CN114409626B - Preparation and antiviral application of baicalein derivatives - Google Patents
Preparation and antiviral application of baicalein derivatives Download PDFInfo
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- CN114409626B CN114409626B CN202210219016.6A CN202210219016A CN114409626B CN 114409626 B CN114409626 B CN 114409626B CN 202210219016 A CN202210219016 A CN 202210219016A CN 114409626 B CN114409626 B CN 114409626B
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- UDFLTIRFTXWNJO-UHFFFAOYSA-N baicalein Chemical class O1C2=CC(=O)C(O)=C(O)C2=C(O)C=C1C1=CC=CC=C1 UDFLTIRFTXWNJO-UHFFFAOYSA-N 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 230000000840 anti-viral effect Effects 0.000 title abstract description 4
- FXNFHKRTJBSTCS-UHFFFAOYSA-N Baicalein Natural products C=1C(=O)C=2C(O)=C(O)C(O)=CC=2OC=1C1=CC=CC=C1 FXNFHKRTJBSTCS-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229940015301 baicalein Drugs 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 102000005348 Neuraminidase Human genes 0.000 claims abstract description 16
- 108010006232 Neuraminidase Proteins 0.000 claims abstract description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000007336 electrophilic substitution reaction Methods 0.000 claims abstract description 8
- 101800000535 3C-like proteinase Proteins 0.000 claims abstract description 7
- 101800002396 3C-like proteinase nsp5 Proteins 0.000 claims abstract description 7
- 241000711573 Coronaviridae Species 0.000 claims abstract description 6
- 102100034866 Kallikrein-6 Human genes 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 239000005457 ice water Substances 0.000 claims abstract description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 4
- 238000001035 drying Methods 0.000 claims abstract description 4
- 238000010791 quenching Methods 0.000 claims abstract description 4
- 230000000171 quenching effect Effects 0.000 claims abstract description 4
- 230000018044 dehydration Effects 0.000 claims abstract 2
- 238000006297 dehydration reaction Methods 0.000 claims abstract 2
- 239000003112 inhibitor Substances 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 14
- 108700003471 Coronavirus 3C Proteases Proteins 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 241000712461 unidentified influenza virus Species 0.000 claims description 6
- 101100491263 Oryza sativa subsp. japonica AP2-4 gene Proteins 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 3
- -1 sulfonyloxy Chemical group 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 abstract description 9
- 239000000203 mixture Substances 0.000 abstract description 9
- 239000012295 chemical reaction liquid Substances 0.000 abstract description 2
- 239000012043 crude product Substances 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 208000002606 Paramyxoviridae Infections Diseases 0.000 abstract 1
- 241000700605 Viruses Species 0.000 abstract 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 45
- 239000000843 powder Substances 0.000 description 31
- 238000001514 detection method Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 238000012216 screening Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 108700002673 Coronavirus M Proteins Proteins 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- DYEFUKCXAQOFHX-UHFFFAOYSA-N Ebselen Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=CC=CC=C1 DYEFUKCXAQOFHX-UHFFFAOYSA-N 0.000 description 3
- 229940123424 Neuraminidase inhibitor Drugs 0.000 description 3
- 108091005804 Peptidases Proteins 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229950010033 ebselen Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 239000002911 sialidase inhibitor Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 2
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 101800000504 3C-like protease Proteins 0.000 description 1
- 229940125673 3C-like protease inhibitor Drugs 0.000 description 1
- SEWNAJIUKSTYOP-UHFFFAOYSA-N 4-chloro-3-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC(S(Cl)(=O)=O)=CC=C1Cl SEWNAJIUKSTYOP-UHFFFAOYSA-N 0.000 description 1
- 241001678559 COVID-19 virus Species 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 102000006833 Multifunctional Enzymes Human genes 0.000 description 1
- 108010047290 Multifunctional Enzymes Proteins 0.000 description 1
- 101100448781 Oryza sativa subsp. indica GL18 gene Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 241000207929 Scutellaria Species 0.000 description 1
- 240000004534 Scutellaria baicalensis Species 0.000 description 1
- 235000017089 Scutellaria baicalensis Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000003271 compound fluorescence assay Methods 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 238000003028 enzyme activity measurement method Methods 0.000 description 1
- 238000007421 fluorometric assay Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
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- Organic Chemistry (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Oncology (AREA)
- Public Health (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses preparation and antiviral application of baicalein derivatives. The baicalein derivative is prepared from baicalein (5, 6, 7-trihydroxyflavone) by electrophilic substitution reaction. The reaction solvent is anhydrous acetone after drying and dehydration, the reaction process is that after the reaction is carried out for 1 hour under the condition of ice bath (0 ℃), the reaction liquid is added with ice water for quenching reaction, and then the mixture is filtered to obtain a yellowish or off-white crude product. Neuraminidase NA of baicalein derivative parainfluenza virus and main protease M of novel coronavirus pro The half inhibition concentration of the baicalein is less than 100 mu M, the synthesis method of the derivative is simple and easy, and the two hydroxyl groups of the baicalein C6-OH and the baicalein C7-OH are replaced by various sulfonyl chloride compounds in the reaction process.
