CN115368252A - 4-aminophenol derivative and application thereof - Google Patents

4-aminophenol derivative and application thereof Download PDF

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CN115368252A
CN115368252A CN202211135773.1A CN202211135773A CN115368252A CN 115368252 A CN115368252 A CN 115368252A CN 202211135773 A CN202211135773 A CN 202211135773A CN 115368252 A CN115368252 A CN 115368252A
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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, wherein the general structural formula is shown as the following formula (I-1) or formula (I-2):
Figure DDA0003852003080000011
according to the invention, N-aryl para-aminophenol is introduced to stabilize the structure, enhance the derivatibility of the compound, evaluate the antibacterial, antioxidant and tyrosine inhibitory activities of the structure, and find out a plurality of compounds simultaneously having tyrosinase inhibitory activity and antibacterial activity. The invention has the characteristics of simple compound synthesis, good antibacterial effect against 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 (tyrosinase, TYR) is a metabolic enzyme mediating melanin synthesis in the human body and is involved in the pathogenesis of various diseases. When the function of the enzyme is reduced or lost, pigment synthesis disorder skin diseases such as leucoderma or albinism can be caused; on the other hand, if the expression level of the enzyme is too high, pigmentation symptoms such as freckles, dark spots, chloasma, and senile plaques may occur due to the vigorous melanin production. With the progress of research, people find that some tyrosinase inhibitors with complex structures can be simultaneously used as antibacterial agents, so that the functions of the compounds are further enriched, and the compounds have great potential in the medical and American racetrack, but the compounds are compounds with complex structures such as barbiturates, pyrazolines, aloe-emodin and the like.
The aminophenol derivatives are receiving a great deal of attention due to their various biological activities, the skeletons are regarded as ampholytes, have good water solubility, and the skeletons can provide hydrogen atoms of phenolic hydroxyl groups to radicals to prevent chain propagation during oxidation, so that the compounds have good biological activities.
However, domestic and foreign research focuses on fatty secondary alkylamino phenol compounds, and due to the fact that the electron cloud density of the compounds is high and stability is poor due to the alkyl electron donating effect, and meanwhile, the special secondary alkylamino phenol structure is one of the reasons for poor derivation, further biological activity research on the structure is less at home and abroad.
At present, aminophenol derivatives have been studied and developed mainly as colorants, but no research has been reported on the development of compounds having tyrosinase activity-inhibiting activity, antioxidant activity and antibacterial activity. Therefore, the invention leads the amino phenol structure to be stable by introducing the N-aryl, and simultaneously enhances the derivatizability of the compound, and finally successfully finds a plurality of compounds with good activity of inhibiting the aminidase, oxidation resistance and antibacterial activity from the derivative compound.
Disclosure of Invention
In order to solve the above technical problems, the present invention aims to provide a 4-aminophenol derivative and applications thereof. The N-aryl is introduced to stabilize the structure of the aminophenol and enhance the derivatizability of the compound, and finally, a plurality of compounds with good activity of inhibiting the aminidase, oxidation resistance and antibacterial activity are successfully found from the derivatized compound.
In order to achieve the above object, the technical solution of the present invention is as follows.
A4-aminophenol derivative having a general structural formula as shown in the following formula (I-1) or formula (I-2):
Figure BDA0003852003060000021
in the formulae (I-1) and (I-2), D 1 、D 2 、D 3 Are respectively and independently selected from the groups shown in formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII):
Figure BDA0003852003060000022
in the formula (II), R 1 Any one of-H, -F, -Cl, -Br, C1-C4 alkyl, nitro, cyano, methoxy, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, substituted or unsubstituted fused heterocycle, substituted or unsubstituted aryl ethynyl;
R 2 any one selected from C1-C14 alkyl, allyl, substituted or unsubstituted single heterocyclic alkyl, substituted or unsubstituted fused heterocyclic alkyl, substituted or unsubstituted aryl, substituted or unsubstituted condensed ring aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted condensed ring aryl alkyl and substituted or unsubstituted arylamino alkyl;
in the formulas (III) to (V), X is any one of an oxygen atom, a sulfur atom and a carbon atom.
Further, in the formula (II), when R is 1 When any one of substituted aryl, substituted condensed ring aryl, substituted condensed heterocycle and substituted aryl ethynyl is selected, 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-heterocyclic alkyl, substituted fused heterocyclic alkyl, substituted aryl, substituted condensed ring aryl, substituted aryl alkyl, substituted condensed ring aryl alkyl and substituted arylamino alkyl, the substituent is any one of-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 formulae:
Figure BDA0003852003060000031
Figure BDA0003852003060000041
further, the group represented by the formula (III) is selected from one of the following structural formulae:
Figure BDA0003852003060000042
further, the compound is specifically one of the following compounds:
Figure BDA0003852003060000051
Figure BDA0003852003060000061
the invention also provides application of the 4-aminophenol derivatives in preparation of tyrosinase inhibitors.
