CN114478354B - 1, 3-disubstituted indole derivatives as hyaluronidase inhibitor and application thereof in cosmetic products - Google Patents

1, 3-disubstituted indole derivatives as hyaluronidase inhibitor and application thereof in cosmetic products Download PDF

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CN114478354B
CN114478354B CN202210130214.5A CN202210130214A CN114478354B CN 114478354 B CN114478354 B CN 114478354B CN 202210130214 A CN202210130214 A CN 202210130214A CN 114478354 B CN114478354 B CN 114478354B
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姜燕飞
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Beijing Qingyan Bozhi Health Management Co ltd
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • A61K8/492—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid having condensed rings, e.g. indol
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
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    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
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Abstract

The invention discloses a 1, 3-disubstituted indole derivative, a preparation method thereof and application thereof as a hyaluronidase inhibitor and in preparing anti-aging cosmetic products. Specifically, the invention discloses a preparation method of 1, 3-disubstituted indole derivatives. In vitro activity test shows that the 1, 3-disubstituted indole derivatives have stronger hyaluronidase inhibition activity and IC 50 About 1-10. mu.g/mL. In addition, the 1, 3-disubstituted indole derivatives have very low cytotoxicity and strong fat solubility, are easy to be absorbed by skin tissues, and can be used as anti-aging ingredients for preparing beauty products. The invention also discloses application of the 1, 3-disubstituted indole derivative as a cosmetic component to preparation of an anti-skin-aging facial mask.

Description

1, 3-disubstituted indole derivatives as hyaluronidase inhibitor and application thereof in cosmetic products
Technical Field
The invention relates to 1, 3-disubstituted indole derivatives, a preparation method thereof, an inhibition effect on hyaluronidase and an application of the derivatives in preparing a cosmetic product, and belongs to the field of cosmetics.
Background
Hyaluronidase is a key enzyme that degrades hyaluronic acid by cleaving the glycosidic bond of hyaluronic acid to catalyze the reaction of hyaluronic acid degradation to form monosaccharides. Hyaluronidases can be classified into different types according to origin and mechanism of action. Hyaluronidases are classified into 3 major groups according to their mechanism of action: the first class, mainly derived from mammals, is endo-beta-N-acetylglucosaminidase which acts on beta-1, 4-glycosidic linkages to form tetrasaccharides; the second type is mainly derived from bacteria, is endo-beta-N-acetylglucosaminidase, acts on beta-1, 4-glycosidic bonds, and obtains 4, 5-unsaturated disaccharide through a beta-elimination mechanism; the third type is derived mainly from leeches, and is endo-beta-glucuronidase which acts on beta-1, 3-glycosidic bonds. Hyaluronic acid is one of the main components constituting the extracellular matrix (ECM) system of skin, is a three-dimensional network, and has important physiological functions of maintaining the structure of skin and retaining water molecules. Published dermatological studies indicate that abnormal overactivity of hyaluronidase may lead to increased degradation of hyaluronic acid in the skin epidermis, which is a histochemical marker of aging skin. The homeostasis of hyaluronic acid-hyaluronidase is a key factor that mediates various skin aging-related physiological events, including ECM structural integrity, wrinkle formation, and skin moisturization. Therefore, hyaluronidase inhibitors are considered promising cosmeceuticals with potential anti-skin aging effects, thus drawing considerable research interest.
Most of the hyaluronidase inhibitors reported to date are natural products and their analogues. Currently reported synthetic hyaluronidase small molecule inhibitors are relatively few. Several synthetic indole, benzoxazole and benzimidazole derivatives were reported to have some hyaluronidase inhibitory activity (FIG. 1), but their inhibitory activity was essentially maintained at IC 50 In the order of tens of micromoles. The indole compounds which are subjected to rational modification so as to improve the inhibition of the compounds on hyaluronidase and enhance the inhibition activity of the compounds on hyaluronidase can be used for preparing cosmetics and used as active ingredients with the effect of resisting skin aging.
Disclosure of Invention
Aiming at the literature report that some indole, benzoxazole and benzimidazole compounds have weak hyaluronidase inhibition activity (figure 1), indole is taken as a mother nucleus, and the structure of the indole is optimized, so that the inhibition activity of derivatives of the indole, benzoxazole and benzimidazole compounds on hyaluronidase is enhanced. The invention mainly aims to provide 1, 3-disubstituted indole derivatives, and a preparation method and application thereof. The invention develops the 1, 3-disubstituted indole derivatives, has obviously enhanced hyaluronidase inhibition activity, and can be used for developing beauty products for resisting skin aging.
