shown in FIG. 3. When the concentration of compound 4ab was increased, the Vmax value was decreased while the Km value was unchanged, indicating that the type of inhibition of mushroom tyrosinase by 4ab was non-competitive.
FIG. 3 is a graph showing the kinetics of tyrosinase oxidation of L-tyrosine in the presence of compound 4 ab. Wherein (a) is a Lineweaver-Burk plot of tyrosinase inhibition by 3-1j at concentrations of 0, 1, 2,4, 8, 16 and 32. Mu.M. The substrate L-tyrosine concentrations were 0.0625, 0.125, 0.25, 0.5, 1, 2 and 4. Mu.M, respectively. (b) is a plot of slope versus inhibitor (4 ab) concentration.
Determination of dissociation constant K by a conic plot of slope versus Compound 4ab concentration i (FIG. 3). From this line, the inhibition constant K of 4ab for the enzyme i 1.76. Mu.M, see Table 2.
TABLE 2 kinetic parameters of enzyme inhibition
Note that: ND (ND) a Indicating no measurement.
5. Antioxidation test
We carried out an antioxidant test on a portion of the compounds prepared in examples 1 to 8 of the present invention. The compounds prepared in examples 1 to 8 all have the corresponding antioxidant effects, and therefore, only the antioxidant effects of the compounds (4 k,4m,4n,4p,4 ab) will be described below.
The method comprises the following steps: according to Sarker [5] The DPPH scavenging activity of the test compounds was measured by the method described by et al, with some modifications (Sarker et al 2005 [5] ). Pipette 100The mL of test compounds (4 k,4m,4n,4p and 4 ab) at different concentrations (3.125, 6.25, 12.5, 25, 50 and 100. Mu.g/mL) were moved into 96-well flat bottom plates. Next, 100. Mu.L of 100mM DPPH methanol solution was added to each well, and the plate was incubated at room temperature for 30 minutes in the absence of light. The absorbance of the solution was measured at λ517nm (V.Padmavithi et al 2011 [6] ). Ascorbic acid and dimethyl sulfoxide served as positive control and blank, respectively. The percentage of DPPH scavenging activity was calculated according to the following equation:
% DPPH clearance= [ (a) Blank space -A Sample of )/A Blank space ]×100
Where the blank is the absorbance of the control reaction (including all reagents except the test compound) and the sample is the absorbance of the test sample. Dose-response curves were plotted between% free radical scavenging activity and drug concentration. Linear regression analysis was performed on drug concentrations that showed 50% free radical inhibitory activity (IC 50). Ascorbic acid was used as a positive control and all experiments were performed in triplicate, with the results averaged.
Positive control: ascorbic acid. Compounds with good antibacterial activity were selected for antioxidant activity assessment at various concentrations (3.125, 6.25, 12.5, 25, 50 and 100 μg/mL) and compared to standard antioxidants (ascorbic acid). We selected the DPPH (1, 1-diphenyl-2-pyridine hydrazide) free radical scavenging activity assessment method as the standard analytical method for antioxidant activity studies. The results are shown in fig. 4. In FIG. 4, the percent (%) scavenging effect of ascorbic acid, 4k,4m,4n,4p and 4ab on DPPH. Each value represents the mean ± standard deviation (n=3).
As shown in the results of FIG. 4, 4- (2, 3-dihydro-4H-benzo [ b ] [1,4] oxazin-4-yl) phenol (compound 4 ab) (IC50=7.82. Mu.g/mL) showed a higher potential for antioxidant activity than the other counterparts, 1.24 times that of ascorbic acid (IC50=9.70. Mu.g/mL). Compounds 4k (ic50=10.45 μg/mL), 4m (ic50=10.22 μg/mL), 4n (ic50=14.04 μg/mL) and 4p (ic50=12.57 μg/mL) showed antioxidant activity comparable to the positive control.
6. Results and analysis
The compounds 4n and 4ab have excellent tyrosinase inhibitory activity, and the IC50 values are 2.65 mu M and 2.53 mu M respectively. The biological activities of these 5 compounds are shown in Table 3.
Biological Activity of the compounds of Table 3
Note that: ND represents unmeasured.
In summary, aiming at the problems that N-monoalkyl substituted para-aminophenol is generally unstable and easy to oxidize and has single derivative structure, the invention introduces N-aryl para-aminophenol to stabilize the structure, enhances the derivatizability of the compound, evaluates the antibacterial, antioxidant and tyrosine inhibitory activities of the structure, and finds a plurality of compounds with tyrosinase inhibitory activity and antibacterial activity at the same time. The invention has the characteristics of simple synthesis of the compound, good antibacterial effect on MRSA (methicillin-resistant staphylococcus aureus), high enzyme inhibition rate and the like, and has wide application prospect.
Citation literature:
[1]H.Qin,J.Liu,W.Fang,L.Ravindar,K.P.Rakesh,Indole-based deriv atives as potential antibacterial activity against methicillin-resistance Staphyloco ccus aureus(MRSA),Eur.J.Med.Chem.194(2020)112245-112261.
[2]H.Mu,Q.Liu,N.Hong,Y.Sun,J.Duan,Gold nanoparticles make chitosan-streptomycin conjugates effective towards Gram-negative bacterial biofil m.RSC Advances,11(2016)8714-8721.
[3]N.Takahashi,M.Imai,K.Yu,Inhibitory effects ofp-alkylaminopheno l on melanogenesis,Bioorg.Med.Chem.22(17)(2014)4677-4683.
[4]G.Karakaya,A.Türe,A.Ercan,S.M.D.Aytemir,Synthesis,computational molecular docking analysis and effectiveness on tyrosinase inhibiti on ofkojic acid derivatives.Bioorg.Chem.88(2019)102950.
[5]L.Nahar,W.R.Russell,M.Middleton,M.Shoeb,S.D.Sarker,Antioxi dant phenylacetic acid derivatives from the seeds ofIlex aquifolium,Acta Pharm aceutica 55(2005)187-193,URI.
[6]A.Padmaja,C.Rajasekhar,A.Muralikrishna,V.Padmavathi,Synthesi s and antioxidant activity ofoxazolyl/thiazolylsulfonylmethyl pyrazoles and isox azoles,Eur.J.Med.Chem.46(10)(2011)5034-5038.
the foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.

Claims (1)

1. The application of the 4-aminophenol derivative in preparing tyrosinase inhibitors is characterized in that the 4-aminophenol derivative is one of the following compounds:
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