Description
Technical Field
The invention relates to baicalein derivatives, in particular to preparation and antiviral application of baicalein derivatives.
Background
Baicalein (5, 6, 7-trihydroxyflavone), also known as baicalein, is initially isolated from the traditional Chinese medicinal material baical skullcap root (Scutellaria baicalensis Georgi). Baicalein has abundant resources, wide sources, low price, easy obtainment, small toxic and side effects, and has proved to have a plurality of good biological activities including anticancer, anti-inflammatory, anti-tumor, antiallergic, antioxidant and the like. Is a considerable resource in the development and research of new drugs, and has better development and utilization prospect. However, three adjacent phenolic hydroxyl groups (5-OH, 6-OH and 7-OH) exist in the baicalein structure, so that intramolecular hydrogen bonds are easy to form, the lipophilicity and the hydrophilicity of the baicalein are poor, and the oral bioavailability is low, so that the clinical application of the baicalein is greatly limited. In recent years, how to improve the solubility and bioavailability of baicalein drugs and increase the absorption in human bodies becomes a research hotspot at home and abroad. In addition, many other researches show that in the baicalein derivatives, the hydroxyl at the C-5 position is unchanged, and the hydroxyl at the C-6 or C-7 position has strong activity after modification. Therefore, on the basis, the baicalein is used as a lead compound in the research, the structure of the baicalein is modified by utilizing a chemical reaction, a functional group is introduced, and a series of baicalein derivatives are designed and synthesized, and meanwhile, the method is also an effective way for drug innovation.
Disclosure of Invention
The invention aims to solve the technical problems of simple and convenient synthesis method, simple post-treatment and low cost of the method for improving the bioavailability of baicalein compounds. The invention solves another technical problem of providing a preparation method of the baicalein derivative and application of the baicalein derivative in pharmacy.
In order to achieve the above purpose, the invention adopts the following technical means:
a baicalein derivative having a compound of the general formula:
in the general formula, R is respectively:
the baicalein derivative is a compound with the following structural formula:
the name is: GL31.
In the preparation method of the baicalein derivatives, baicalein is used as a raw material, and hydroxyl groups of C-6 and C-7 are substituted by sulfonyloxy through electrophilic substitution reaction, and the reaction equation is as follows:
the reaction solvent of the electrophilic substitution reaction is anhydrous acetone after drying.
The electrophilic substitution reaction is carried out under the condition of ice bath for 1 hour, and the reaction solution is added with ice water for quenching reaction and then filtered.
The application of the baicalein derivative in preparing influenza virus neuraminidase NA inhibitor.
The application of the baicalein derivative in preparing an influenza virus neuraminidase NA inhibitor is that the compound is as follows: GL09, GL15, GL25, GL31.
The baicalein derivative is used for preparing novel coronavirus main protease M pro Use of inhibitors.
The baicalein derivative is used for preparing novel coronavirus main protease M pro Use in an inhibitor of: GL08, GL10, GL29.
The baicalein derivative is used for preparing influenza virus neuraminidase NA inhibitor and preparing novel coronavirus main protease M pro Use of inhibitors.
The beneficial effects obtained by the invention are as follows:
1. baicalein derivatives GL01-GL31 are provided.
2. Provides a preparation method of baicalein derivatives GL01-GL31.
3. The prepared baicalein derivative GL01-GL31 shows good enzyme inhibition activity.
4. The preparation method of the baicalein derivative GL01-GL31 is simple and easy to implement.
Detailed Description
The structure and atomic number of baicalein are as follows:
the baicalein derivative GL01-GL31 is prepared by taking baicalein (5, 6, 7-trihydroxyflavone) as a raw material and carrying out electrophilic substitution reaction, and has the following structures:
the reaction solvent is anhydrous acetone after drying, the reaction process is that after the reaction is carried out for 1 hour under the condition of ice bath (0 ℃), the reaction liquid is added with ice water for quenching reaction, and then the mixture is filtered to obtain a light yellow or off-white crude product.