In order to achieve the purpose, the invention comprises the following technical scheme:
in a first aspect, the present invention provides a 1, 3-disubstituted indole compound, wherein the structure is represented by general formula (I):
Figure BDA0003502313770000021
wherein R is a ，R b ，R c ，R d ，R e Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, methoxy, trifluoromethyloxy, carboxamido, methylsulfonyl, isopropylsulfonyl, mesylate, isopropylsulfonate, trifluoromethyl, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl group.
Above C 1-8 Means that the number of carbon atoms of the substituent is 1,2, 3, 4, 5, 6, 7 or 8; c 2-8 The number of carbon atoms of the substituent is 2, 3, 4, 5, 6, 7 or 8.
The 1, 3-disubstituted indole compounds related by the invention are compounds with a brand new structure, and have hyaluronidase inhibition activity which is obviously enhanced compared with oleanolic acid in vitro. Therefore, can be used for preparing cosmetics for resisting skin aging.
Preferably, in the formula (I), R a ，R b ，R c ，R d ，R e Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, trifluoromethyl, C 1-4 Alkyl radical, C 2-4 An alkenyl group.
C above 1-4 Means that the number of carbon atoms of the substituent is 1,2, 3 or 4; c 2-4 The number of carbon atoms of the substituent is 2, 3 or 4.
Further preferably, the 1, 3-disubstituted indole compound is selected from the following compound structures:
Figure BDA0003502313770000031
Figure BDA0003502313770000041
in a second aspect, the present invention provides a compound composition comprising one or more indoles of the 1, 3-disubstituted indoles, stereoisomers, chemically acceptable salts thereof, as described in the first aspect above; preferably, the compound composition further comprises cosmetically acceptable adjuvants such as carriers, diluents, excipients, fillers, binders, wetting agents, disintegrants, emulsifiers, cosolvents, solubilizers, tonicity adjusting agents, surfactants, colorants, pH adjusting agents, antioxidants, bacteriostats, or buffers, and the like.
The chemically acceptable salt of the 1, 3-disubstituted indole compound related by the invention is a salt formed by the 1, 3-disubstituted indole compound and a base selected from the following bases: acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like; acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.
In a third aspect, the invention provides a preparation method of a 1, 3-disubstituted indole compound, which comprises the following steps:
equal amounts of 3- ((1, 1' -biphenyl) -4-thio) -indole, AlMe 3 Mixing and reacting for 1h, adding various isocyanates, e.g.
Figure BDA0003502313770000051
Reacting for 16h to obtain the product; wherein the substituent group R a ，R b ，R c ，R d ，R e Is in accordance with the range defined in the first aspect;
the reaction formula is shown as follows:
Figure BDA0003502313770000052
preferably, the 3- ((1, 1' -biphenyl) -4-thio) -indoles are prepared as follows:
indole, mercaptan and TBHP in a methyl cyanide solvent, and then I is added 2 As a catalyst, continuously reacting at room temperature to obtain an intermediate 3- ((1, 1' -biphenyl) -4-sulfenyl) -indole,
the reaction formula is shown as follows:
Figure BDA0003502313770000061
in a fourth aspect, the present invention provides a 1, 3-disubstituted indole compound as described in the first aspect, or an indole compound composition as described in the second aspect, for use in the preparation of a cosmetic for delaying skin aging by inhibiting hyaluronidase activity.
In a fifth aspect, the present invention provides an anti-skin aging facial mask, which comprises the compound according to the first aspect or the compound composition according to the second aspect, and the formula and the parts by weight of the facial mask are as follows:
phase A: 92.68 parts of water, 2 parts of 1, 2-butanediol, 0.1 part of methyl hydroxybenzoate, 0.16 part of carbomer, 0.05 part of hydroxyethyl cellulose, 0.03 part of EDTA disodium, 0.05 part of sodium hyaluronate, 0.4 part of 1, 2-hexanediol and 0.1 part of panthenol;
phase B: 3 parts of water and 0.12 part of triethanolamine;
and C phase: 0.1 part of the compound according to the first aspect or the compound composition according to the second aspect, 1 part of ethanol, and 0.1 part of phenoxyethanol
Phase D: essence 0.01 weight portions and PEG-40 hydrogenated castor oil 0.1 weight portions
Drawings
Figure 1, synthetic hyaluronidase small molecule inhibitors that have been reported.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitation of the present invention. For all of the following examples or preparations, standard procedures and purification methods known to those skilled in the art may be used. Unless otherwise indicated, all temperatures are in degrees celsius (degrees celsius) and the structure of a compound is determined by nuclear magnetic resonance spectroscopy (NMR) and/or Mass Spectroscopy (MS).