The invention also provides application of the 4-aminophenol derivatives in preparing an antibacterial agent for MRSA (methicillin-resistant Staphylococcus aureus).
The invention also provides an application of the 4-aminophenol derivative in preparing an antioxidant.
The invention has the beneficial effects that:
1. according to the invention, the N-aryl is introduced to stabilize the structure of the aminophenol and enhance the derivatizability of the compound, so that a plurality of compounds with good activity of inhibiting the aminidase, oxidation resistance and antibacterial activity are successfully found from the derivatized compound.
2. Aiming at the problems that N-monoalkyl substituted p-aminophenol is generally unstable and easy to oxidize and has a single derivative structure, the invention leads the structure to be stable by introducing N-aryl p-aminophenol, enhances the derivatizability of the compound, evaluates the antibacterial, antioxidant and tyrosine inhibitory activities of the structure and finds a plurality of compounds simultaneously having tyrosinase inhibitory activity and antibacterial activity. The invention has the characteristics of simple compound synthesis, good antibacterial effect aiming at 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 compound 4k,4m,4n,4p,4ab.
FIG. 2 shows the effect of compounds on tyrosinase. Wherein (a) is the effect of each compound on tyrosinase activity at 16. Mu.M. (b) Is the concentration dependent effect of the compound on mushroom tyrosinase activity (mean).
FIG. 3 is a graph of the kinetics of tyrosinase oxidation of L-tyrosine in the presence of compound 4 ab. Wherein (a) is a Lineweaver-Burk plot of 3-1j inhibition of tyrosinase at concentrations of 0, 1, 2,4, 8, 16, and 32 μ M. (b) Is a plot of slope versus inhibitor (3-1 j) concentration.
FIG. 4 is a bar graph of the scavenging effect of various concentrations of ascorbic acid, 4k,4m,4n,4p and 4ab on DPPH.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Cu(OTf) 2 Copper (II) trifluoromethanesulfonate. Schlenk tube, schlenk tube. THF, tetrahydrofuran. Buchwald-Hartwig coupling reaction, buhwald-Hartwig reaction. Pd 2 (dba) 3 Tris (dibenzylideneacetone) dipalladium. Davophos, 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl. LiN (TMS) 2 Lithium bis- (trimethylsilyl) amide. RuPhos, 2-bicyclohexylPhosphine-2 ',6' -diisopropoxy biphenyl. 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.
We now provide synthetic methods for these compounds, taking as an example different types of compounds.
Example 1
The synthesis process of N-aryl p-amino phenol derivative includes the first synthesizing cyclohexenone and N-alkyl aniline as substrate and the second synthesizing Cu (OTf) 2 The target product N-aryl-p-aminophenol derivative is obtained by taking L as a catalyst, taking methylbenzene as a solvent and reacting for 8-60 hours at 80 ℃ in an oxygen atmosphere, wherein the reaction process is as follows:
Figure BDA0003852003060000081
the specific operation is as follows: removing water from the Schlenk tube with magnetons, and sequentially adding MgSO 4 (3.0 eq., desiccant), cu (OTf) 2 (5.0 mol%) and L (10.0 mol%), then evacuated and replaced with oxygen (three times). Cyclohexenone (3.0 eq.), N-alkylaniline (0.3 mmol,1.0 eq.) and trifluoroacetic acid (2.5 mol%, prepared as trifluoroacetic acid-toluene solution in advance, ready to use) were added sequentially to the reaction tube by syringe and reacted at 80 ℃ for 8-60h depending on the substrates. After the reaction is completed, filtering insoluble substances, washing the insoluble substances for three times by using ethyl acetate, and carrying out column chromatography after concentration to obtain the target product N-aryl-p-aminophenol derivative. 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-cycloalkylaminophenol derivative includes the steps of using p-bromophenol and secondary amine as substrate and Pd 2 (dba) 3 Taking Davephos (2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl) as a ligand and THF as a solvent as a catalyst, and reacting for 8-12h at 65 ℃ in a nitrogen atmosphere to obtain a target product N-aryl-p-cycloalkylaminophenol derivative, wherein the reaction process is as follows:
Figure BDA0003852003060000082
pd is added 2 (dba) 3 (2.0mol% Pd), davephos (2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl) (2.4 mol%), p-bromophenol (5.0 mmol) and secondary amine (6.0 mmol) were sequentially added to a water-removed Schlenk flask, and after three times of nitrogen substitution, liN (TMS) was slowly added through a needle in an ice-water bath 2 (1M，LiN(TMS) 2 THF solution, 5.5 mL), reacted at 65 ℃ for 8-12h, cooled to room temperature, quenched with 1M HCl (5-10 mL), and quenched with saturated NaHCO 3 Adjusting to alkalinity, extracting with ethyl acetate for three times, combining organic phases, drying, concentrating, performing silica gel column chromatography, and eluting with ethyl acetate: petroleum ether = 1. Compounds 32 to 34 were prepared using the procedure of example 2.