The reaction for preparing the baicalein derivative is shown as the following reaction formula:
example 1 preparation of GL01
Preparation of GL01
Accurately weighing 0.2206g of baicalein with the purity of 98%, 0.8mmol and 0.3053g of 4-morpholinocarbonyl chloride with the purity of more than 98%, placing 2mmol in a 50ml round bottom flask, adding 10ml of anhydrous acetone to dissolve the mixture, and then adding 2ml of pyridine. The reaction mixture was stirred for 1h under ice-bath (0 ℃ C.). And nitrogen is used for protecting the whole reaction process. After the completion of the reaction was monitored by Thin Layer Chromatography (TLC), 20ml of ice water was added to the reaction solution, and the mixture was left standing for a while, and after precipitation of a solid, the mixture was suction-filtered, and the cake was washed with 20ml of 0 ℃ ethanol. The residue was purified by column chromatography on silica gel (mobile phase: DCM) and recrystallized to give a golden yellow powdered solid in 79% yield.
EXAMPLE 2 preparation of GL02
Preparation of GL02
Baicalein (purity: 98%) (0.2206 g,0.8 mmol) and 4-chloro-3-nitrobenzenesulfonyl chloride (purity: 98%) (0.5226 g,2 mmol) were accurately weighed into a 50ml round bottom flask, dissolved by adding anhydrous acetone (10 ml), and pyridine (2 ml) was then added. The reaction mixture was stirred for 1h under ice-bath (0 ℃ C.). The whole reaction process needs nitrogen protection. After the completion of the reaction was monitored by Thin Layer Chromatography (TLC), 20ml of ice water was added to the reaction solution, and the mixture was left standing for a while, and after precipitation of a solid, the mixture was suction-filtered, and the cake was washed with 20ml of 0 ℃ ethanol. The residue was purified by column chromatography on silica gel (mobile phase: DCM) and recrystallized to give an off-white powdery solid in 84% yield.
GL03-GL31 is prepared by the process described in reference to GL01 and GL02.
The structure identification data of the baicalein derivatives are as follows:
GL01 yield 79%; mp 239.6-239.6; a golden yellow powder; 1 HNMR(500MHz,Chloroform-d)δ12.86(s,1H),7.82(t,J＝1.4Hz,1H),7.81(d,J＝1.7Hz,1H),7.53–7.49(m,1H),7.48(d,J＝1.7Hz,1H),7.46(d,J＝6.8Hz,1H),6.99(s,1H),6.66(s,1H),3.70(dt,J＝7.2,4.0Hz,8H),3.63–3.58(m,4H),3.53(t,J＝4.9Hz,4H). 13 C NMR(126MHz,Chloroform-d)δ182.95,164.97,153.50,153.28,152.33,151.60,149.44,132.22,130.93,129.18,126.95,126.42,109.21,105.69,101.50,66.59,66.47,45.34,45.15,44.60,44.41.HRMS(m/z):cacld for C 25 H 24 N 2 O 9 [M-H] - 495.14090,found 495.14001.
GL02 yield 84%; mp 215.5-215.5; an off-white powder; 1 H NMR(500MHz,DMSO-d 6 )δ13.26(d,J＝9.8Hz,1H),8.61(d,J＝2.3Hz,1H),8.59(d,J＝2.1Hz,1H),8.21(dd,J＝8.6,2.3Hz,1H),8.19(t,J＝1.4Hz,1H),8.18(d,J＝1.5Hz,1H),8.16(dd,J＝8.6,2.2Hz,1H),8.13(d,J＝8.6Hz,1H),8.11(d,J＝8.6Hz,1H),7.71–7.66(m,1H),7.65–7.57(m,2H),7.52(s,1H),7.29(s,1H). 13 CNMR(126MHz,DMSO-d 6 )δ183.00,165.63,154.40,154.32,148.32,148.19,146.08,135.64,134.26,134.07,133.97,133.35,133.29,133.17,132.61,130.42,129.73,127.40,126.14,125.93,124.75,110.91,106.27,103.83,55.37.HRMS(m/z):cacld for C 27 H 14 Cl 2 N 2 O 13 S 2 [M-H] - 707.92416,found 706.92236.