For all the following examples or preparations, the structure of the compounds is determined by NMR 1 H NMR) or Mass Spectrometry (MS). The nuclear magnetic resonance hydrogen spectral shift (δ) is given in parts per million (ppm). NMR spectra were measured using a Mercury-400 NMR spectrometer using deuterated chloroform (CDCl) 3 ) As solvent, Tetramethylsilane (TMS) or sodium 3- (trimethylsilyl) deuteropropionate (TSM) was used as internal standard.
The electronic balance used was an electronic balance model Yanaco LY-300, Japan.
The column chromatography uses 200-300 mesh or 300-400 mesh silica gel as a carrier.
The anhydrous solvents were all processed by standard methods. Other reagents were commercially available analytical grade from Sigma-Aldrich Sigma Aldrich trade, Inc. of Beijing YinuoKa technology, Inc., Alfa Anga chemical, Inc. of China, and Shanghai Arlatin Biochemical technology, Inc., respectively.Preparation example 1: 3- ((1, 1' -biphenyl) -4-thio) -indole Indole (A)
This preparation example prepared 3- ((1, 1' -biphenyl) -4-thio) -indole via the following synthetic route:
Figure BDA0003502313770000071
indole (0.5mmol), thiol (0.505mmol) and TBHP (0.51mmol) were combined and dissolved in MeCN (2.0mL) and heated to 60 ℃ with stirring. Iodine (0.10mmol,10 mol%) was then added to the reaction. The reaction was stirred at room temperature for 1 hour until complete consumption of starting material was monitored by TLC. By adding saturated Na 2 S 2 O 3 The reaction was quenched. Then extracted with EtOAc and the combined organic layers were separated, MgSO 4 Drying, filtration and concentration in vacuo afforded 3- ((1, 1' -biphenyl) -4-sulfanyl) -indole as a white solid, purified by column chromatography using petroleum ether/ethyl acetate as eluent 91.5mg (61%). The product was characterized as follows: 1 H NMR(400MHz,CDCl 3 ):δ.d 8.98(br s,1H),7.79(d,J＝8.0Hz,1H),7.64-7.54(m,1H),7.55-7.41(m,6H),7.38-7.28(m,4H),7.06-7.02(m,1H),6.92-6.84(m,1H)；HR-MS(ESI):[M+H]+ C20H15NS calculated 301.4070, found 301.4021.
Example 1: this example prepares 3- ([1,1' -biphenyl)]-4-thio) -N- (phenyl-carboxamido) -indole,the structural formula is as follows:
Figure BDA0003502313770000081
at 0 deg.C, take 3mL of 6.0mmol of AlMe 3 (2M in toluene) was added dropwise to a mixture containing 3- ((1, 1' -biphenyl) -4-thio) -indole (600mg, 2.0mmol) in dry toluene (6 mL). Toluene isocyanate (577mg, 2.2mmol) was slowly added thereto. The reaction was continued for 4 hours and checked by TLC, followed by saturated NaHCO 3 The solution (8mL) was quenched and the product was purified by column chromatography to give compound 302mg (36%) as a white solid. The product was characterized as follows: 1 H NMR(400MHz,CDCl 3 ):δ9.97(br s,1H),7.79(d,J＝5.0Hz,1H),7.65(m,1H),7.63-7.41(m,8H),7.38-7.12(m,7H),7.09-7.05(m,1H),7.03-6.95(m,1H)；HR-MS(ESI):[M+H]+ C27H21N2OS calculated 421.5380, found 421.5361.