Example 3
The synthesis process of N-aryl p-benzo naphthenic amino phenol derivative includes the first reaction of p-bromo anisole and secondary amine as substrate and Pd (OAc) 2 As catalyst, ruPhos as 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-benzo-cyclane-alkylamine phenol derivative, wherein the reaction process is as follows:
Figure BDA0003852003060000091
to a round-bottomed flask with water removed was added p-bromoanisole (5.1 mmol), a secondary amine (5.0 mmol), pd (OAc) 2 (0.05 mmol), ruPhos (0.10 mmol) and NaO t Bu (6.0 mmol), nitrogen displacement three times, reaction at 110 ℃ for 8-12H, addition of DCM/H2O =1 mixture after cooling to room temperature. The organic phase is extracted three times, dried, concentrated and subjected to column chromatography, and an eluent is dichloromethane/methyl tertiary ether.
The resulting p-aminoether was dissolved in water-depleted DCM (30 mL) and added to a 100mL round-bottom flask (2.2 mmol), and 1M BBr was added dropwise slowly at-78 deg.C 3 (3 mL,3.0 mmol) and reacted at room temperature for 3 hours, and then the mixture was poured outAdding into ice water, slowly dropwise adding saturated NaHCO 3 Until the solution becomes alkaline, DCM is extracted, dried, concentrated and subjected to silica gel column chromatography, and an eluent is ethyl acetate: petroleum ether = 1. Compounds 28, 30 were prepared using the method of example 3.
Example 4
The synthesis process of N-aryl p-fused heterocyclic alkylamino phenol derivative includes the steps of using p-bromoanisole and secondary amine as substrate and Pd (OAc) 2 As catalyst, ruPhos as 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 para-fused heterocyclic alkylamino phenol derivative, wherein the reaction process is as follows:
Figure BDA0003852003060000101
to a round bottom flask with water removed was added p-bromoanisole (5.1 mmol), a secondary amine (5.0 mmol), pd (OAc) 2 (0.05 mmol), ruPhos (0.10 mmol) and NaO t Bu (6.0 mmol), nitrogen displacement three times, reaction at 110 ℃ for 8-12H, addition of DCM/H2O =1 mixture after cooling to room temperature. The organic phase is extracted three times, dried, concentrated and subjected to column chromatography, and an eluent is dichloromethane/methyl tertiary ether.
The resulting p-aminoether was dissolved in water-depleted DCM (30 mL) and added to a 100mL round-bottom flask (2.2 mmol), and 1M BBr was added dropwise slowly at-78 deg.C 3 (3 mL,3.0 mmol) and after reacting for 3h at room temperature, the mixture was poured into ice water and saturated NaHCO was slowly added dropwise 3 Until the solution becomes alkaline, DCM is used for extraction, drying, concentration and silica gel column chromatography are carried out, and an eluent is ethyl acetate: petroleum ether = 1. Compounds 29, 59, 61 were prepared using the procedure of example 4.
Example 5
The synthesis process of N-aryl p-fused heterocyclic alkylamino phenol derivative includes the steps of using p-bromoanisole and secondary amine as substrate and Pd (OAc) 2 As catalyst, ruPhos as ligand, DCM/H 2 O is taken as a solvent, and reacts for 8 to 12 hours at the temperature of 110 ℃ in the nitrogen atmosphere to obtain the target product N-aryl pairThe reaction process of the fused heterocyclic alkylamino phenol derivative is as follows:
Figure BDA0003852003060000102
to a round-bottomed flask with water removed was added p-bromoanisole (5.1 mmol), a secondary amine (5.0 mmol), pd (OAc) 2 (0.05 mmol), ruPhos (0.10 mmol) and NaO t Bu (6.0 mmol), nitrogen displacement three times, reaction at 110 ℃ for 8-12H, addition of DCM/H2O =1 mixture after cooling to room temperature. The organic phase is extracted three times, dried, concentrated and subjected to column chromatography, and an eluent is dichloromethane/methyl tertiary ether.
The resulting p-aminoether was dissolved in water-removed DCM (30 mL) and added to a 100mL round-bottomed flask (2.2 mmol), and 1M BBr was slowly added dropwise at-78 deg.C 3 (3 mL,3.0 mmol) and after reacting for 3h at room temperature, the mixture was poured into ice water and saturated NaHCO was slowly added dropwise 3 Until the solution becomes alkaline, DCM is extracted, dried, concentrated and subjected to silica gel column chromatography, and an eluent is ethyl acetate: petroleum ether = 1. Compound 60 was prepared using the procedure of example 5.