GL03 yield 86%; mp 255.4-255.4; an off-white powder; 1 H NMR(500MHz,DMSO-d 6 )δ13.26(s,1H),8.19(d,J＝1.9Hz,2H),8.18(d,J＝1.7Hz,2H),8.17(d,J＝1.9Hz,1H),8.16(d,J＝2.0Hz,1H),8.08(d,J＝2.0Hz,1H),8.07(d,J＝2.0Hz,1H),8.02(d,J＝1.9Hz,1H),8.00(d,J＝1.9Hz,1H),7.71–7.64(m,1H),7.62(dd,J＝8.3,6.7Hz,2H),7.47(s,1H),7.28(s,1H). 13 C NMR(126MHz,DMSO-d 6 )δ183.06,165.61,154.43,154.23,146.12,139.62,138.00,134.48,134.26,133.32,130.43,129.72,129.57,129.39,127.41,124.67,118.36,117.85,117.79,117.65,110.72,106.22,103.64.HRMS(m/z):cacld for C 29 H 16 N 2 O 9 S 2 [M-H] - 599.02002,found 599.02244.
GL04 yield 82%; mp 182.9-183.1; an off-white powder; 1 H NMR(500MHz,Chloroform-d)δ13.04(s,1H),8.01–7.96(m,2H),7.94–7.88(m,4H),7.64–7.59(m,1H),7.59–7.53(m,2H),7.25(d,J＝5.9Hz,2H),7.23–7.17(m,3H),6.76(s,1H). 13 C NMR(126MHz,Chloroform-d)δ182.63,167.53,167.24,165.64,165.47,165.19,154.82,153.83,147.36,132.72,132.45,132.42,131.78,131.70,131.54,131.46,130.79,130.77,130.35,129.35,126.56,125.32,116.83,116.65,116.52,116.34,110.15,105.90,102.29.HRMS(m/z):cacld for C 27 H 16 F 2 O 9 S 2 [M-H] - 585.01310,found 585.01044.
GL05 yield 73%; mp 126.9-128.1; a pale yellow powder; 1 H NMR(500MHz,Chloroform-d)δ12.79(s,1H),8.07(dd,J＝8.0,1.7Hz,1H),7.90(ddd,J＝10.4,7.5,1.7Hz,3H),7.77(ddd,J＝8.8,7.7,1.7Hz,1H),7.72–7.64(m,1H),7.63–7.52(m,3H),7.51–7.44(m,2H),7.41(dt,J＝8.4,1.6Hz,1H),7.35(t,J＝7.7Hz,1H),7.23(s,1H),6.73(s,1H). 13 C NMR(126MHz,Chloroform-d)δ182.60,165.59,154.62,153.76,147.44,147.01,136.63,135.76,132.67,131.82,131.14,130.39,129.61,129.32,127.83,126.64,126.55,126.15,125.55,121.17,121.09,120.81,120.80,120.36,120.34,119.10,119.01,109.97,105.88,102.18.HRMS(m/z):cacld for C 29 H 16 F 6 O 11 S 2 [M-H] - 716.99655,found 716.99426.
GL06 yield 82%; mp 235.2-235.2; lemon yellow powder; 1 H NMR(500MHz,Chloroform-d)δ12.76(s,1H),8.57(ddt,J＝18.4,8.6,1.1Hz,2H),8.28(dt,J＝8.6,0.9Hz,1H),8.14–8.06(m,3H),7.89–7.80(m,2H),7.59–7.56(m,1H),7.56(s,1H),7.55(dd,J＝2.8,1.4Hz,1H),7.52(d,J＝7.0Hz,1H),7.46(dd,J＝8.7,7.6Hz,1H),7.40(ddd,J＝8.5,7.4,6.2Hz,2H),7.19(ddd,J＝8.8,7.7,1.0Hz,2H),7.13(s,1H),6.68(s,1H),2.89(d,J＝6.9Hz,12H). 13 C NMR(126MHz,Chloroform-d)δ182.52,165.31,155.09,153.72,151.63,147.98,133.06,132.57,132.52,131.73,130.95,130.78,130.53,130.26,129.85,129.76,129.72,129.26,129.23,128.50,126.51,125.36,122.80,122.73,119.88,119.50,115.80,115.31,109.67,105.89,100.75,45.46.HRMS(m/z):cacld for C 39 H 32 N 2 O 9 S 2 [M-H] - 735.14765,found 735.14508.