Example 2: this example prepares 3- ([1,1' -biphenyl)]-4-thio) -N- ([ 3-fluoro-phenyl)]Carboxamide group) - Indole, the structural formula of which is as follows:
Figure BDA0003502313770000082
3mL of 6.0mmol of AlMe were taken at 0 deg.C 3 (2M in toluene) was added dropwise to dry toluene (6mL) containing 3- ((1, 1' -biphenyl) -4-sulfanyl) -indole (600mg, 2.0 mmol). 3-fluorobenzeneisocyanate (301mg, 2.2mmol) was slowly added thereto. The reaction was continued for 4 hours and checked by TLC, followed by saturated NaHCO 3 The solution (8mL) was quenched and the product was purified by column chromatography to give 302mg (36%) of compound as a white solid. The product was characterized as follows: 1 H NMR(400MHz,CDCl 3 ):δ9.97(br s,1H),7.78(d,J＝5.0Hz,1H),7.66(m,1H),7.61-7.43(m,8H),7.38-7.12(m,6H),7.09-7.05(m,1H),7.03-6.94(m,1H)；HR-MS(ESI):[M+H]+ C27H20FN2OS calculated 439.5284, found 439.5236.
Example 3: this example prepares 3- ([1,1' -biphenyl)]-4-thio) -N- ([3, 4-difluoro-phenyl ] -phenyl)]-carboxamides Yl) -indole, the structural formula of which is as follows:
Figure BDA0003502313770000091
3mL of 6.0mmol of AlMe were taken at 0 deg.C 3 (2M in toluene) was added dropwise to dry toluene (6mL) containing 3- ((1, 1' -biphenyl) -4-sulfanyl) -indole (600mg, 2.0 mmol). 3, 4-difluoropolyisocyanate (341mg, 2.2mmol) was slowly added thereto. The reaction was continued for 4 hours and checked by TLC, followed by saturated NaHCO 3 The solution (8mL) was quenched and the product was purified by column chromatography to give compound 255mg (28%) as a white solid. The product was characterized as follows: 1 H NMR(400MHz,CDCl 3 ):δ9.97(br s,1H),7.78(d,J＝5.0Hz,1H),7.66(m,1H),7.60-7.44(m,8H),7.40-7.11(m,5H),7.09-7.05(m,1H),7.03-6.94(m,1H)；HR-MS(ESI):[M+H]+ C27H20FN2OS calculated 439.5284, found 439.5236.
Example 4: this example prepares 3- ([1,1' -biphenyl)]-4-thio) -N- ([ 3-chloro, 4-fluoro-phenyl]-carboxamides Yl) -indole, the structural formula of which is as follows:
Figure BDA0003502313770000101
at 0 deg.C, take 3mL of 6.0mmol of AlMe 3 (2M in toluene) was added dropwise to dry toluene (6mL) containing 3- ((1, 1' -biphenyl) -4-sulfanyl) -indole (600mg, 2.0 mmol). 3-chloro, 4-fluorobenzeneisocyanate (376mg, 2.2mmol) was slowly added thereto. The reaction was continued for 4 hours and checked by TLC, followed by saturated NaHCO 3 The solution (8mL) was quenched and the product was purified by column chromatography to give 236mg (25%) of compound as a white solid. The product was characterized as follows: 1 H NMR(400MHz,CDCl 3 ):δ9.97(br s,1H),7.78(d,J＝5.0Hz,1H),7.66(m,1H),7.60-7.46(m,8H),7.42-7.11(m,5H),7.09-7.05(m,1H),7.03-6.96(m,1H)；HR-MS(ESI):[M+H]+ C27H19ClFN2OS calculated 473.9703, found 473.9725.
Example 5: this example prepares 3- ([1,1' -biphenyl)]-4-thio) -N- ([ 3-trifluoromethyl-phenyl)]-formyl Amino) -indoles of the formula:
Figure BDA0003502313770000102
3mL of 6.0mmol of AlMe were taken at 0 deg.C 3 (2M in toluene) was added dropwise to dry toluene (6mL) containing 3- ((1, 1' -biphenyl) -4-sulfanyl) -indole (600mg, 2.0 mmol). 3-Trifluoromethylphenylisocyanate (411mg, 2.2mmol) was slowly added thereto. The reaction was continued for 4 hours and checked by TLC, followed by saturated NaHCO 3 The solution (8mL) was quenched and the product was purified by column chromatography to give compound 370mg (38%) as a white solid. The product was characterized as follows: 1 H NMR(400MHz,CDCl 3 ):δ9.97(br s,1H),7.78(d,J＝5.0Hz,1H),7.69(m,1H),7.64-7.43(m,8H),7.38-7.10(m,6H),7.09-7.05(m,1H),7.03-6.96(m,1H)；HR-MS(ESI):[M+H]+ C27H20FN2OS calculated 489.1248, found 489.1259.