Example 6
The synthesis process of N-aryl p-fused heterocyclic alkylamino phenol derivative includes the steps of using p-bromoanisole and secondary amine as substrate and Pd (OAc) 2 As catalyst, ruPhos as 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 para-fused heterocyclic alkylamino phenol derivative, wherein the reaction process is as follows:
Figure BDA0003852003060000111
to a round-bottomed flask with water removed was added p-bromoanisole (5.1 mmol), a secondary amine (5.0 mmol), pd (OAc) 2 (0.05 mmol), ruPhos (0.10 mmol) and NaO t Bu (6.0 mmol), nitrogen exchanged three times, reacted at 110 ℃ for 8-12H, cooled to room temperature and added DCM/H2O =1 mixture. Extracting organic phase for three times, drying, concentrating, performing column chromatography,the eluent was dichloromethane/tert-methyl ether.
The resulting p-aminoether was dissolved in water-depleted DCM (30 mL) and added to a 100mL round-bottom flask (2.2 mmol), and 1M BBr was added dropwise slowly at-78 deg.C 3 (3 mL,3.0 mmol), after reaction at room temperature for 3h, the mixture was poured into ice water and saturated NaHCO was slowly added dropwise 3 Until the solution becomes alkaline, DCM is used for extraction, drying, concentration and silica gel column chromatography are carried out, and an eluent is ethyl acetate: petroleum ether = 1. Compound 31 was prepared using the procedure of example 6.
Example 7
The synthesis process of N-aryl p-fused heterocyclic alkylamino phenol derivative includes the steps of using p-bromoanisole and secondary amine as substrate and Pd (OAc) 2 As catalyst, ruPhos as ligand, DCM/H 2 Taking O as a solvent, reacting for 8-12h at 110 ℃ in a nitrogen atmosphere to obtain the target product N-aryl-p-fused heterocyclic alkylamino phenol derivatives, wherein the reaction process is as follows:
Figure BDA0003852003060000121
to a round-bottomed flask with water removed was added p-bromoanisole (5.1 mmol), a secondary amine (5.0 mmol), pd (OAc) 2 (0.05 mmol), ruPhos (0.10 mmol) and NaO t Bu (6.0 mmol), nitrogen exchanged three times, reacted at 110 ℃ for 8-12H, cooled to room temperature and added DCM/H2O =1 mixture. The organic phase is extracted three times, dried, concentrated and subjected to column chromatography, and an eluent is dichloromethane/methyl tertiary ether.
The resulting p-aminoether was dissolved in water-depleted DCM (30 mL) and added to a 100mL round-bottom flask (2.2 mmol), and 1M BBr was added dropwise slowly at-78 deg.C 3 (3 mL,3.0 mmol) and after reacting for 3h at room temperature, the mixture was poured into ice water and saturated NaHCO was slowly added dropwise 3 Until the solution becomes alkaline, DCM is used for extraction, drying, concentration and silica gel column chromatography are carried out, and an eluent is ethyl acetate: petroleum ether = 1. Compound 62 was prepared using the procedure of example 7.
Example 8
2, 4-diamino phenolsThe synthesis method of the derivative takes N-methylaniline and p-aminophenol compound as substrates and Cu (OTf) 2 As catalyst, ti (OiPr) 4 Toluene is used as an additive, and the toluene is used as a solvent, and reacts for 7-10h at room temperature to obtain the target product 2, 4-diamino phenol derivative, wherein the reaction process is shown as follows.
Figure BDA0003852003060000122
Adding magneton and Na into a reaction tube for removing water 2 SO 4 (85mg, 2.0eq, 0.6 mmol) and Cu (OTf) 2 (16mg, 0.045mmol, 15mol%), N-methylaniline (35mg, 0.33mmol, 1.1eq.), p-aminophenol compound (0.3mmol, 1.0eq.) were dissolved in 3mL of dehydrated toluene, and then added to the reaction tube, the reaction tube was sealed, and Ti (OiPr) was slowly added thereto through a needle tube 4 (25.0 mg, 30mol%) and reacted at room temperature for 7-10h, after the reaction is finished, quenched with 0.1M HCl (5 mL), extracted with saturated sodium bicarbonate to pH>And 8, drying by anhydrous sodium sulfate, and separating by silica gel column chromatography. Compounds 35-39 were prepared using the method of example 8.
The yields and nuclear magnetic spectrum data for the series of compounds prepared using 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 procedure, 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 procedure, light 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 procedure, 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): example 1 procedure, light yellow solid, 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): example 1 procedure, light 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 procedure, 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 procedure, 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 procedure, grey 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, grey 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 procedure, 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 procedure, pale yellow solidBody, 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 procedure, 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 procedure, light 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 procedure, 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 procedure, light 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): example 1 procedure, light 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): example 1 procedure, 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 ×): 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): example 1 procedure, light yellow solid, 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, purple 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 procedure, white solid, 88% yield. Nuclear magnetic spectral 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. Nuclear magnetic 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 procedure, 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 procedure, grey 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 procedure, 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 procedure, 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 procedure, 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 procedure, 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)。
decaaminophenol: 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 test, MTT cell activity assay, tyrosinase inhibition test, kinetic analysis of tyrosinase inhibition, and antioxidant test.