GL07 yield 66%; mp 189.5-190.2; a pale pink powder; 1 H NMR(500MHz,Chloroform-d)δ13.03(s,1H),8.03–7.97(m,1H),7.94–7.85(m,3H),7.65–7.60(m,1H),7.57(dd,J＝8.3,6.6Hz,2H),7.25(s,1H),7.17(t,J＝8.6Hz,1H),7.12(t,J＝8.6Hz,1H),6.77(s,1H). 13 C NMR(126MHz,Chloroform-d)δ182.57,165.87,163.77,163.20,161.67,161.12,159.92,157.82,154.59,153.97,146.88,132.84,132.67,132.15,130.24,129.38,126.60,125.12,110.36,107.81,107.61,107.40,107.31,107.11,106.90,105.99,102.72.HRMS(m/z):cacld for C 27 H 12 Cl 2 F 4 O 9 S 2 [M-H] - 688.91631,found 688.91412.
GL08 yield 74%; mp 222.5-223.0; a pale yellow powder; 1 H NMR(500MHz,Chloroform-d)δ12.88(s,1H),8.07(dd,J＝8.0,1.6Hz,1H),7.94(dd,J＝8.0,1.6Hz,1H),7.91–7.85(m,2H),7.67–7.57(m,3H),7.57–7.49(m,3H),7.49–7.43(m,2H),7.34(ddd,J＝7.9,7.2,1.4Hz,1H),7.20(s,1H),6.72(s,1H). 13 C NMR(126MHz,Chloroform-d)δ182.56,165.54,154.92,153.75,147.38,135.61,135.56,134.77,133.81,133.72,133.53,132.65,132.50,132.00,131.90,131.20,130.40,129.31,127.18,126.70,126.54,125.47,109.92,105.92,101.72.HRMS(m/z):cacld for C 27 H 16 Cl 2 O 9 S 2 [M-H] - 616.95400,found 619.95190.
GL09 yield 75%; mp 225.8-225.9; a pale yellow powder; 1 H NMR(500MHz,Chloroform-d)δ12.90(s,1H),7.90–7.85(m,2H),7.62–7.51(m,3H),7.18(s,1H),6.91(d,J＝62.2Hz,4H),6.72(s,1H),2.54(d,J＝30.3Hz,12H),2.33(d,J＝30.1Hz,6H). 13 C NMR(126MHz,Chloroform-d)δ182.67,165.32,155.14,153.57,147.80,143.23,140.69,139.74,132.71,132.50,131.89,131.39,130.62,130.56,129.26,126.50,125.58,109.63,105.85,101.43,22.83,22.69,21.22,21.15.HRMS(m/z):cacld for C 33 H 30 O 9 S 2 [M-H] - 633.12585,found 633.12323.
GL10 yield 85%; mp 199.4-199.5; a pale pink powder; 1 H NMR(500MHz,Chloroform-d)δ13.15(s,1H),8.36(d,J＝2.2Hz,1H),8.29(d,J＝2.2Hz,1H),8.08(dt,J＝8.5,2.1Hz,2H),7.94–7.89(m,2H),7.73(dd,J＝8.4,4.0Hz,2H),7.66–7.54(m,3H),7.29(s,1H),6.78(s,1H). 13 C NMR(126MHz,Chloroform-d)δ182.59,165.90,154.64,154.01,146.97,140.06,139.38,135.50,133.98,132.87,132.80,132.69,132.61,132.44,130.22,129.40,128.48,128.44,128.03,127.99,126.61,125.04,122.88,122.81,110.40,105.98,102.57.HRMS(m/z):cacld for C 29 H 14 Cl 2 F 6 O 9 S 2 [M-H] - 752.92877,found 752.92645.
GL11 yield 70%; mp 189.7-189.9; a pale yellow powder; 1 H NMR(500MHz,Chloroform-d)δ12.91(s,1H),8.27(d,J＝8.3Hz,1H),8.12–8.06(m,2H),7.97(d,J＝1.7Hz,1H),7.91–7.86(m,2H),7.79(dd,J＝8.4,1.8Hz,1H),7.67(dd,J＝8.5,1.8Hz,1H),7.64–7.52(m,3H),7.19(s,1H),6.75(s,1H). 13 C NMR(126MHz,Chloroform-d)δ182.49,165.77,154.70,153.88,147.08,140.96,139.17,137.10,136.83,136.36,136.09,133.16,133.13,132.81,132.68,132.47,132.44,131.85,130.24,129.37,126.57,125.30,124.83,124.80,124.36,124.33,122.35,122.00,110.15,105.98,102.14.HRMS(m/z):cacld for C 29 H 14 Br 2 F 6 O 9 S 2 [M-H] - 842.82569,found 842.82245.