Example 6: this example prepares 3- ([1,1' -biphenyl)]-4-thio) -N- ([ 3-methyl-phenyl)]-carboxamides Yl) -indole, the structural formula of which is as follows:
Figure BDA0003502313770000111
at 0 deg.C, take 3mL of 6.0mmol of AlMe 3 (2M in toluene) was added dropwise to dry toluene (6mL) containing 3- ((1, 1' -biphenyl) -4-sulfanyl) -indole (600mg, 2.0 mmol). 3-methylbenzene isocyanate (292mg, 2.2mmol) was slowly added thereto. The reaction was continued for 4 hours and checked by TLC, followed by saturated NaHCO 3 The solution (8mL) was quenched and the product was purified by column chromatography to give compound 234mg (27%) as a white solid. The product was characterized as follows: 1 H NMR(400MHz,CDCl 3 ):δ9.97(br s,1H),7.75(d,J＝5.0Hz,1H),7.64(m,1H),7.56-7.39(m,8H),7.27-7.09(m,6H),7.05-7.01(m,1H),6.95-6.89(m,1H)，2.29(s,3H)；HR-MS(ESI):[M+H]+ C28H23N2OS calculated 435.5650, found 435.5621.
Example 7: this example prepares 3- ([1,1' -biphenyl)]-4-thio) -N- ([3, 4-dimethyl-phenyl)]-formyl Amino) -indoles of the formula:
Figure BDA0003502313770000121
at 0 deg.C, take 3mL of 6.0mmol of AlMe 3 (2M in toluene) was added dropwise to dry toluene (6mL) containing 3- ((1, 1' -biphenyl) -4-sulfanyl) -indole (600mg, 2.0 mmol). 3, 5-Dimethylbenzene isocyanate (323mg, 2.2mmol) was slowly added thereto. The reaction was continued for 4 hours and checked by TLC, followed by saturated NaHCO 3 The solution (8mL) was quenched and the product was purified by column chromatography to give 179mg (20%) of compound as a white solid. The product was characterized as follows: 1 H NMR(400MHz,CDCl 3 ):δ9.97(br s,1H),7.75(d,J＝5.0Hz,1H),7.64(m,1H),7.59-7.32(m,6H),7.29-7.09(m,7H),7.05-7.01(m,1H),6.95-6.89(m,1H),2.29(s,6H)；HR-MS(ESI):[M+H]+ C29H25N2OS calculated 449.5920, found 449.5965.
Example 8: this example prepares 3- ([1,1' -biphenyl)]-4-thio) -N- ([ 4-tert-butyl-phenyl]-carboxamides Yl) -indole, the structural formula of which is as follows:
Figure BDA0003502313770000122
3mL of 6.0mmol of AlMe3(2M in toluene) was added dropwise to dry toluene (6mL) containing 3- ((1, 1' -biphenyl) -4-sulfanyl) -indole (600mg, 2.0mmol) at 0 ℃. To this was slowly added 4- (tert-butyl) phenyl isocyanate (385mg, 2.2 mmol). The reaction was continued for 4 hours and checked by TLC, followed by saturated NaHCO 3 The solution (8mL) was quenched and the product was purified by column chromatography to give compound 233mg (26%) as a white solid. The product was characterized as follows: 1 H NMR(400MHz,CDCl 3 ):δ9.98(br s,1H),7.79(d,J＝5.0Hz,1H),7.65(m,1H),7.63-7.41(m,8H),7.34-7.11(m,6H),7.07-7.01(m,1H),6.95-6.84(m,1H),2.28(s,9H)；HR-MS(ESI):[M+H]+ C31H29N2OS calculated 477.6460, practiceMeasured value 477.6453.