1. In vitro antibacterial test
We performed in vitro antibacterial tests on a portion of the compounds provided in the above examples of the invention.
The method comprises the following steps: MIC was determined according to the method of the national Committee for clinical laboratory standards.
As test bacteria, 3 gram-positive bacteria and 3 gram-negative bacteria were selected. Bacillus cereus and Escherichia coli were purchased from China general microbiological culture Collection center. MRSA (Staphylococcus aureus ATCC 43300) and Bacillus subtilis are provided by the chemical and pharmaceutical college of northwest university of agriculture and forestry. The cabbage soft rot and the konjak soft rot are provided by the plant protection institute of northwest agriculture and forestry science and technology university. MIC was defined as the minimum inhibitory concentration, and each compound produced 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, compounds were dissolved in dimethyl sulfoxide (DMSO) to prepare stock solutions. Test compounds and control drugs were then prepared in liquid Luriae Bertan medium. The desired concentrations were 128, 64, 32, 16, 8, 4, 2, 1, 0.5 and 0.25. Mu.g/mL (dimethyl sulfoxide), respectively<0.5%). Ciprofloxacin and gentamicin were selected as positive controls (k.p. rakesh et al.2020. [1] )。
The minimum inhibitory concentration (MIC value) of 40 test compounds was determined by a two-fold dilution method in this experiment. 3mL of sterilized LB medium was added to a 5mL centrifuge tube under aseptic conditions, and the mixture was used againA small amount of bacteria to be tested is picked up by a sterilized inoculating needle and added into the culture solution, and after the opening is sealed, the bacteria are cultured in a constant temperature incubator at 37.5 ℃ for 12 hours. 100 μ L of the sterilized culture medium was measured for absorbance at 600nm, and LB medium without test bacteria was used as a blank, which corresponds to a concentration of 1X 10 in terms of 0.1OD600 8 CFU/mL, then 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 prepared as a DMSO solution at 51200. Mu.g/mL, 5. Mu.L of the solution was aspirated, and 1995. Mu.L of sterile water was added to prepare a stock solution at an initial concentration of 128. Mu.g/mL. Adding 100 mu L of sterile water into each of the 2 nd to 8 th holes, adding 200 mu L of mother liquor into the 1 st hole, uniformly mixing the solution in the 1 st hole, then using a pipette to pipette 100 mu L to the 2 nd hole, repeating the process to dilute the 2 to 8 th holes twice, finally sucking out the mixed 100 mu L of solution from the 8 th hole and discarding the solution, thus obtaining the concentration gradient of 128 to 1 mu g/mL. 100 mu L of bacterial liquid is added into each of the 1-8 and 10 holes, and then a concentration gradient of 64-0.5 mu g/mL can be obtained from the 1-8 holes. 10. 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.
Uniformly shaking the solution in the micropores, and culturing in a constant-temperature incubator at 37 ℃; gentamicin and ciprofloxacin were used as positive controls, and 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). Compounds initially tested at 0.5. Mu.g/mL for MICs were further tested for their MIC values at concentrations ranging from 0.5 to 0.015. Mu.g/mL using the same procedure. Observing the result after culturing for 12-16h, the sediment appears in the hole with the growth of the hypha, and the liquid medicine concentration in the hole with the growth of the aseptic hypha is the MIC value of the sample.
Test bacteria: bacillus cereus (1.1846), bacillus subtilis (1.88), methicillin-resistant Staphylococcus aureus (1.89), escherichia coli (1.1574), peronospora brassicae (Erwinia carotovora.a) and konjac carotovora (Erwinia carotovora.b). Positive control drug: ciprofloxacin, gentamicin.
Table 1 antimicrobial activity data
Figure BDA0003852003060000201
Figure BDA0003852003060000211
a MRSA = methicillin-resistant Staphylococcus aureus (methicillin-resistant Staphylococcus aureus), b.cereus = Bacillus cereus (Bacillus cereus), b.subtilis = Bacillus subtilis (Bacillus subtilis), e.coli = Escherichia coli (Escherichia coli).
b Erwinia carotovora subsp. Carotovora isolated from cabbage.
c Erwinia carotovora subsp.
d DAP = p-decylaminophenol (p-decylaminophenol).
e CIP = ciprofloxacin (ciprofloxacin), gent = gentamicin.