Example 9: hyaluronidase inhibitory Activity screening assay
The experimental method comprises the following steps:hyaluronidase is derived from bovine testis, and hyaluronidase inhibitory activity screening references (Molecules, 2020; 25: 1923). Notably, under low negative ion conditions, long-chain hyaluronic acid and hyaluronidase readily form an inactive complex, which can hinder the catalytic activity of hyaluronidase and interfere with hyaluronidase inhibition activity screening assays. Therefore, it should be avoided to add too much positively charged protein to interfere with the negative ion concentration in the buffer system when testing, which will restore hyaluronidase activity. For the specific assay, bovine serum albumin was added to a final concentration of 0.01% in 20mM PBS, pH 3.75, as prepared reaction buffer. mu.L of the sample (concentration range 1-400. mu.g/mL) was mixed with 95. mu.L of the reaction solution containing hyaluronidase (7.5U/mL) and incubated at 37 ℃ for 10 minutes. Then, 100. mu.L of hyaluronic acid was added to the above reaction solution, and incubation was continued at 37 ℃ for 45 minutes. After the degradation reaction, hyaluronic acid which was not degraded was removed by precipitation after mixing for 10 minutes by adding a stop solution containing 1mL (containing 0.1% BSA, 24mM sodium acetate and 79mM acetic acid, pH 3.75). The absorbance at a wavelength of 600nm was measured using a PE microplate reader. Each sample was tested in at least triplicate. The compound Vcpal (L-ascorbyl acid 6-hexadecanoate) is an activity screening control compound.
The inhibitory activity of the sample on hyaluronidase was calculated by the following formula:
inhibitory activity (%) [ 1- (OD hyaluronic acid-OD sample)/(OD hyaluronic acid-OD hyaluronidase) ] × 100%
Calculation of IC by inhibitory Activity at different concentrations 50 The calculation was performed using the software GraphPad Prism 8.0.
The results are as follows: in vitro hyaluronidase inhibition activity screening shows that the synthesized 1, 3-disubstituted indole derivatives have stronger hyaluronidase inhibition activity. Wherein the inhibitory activity IC of compound Q5 on hyaluronidase 50 Is 2.1 mu g/mL,is the most active inhibitor in the series. The inhibitory activity of the compound Q4 and Q5 is enhanced by more than 10 times compared with that of oleanolic acid.
TABLE 1 inhibitory Activity of various Compounds on Hyaluronidase
Figure BDA0003502313770000141
Example 8: detection of skin permeability of compounds
The experimental method comprises the following steps:the prediction of skin permeability was performed using the software SwissADE (http:// www.swisadme.ch /). The specific operation is calculated according to the software using instructions. The formula of the compound or SMILES is copied into a software window and calculated to obtain a constant, Log K, related to skin permeability as follows p 。
The results are as follows:
the results are shown in Table 2, and the Log K of the compound is calculated by using a computer simulation method p The more negative this constant is, the less likely it is that the compound is able to penetrate the skin. According to the calculated results, the 8 1, 3-disubstituted indole derivatives have good lipid solubility, namely skin penetration effect, and are more suitable for being applied to skin to inhibit skin aging. Compound B8 had the best skin penetration effect, with similar skin penetration of the other compounds.
Table 2: log K calculated for various compounds p
Figure BDA0003502313770000151
Example 9: screening for cytotoxicity
The experimental method comprises the following steps:
the cytotoxicity of the compound is detected by adopting a CCK-8 kit. Specifically, HepG2 cells, MCF-7 cells and A549 cells were inoculated into 96-well plates at a cell density of about 5000 cells/200. mu.L of culture medium per well, and the cells were cultured overnight. Different concentrations of test compound were added to each well and incubation was continued for 48 hours. Adding 10 mu L of CCK-8 reagent into each hole, uniformly mixing, continuously culturing for 1-4 hours, observing the obvious change of the color of the culture solution, detecting by using an enzyme-labeling instrument, and determining the light absorption value of 450 nm. Paclitaxel was used as a positive control.
The results are as follows:
the results are shown in table 3, and cell experiments prove that 8 1, 3-disubstituted indole derivatives have no obvious cytotoxicity. Therefore, the 8 1, 3-disubstituted indole derivatives are suitable for preparing cosmetic products.
Table 3: cytotoxicity of various compounds on mammalian cells
Figure BDA0003502313770000152
Figure BDA0003502313770000161
Example 10: compound B5 used as anti-skin aging component for preparing facial mask
The formula and the parts by weight of the anti-skin-aging mask are as follows:
the names of the Cosmetic ingredients presented herein are all inci (international Nomenclature of Cosmetic ingredients), i.e. the names specified by international Nomenclature of Cosmetic ingredients.