As shown in Table 1, most of the compounds prepared in examples 1 to 8 of the present invention had antibacterial activity against gram-positive bacteria (especially methicillin-resistant Staphylococcus aureus), and low antibacterial activity against gram-negative bacteria. Wherein, the general structural formula of the compound with antibacterial activity to MRSA is shown as the following formulas A1 and A2:
Figure BDA0003852003060000221
in the formulae A1 and A2, R 1 Selected from-Me, -Et, -F, -Cl, -Br, -OMe, -iPr, -CN, -NO 2 Any one of the above; r 2 Selected from-Ph or H; x is selected from any one of C, O, S and N; n =0 or 1.
Among the above-mentioned compounds, the compounds of formula (I), compounds 4k,4m,4n,4p and 4ab are the most potent compounds against MRSA with a minimum MIC of 0.5. Mu.g/mL, close to the positive control (MIC) Cip ＝0.25μg/mL；MIC Gen =0.25 μ g/mL). Compounds 4k,4o and 4ab show certain inhibitory activity against Bacillus cereus although the MIC values are higher than those of the positive control, and the MIC values are 16 mug/mL; compound 4m showed better activity against bacillus subtilis (MIC =8 μ g/mL), showing potential derivatization prospects; all compounds were less active against gram-negative bacteria with a minimum MIC of 64. Mu.g/mL.
2. MTT cell Activity assay
We performed MTT cell activity assays on a portion 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, the MTT cell activity is described below only as compound (4k, 4m,4n,4p, 4ab).
The method comprises the following steps: cell viability of test Compound (4k,4m,4n,4p,4ab) according to Duan [2] Et al (j.duan et al.2016. [2] ). Compounds tested for anti-MRSA activity against the RAW264.7 cell line (concentrations of 0.5, 1, 2,4, 8, 16 and 32 μ g/mL) were tested in 3 replicates of in vitro cell activity assay per compound 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% of compounds with different concentrations and cells at 37 deg.C CO 2 In 96-well plates for 12h. The medium was removed and cultured for 4h with the addition of 0.5mg/mL MTT. The medium was removed. DMSO (100 μ L) was then added to each well. Shaking for 15min to dissolve purple formazan crystals. Finally, the plate was selected to test at a wavelength of 570 nm. Blank group served as control group. Data were analyzed by GraphPad Prism 6.0. The formula for cell viability was (absorbance of treated cells/absorbance of untreated cells) × 100%.
The test cells: RAW264.7 cells
The biological activity was further assessed using the MTT method, and the toxicity of compound 4k,4m,4n,4p,4ab to RAW264.7 cells was shown in figure 1.
As can be seen from the results in FIG. 1, MTT assay detects the cytotoxicity of 4k,4m,4n,4p and 4ab in RAW264.7 cell line (error bars represent standard deviation values of absorbance values. P <0.05,. P <0.01 or. P <0.001. As compared to control groups as measured by Student's t-test.)
After the compound and the cells are cultured for 24 hours, the cell survival rate of the 4k,4m,4n,4p,4ab is over 95 percent at the concentration of 0.5 mu g/mL. While compound 4k,4m,4n showed excellent survival (105%, 103% and 103%) for RAW264.7 cells at an effective antibacterial dose (0.5 μ g/mL). Compounds 4k,4m,4n,4p and 4ab were not toxic to RAW264.7 cells at a concentration of 8 μ g/mL. The results of the experiments show that all tested compounds are less toxic to cells at effective concentrations.
3. Tyrosinase inhibition assay
We performed tyrosinase inhibition assays on a portion of the compounds provided in the above examples of the invention.
The compounds having inhibitory effect on tyrosinase activity are represented by the following formulae A3 and A4:
Figure BDA0003852003060000231
in the formulae A3 and A4, R 3 Any one selected from Me, F, cl and Br.
Since the compounds represented by formulas A3 and A4 have almost the same inhibitory effect on tyrosinase activity, the inhibitory effect on tyrosinase activity will be described below with respect to compound (4k, 4m,4n,4p, 4ab) alone.
The method comprises the following steps: mushroom tyrosinase (EC 1.14.18.1) (Sigma Chemical Co.) an enzyme inhibition assay was performed using L-tyrosine as a substrate (V.N.Takahashi et al 2014 [3] ). Stock solutions of test compounds 4k,4m,4n,4p and 4ab, as well as kojic acid, were prepared in DMSO (40 mM) and then diluted to the desired concentration with phosphate buffer (pH = 6.8). First, 10 μ L of mushroom tyrosinase (0.5 mg/mL) was mixed with 160 μ L of phosphate buffer (50mm, ph = 6.8) in a 96-well microplate, and then 10 μ L of test compound was added. After pre-incubating the mixture at 28 ℃ for 20min, themu.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. Mu.M. Triplicate 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 rate was calculated according to the following equation:
inhibition (%) =100 × (test compound)/control
The inhibitory effect of each compound was expressed as the concentration required to inhibit enzyme activity by 50% (IC 50).
Test enzymes: mushroom tyrosinase (EC 1.14.18.1)
To verify the relationship between anti-MRSA activity and tyrosinase inhibitory activity of N-aryl para-aminophenol, we selected compounds 4k,4m, 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 μ M (m.d. aytemir et al.2019) [4] ). When L-tyrosine was used as a reaction substrate, all compounds showed significantly good anti-tyrosinase activity.
FIG. 2 shows the effect of compounds on tyrosinase. Wherein (a) is the effect of each compound on tyrosinase activity at 16. Mu.M. Results represent mean ± SD of each group. P <0.05, p <0.01 or p <0.001 by Student's t-test compared to control group. (b) Is the concentration dependent effect of the compound on mushroom tyrosinase activity (mean).
From the results in FIG. 2, it can be seen that 4k,4m,4p,4ab and KA inhibited the tyrosinase activities by 47%, 39%, 44%, 49%, 53% and 26%, respectively, as compared with the control group. We also investigated the effect of different concentrations of 4k,4m,4n,4p and 4ab on mushroom tyrosinase activity and calculated IC50 values for 5 compounds. These compounds all show higher activity than KA. The IC50 values for compounds 4k,4m,4p and 4ab are 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 effective inhibitor of mushroom tyrosinase activity.
4. Kinetic analysis of tyrosinase inhibition
We performed a kinetic analysis of tyrosinase inhibition on a portion 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 chose the concentrations: 0.1, 2,4, 8, 16 and 32 μ M. Substrate L-tyrosine concentrations were 0, 0.062, 0.125, 0.25, 0.5, 1, 2 and 4mM with a concentration of 0.5mg/mL of tyrosinase in all kinetic studies. The pre-incubation and measurement times were the same as in the mushroom tyrosinase inhibition protocol. Inhibition type passage rate (1/V) and substrate concentration (1/[ S ]]) The inverse of (a) is analyzed in a Lineweavere-Burk plot. Dissociation constant K i Determined from a quadratic plot of slope versus inhibitor concentration.
The most effective inhibition mechanism of compound 4ab was analyzed by Lineweaver-Burk double reciprocal method. Kinetic studies of the enzyme were performed by plotting 1/V versus 1/[ S ] in the presence of different inhibitor concentrations, resulting in a series of straight lines crossing the X-axis in the second quadrant, as shown in FIG. 3. When the concentration of compound 4ab was increased, the Vmax value decreased while the Km value was unchanged, indicating that 4ab is non-competitive for the type of mushroom tyrosinase inhibition.
FIG. 3 is a graph of the kinetics of tyrosinase oxidation of L-tyrosine in the presence of compound 4 ab. Wherein (a) is a Lineweaver-Burk plot of 3-1j inhibition of tyrosinase at concentrations of 0, 1, 2,4, 8, 16, and 32 μ M. The concentrations of the substrate L-tyrosine 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 the dissociation constant K by means of a quadratic plot of the slope against the concentration of Compound 4ab i (FIG. 3). From this line, the inhibition constant K of 4ab for the enzyme i At 1.76. Mu.M, see Table 2.
TABLE 2 kinetic parameters for enzyme inhibition
Figure BDA0003852003060000251
Note: ND a Indicating that no measurement was made.
5. Oxidation resistance test
We performed an antioxidant test on a portion of the compounds prepared in examples 1-8 of the present invention. The compounds prepared in examples 1 to 8 all have corresponding antioxidant effects, and therefore, the antioxidant effect is described below only as compound (4k,4m,4n,4p,4ab).
The method comprises the following steps: according to Sarker [5] The method described by et al measures DPPH scavenging activity of test compounds with some modifications (Sarker et al 2005) [5] ). 100mL of different concentrations (3.125, 6.25, 12.5, 25, 50 and 100. Mu.g/mL) of test compounds (4 k,4m,4n,4p and 4 ab) were pipetted 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 30min in the dark. The absorbance of the solution was measured at λ 517nm (V.Padmavathi et al.2011) [6] ). Ascorbic acid and dimethyl sulfoxide were used as positive control and blank, respectively. The percentage DPPH clearance activity was calculated according to the following equation:
% DPPH clearance = [ (A) Blank space -A Sample (I) )/A Blank space ]×100
Where blank is the absorbance of the control reaction (containing all reagents except the test compound) and sample is the absorbance of the test sample. A dose-response curve was plotted between% free radical scavenging activity and drug concentration. Linear regression analysis was performed on drug concentrations showing 50% free radical inhibitory activity (IC 50). Ascorbic acid was used as a positive control and all experiments were performed in triplicate and the results averaged.