Combined with the inhibitory activity of compound B5 on hyaluronidase, cytotoxicity of B5, skin permeability of B5, which was selected as an anti-skin aging active ingredient for the preparation of cosmetic masks.
Phase A: 92.68 parts of water, 2 parts of 1, 2-butanediol, 0.1 part of methyl hydroxybenzoate, 0.16 part of carbomer, 0.05 part of hydroxyethyl cellulose, 0.03 part of EDTA disodium, 0.05 part of sodium hyaluronate, 0.4 part of 1, 2-hexanediol and 0.1 part of panthenol;
phase B: 3 parts of water and 0.12 part of triethanolamine;
and C phase: 50.1 parts of compound B, 1 part of ethanol and 0.1 part of phenoxyethanol
Phase D: 0.01 part of (daily) essence and 0.1 part of PEG-40 hydrogenated castor oil
The preparation method comprises the following steps: the respective components were weighed according to the above formulation, wherein each part by mass was 1 g. Mixing the phase A components, homogenizing for 5 minutes (2000r/min), stirring and heating to 80 ℃, keeping the temperature constant at 80 ℃, and continuing stirring for 5 minutes; cooling to 45 deg.C, adding phase B under stirring, and stirring for 5 min; adding phase C and phase D, stirring, cooling to 25 deg.C, and packaging.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.

Claims (8)

1. A1, 3-disubstituted indole compound is characterized by having a structure shown in a general formula (I):
Figure DEST_PATH_IMAGE002
general formula (I)
Wherein R is a ，R b ，R c ，R d ，R e Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, methoxy, trifluoromethyloxy, trifluoromethyl, C 1-8 An alkyl group.
2. The 1, 3-disubstituted indole compound according to claim 1, wherein in the general formula (I), R is a ，R b ，R c ，R d ，R e Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, trifluoromethyl, C 1-4 An alkyl group.
3. The 1, 3-disubstituted indole compound of claim 1 or claim 2, wherein said compound is selected from the following structures:
Figure DEST_PATH_IMAGE004
。
4. a composition comprising the 1, 3-disubstituted indole of any one of claims 1 to 3 or a chemically acceptable salt thereof, and a cosmetically acceptable vehicle.
5. A process for the preparation of a 1, 3-disubstituted indole according to any of claims 1 to 3, comprising the steps of:
equal amounts of 3- ((1, 1' -biphenyl) -4-thio) -indole, AlMe 3 Mixing and reacting for 1h, adding
Figure DEST_PATH_IMAGE006
Reacting for 16 hours to obtain the product; wherein the substituent group R a ，R b ，R c ，R d ，R e Is in accordance with the scope defined in any one of claims 1 to 3;
the reaction formula is shown as follows:
Figure DEST_PATH_IMAGE008
。
6. the method for preparing 1, 3-disubstituted indoles as claimed in claim 5, wherein the method for preparing 3- ((1, 1' -biphenyl) -4-thio) -indoles is as follows:
indole, mercaptan and TBHP in a methyl cyanide solvent, and then I is added 2 As a catalyst, and continuously reacting at room temperature to obtain an intermediate 3- ((1)1' -biphenyl) -4-thio) -indole,
the reaction formula is shown as follows:
Figure DEST_PATH_IMAGE010
。
7. use of the 1, 3-disubstituted indole compound of any one of claims 1 to 3 or the composition of claim 4 for the preparation of a cosmetic for delaying skin aging by inhibiting hyaluronidase activity.
8. An anti-skin aging facial mask is characterized in that: the facial mask comprises the compound of any one of claims 1-3 or the composition of claim 4, and the formula and the parts by weight of the facial mask are as follows:
phase A: 92.68 parts of water, 2 parts of 1, 2-butanediol, 0.1 part of methyl hydroxybenzoate, 0.16 part of carbomer, 0.05 part of hydroxyethyl cellulose, 0.03 part of EDTA disodium, 0.05 part of sodium hyaluronate, 0.4 part of 1, 2-hexanediol and 0.1 part of panthenol;
phase B: 3 parts of water and 0.12 part of triethanolamine;
and C phase: 0.1 part of the compound of any one of claims 1 to 3 or the composition of claim 4, 1 part of ethanol, 0.1 part of phenoxyethanol
Phase D: 0.01 part of essence for daily use and 0.1 part of PEG-40 hydrogenated castor oil.
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