Positive control: ascorbic acid. Compounds with good antimicrobial activity were selected for antioxidant activity evaluation at different concentrations (3.125, 6.25, 12.5, 25, 50 and 100 μ g/mL) and compared to a standard antioxidant (ascorbic acid) for studies. We chose DPPH (1, 1-diphenyl-2-pyridinehydrazide) free radical scavenging activity assessment as the standard assay for antioxidant activity studies. The results are shown in fig. 4. In FIG. 4, the percentage (%) of DPPH scavenging effect of ascorbic acid, 4k,4m,4n,4p and 4 ab. Each value represents mean ± standard deviation (n = 3).
As shown by the results in fig. 4, 4- (2, 3-dihydro-4H-benzo [ b ] [1,4] oxazin-4-yl) phenol (compound 4 ab) (IC 50=7.82 μ g/mL) showed a higher potential for antioxidant activity than the other counterparts, 1.24 times higher than ascorbic acid (IC 50=9.70 μ g/mL). Compound 4k (IC 50=10.45 μ g/mL), 4m (IC 50=10.22 μ g/mL), 4n (IC 50=14.04 μ g/mL) and 4p (IC 50=12.57 μ g/mL showed antioxidant activity comparable to the positive control.
6. Results and analysis
The screened 5 compounds all show lower cytotoxicity, good antioxidant activity and tyrosinase inhibitory activity, wherein the tyrosinase inhibitory activity of the compounds 4n and 4ab is excellent, and IC50 values are respectively 2.65 mu M and 2.53 mu M. The biological activities of these 5 compounds are shown in table 3.
Biological Activity of the Compounds of Table 3
Figure BDA0003852003060000271
Note: ND means not measured.
In conclusion, aiming at the problems that N-monoalkyl substituted p-aminophenol is generally unstable and easy to oxidize and has a single derivative structure, the invention leads the structure to be stable by introducing N-aryl p-aminophenol, enhances the derivatizability of the compound, evaluates the antibacterial, antioxidant and tyrosine inhibitory activities of the structure and finds a plurality of compounds simultaneously having tyrosinase inhibitory activity and antibacterial activity. The invention has the characteristics of simple compound synthesis, good antibacterial effect against MRSA (methicillin-resistant staphylococcus aureus), high enzyme inhibition rate and the like, and has wide application prospect.
Cited documents:
[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.
Figure BDA0003852003060000281
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 present invention is not limited to the above preferred embodiments, and any modifications, equivalent substitutions and improvements made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (8)

1. A4-aminophenol derivative characterized by having a general structural formula represented by the following formula (I-1) or formula (I-2):
Figure FDA0003852003050000011
in the formulae (I-1) and (I-2), D 1 、D 2 、D 3 Are respectively and independently selected from the groups shown in formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII):
Figure FDA0003852003050000012
in the formula (II), R 1 Any one of-H, -F, -Cl, -Br, C1-C4 alkyl, nitro, cyano, methoxy, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, substituted or unsubstituted fused heterocycle, substituted or unsubstituted aryl ethynyl;
R 2 any one selected from C1-C14 alkyl, allyl, substituted or unsubstituted single heterocyclic alkyl, substituted or unsubstituted fused heterocyclic alkyl, substituted or unsubstituted aryl, substituted or unsubstituted condensed ring aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted condensed ring aryl alkyl and substituted or unsubstituted arylamino alkyl;
in the formulas (III) to (V), X is any one of an oxygen atom, a sulfur atom and a carbon atom.
2. 4-aminophenol derivatives according to claim 1, wherein in formula (II), when R is 1 When any one of substituted aryl, substituted condensed ring aryl, substituted condensed heterocycle and substituted aryl ethynyl is selected, 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-heterocyclic alkyl, substituted fused heterocyclic alkyl, substituted aryl, substituted condensed ring aryl, substituted aryl alkyl, substituted condensed ring aryl alkyl and substituted arylamino alkyl, the substituent is any one of-F, -Cl, -Br, C1-C4 alkyl, nitro, cyano and methoxy.
3. 4-aminophenol derivatives according to claim 2, wherein the radical of formula (II) is chosen from one of the following formulae:
Figure FDA0003852003050000021
Figure FDA0003852003050000031
4. 4-aminophenol derivatives according to claim 2, wherein the group represented by formula (III) is selected from one of the following formulae:
Figure FDA0003852003050000032
5. 4-aminophenol derivatives according to claim 1, characterized in that they are in particular one of the following compounds:
Figure FDA0003852003050000041
Figure FDA0003852003050000051
Figure FDA0003852003050000061
6. use of a 4-aminophenol derivative according to any one of claims 1 to 5, for the preparation of tyrosinase inhibitors.
7. Use of a 4-aminophenol derivative according to any one of claims 1 to 5, for the preparation of an antibacterial agent against MRSA.
8. Use of a 4-aminophenol derivative according to any one of claims 1 to 5 for the preparation of an antioxidant.
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