GL12 yield 79%; mp 213.9-214.4; a golden yellow powder; 1 H NMR(500MHz,Chloroform-d)δ12.90(s,1H),8.12(dd,J＝8.9,5.6Hz,1H),7.95(dd,J＝8.9,5.7Hz,1H),7.91–7.86(m,2H),7.64–7.51(m,3H),7.37(dd,J＝8.2,2.5Hz,1H),7.26–7.23(m,1H),7.22(s,1H),7.18(ddd,J＝9.0,7.4,2.5Hz,1H),7.05(ddd,J＝8.8,7.4,2.5Hz,1H),6.74(s,1H). 13 C NMR(126MHz,Chloroform-d)δ182.56,166.88,166.32,165.66,164.80,164.25,154.78,153.82,147.30,136.16,136.07,135.75,135.66,134.34,134.26,133.48,133.40,132.72,131.94,131.92,130.34,130.05,130.02,129.34,126.56,125.37,120.31,120.11,119.69,119.48,114.81,114.64,114.24,114.06,110.00,105.94,101.96.HRMS(m/z):cacld for C 27 H 14 Cl 2 F 2 O 9 S 2 [M-H] - 652.93516,found 652.93280.
GL13 yield 73%; mp 215.9-215.9; a pale yellow powder; 1 H NMR(500MHz,Chloroform-d)δ13.09(s,1H),8.04–7.99(m,2H),7.92–7.85(m,4H),7.72–7.64(m,4H),7.62–7.58(m,3H),7.57–7.54(m,4H),7.51–7.39(m,6H),7.29(s,1H),6.76(s,1H). 13 C NMR(126MHz,Chloroform-d)δ182.69,165.54,155.09,153.80,147.73,147.50,147.23,138.98,138.68,134.94,133.27,132.65,130.46,129.33,129.17,129.14,129.07,128.95,128.81,127.73,127.56,127.43,127.41,126.57,125.46,110.14,105.91,102.34.HRMS(m/z):cacld for C 39 H 26 O 9 S 2 [M-H] - 701.09455,found701.09235.
GL14 yield 55%; mp 141.2-141.3; a pale yellow powder; 1 H NMR(500MHz,Chloroform-d)δ13.00(s,1H),7.92–7.89(m,2H),7.88–7.84(m,2H),7.68–7.63(m,2H),7.61–7.58(m,1H),7.57–7.53(m,2H),7.36(d,J＝1.8Hz,1H),7.35(d,J＝2.0Hz,1H),7.27(d,J＝1.7Hz,1H),7.25(s,1H),7.24(s,1H),6.74(s,1H),2.72(dd,J＝8.4,6.8Hz,2H),2.68–2.62(m,2H),1.73–1.62(m,4H),0.98(t,J＝7.3Hz,3H),0.93(t,J＝7.3Hz,3H). 13 C NMR(126MHz,Chloroform-d)δ182.70,165.47,154.98,153.70,150.74,150.14,147.62,133.65,132.61,131.88,130.48,129.31,129.23,129.07,128.68,128.67,126.55,125.54,110.04,105.86,102.32,38.06,38.00,24.21,24.03,13.71,13.64.HRMS(m/z):cacld for C 33 H 30 O 9 S 2 [M-H] - 633.12585,found 633.12323.
GL15 yield 67%; mp 191.9-192.1; a pale yellow powder; 1 H NMR(500MHz,Chloroform-d)δ13.02(s,1H),7.93–7.85(m,4H),7.70–7.66(m,2H),7.63–7.58(m,1H),7.57–7.51(m,2H),7.44–7.39(m,2H),7.34–7.29(m,2H),7.24(s,1H),6.74(s,1H),3.01(dp,J＝31.6,6.9Hz,2H),1.32(d,J＝6.9Hz,6H),1.26(d,J＝6.9Hz,6H). 13 C NMR(126MHz,Chloroform-d)δ182.69,165.45,156.68,156.16,154.99,153.69,147.63,133.70,132.60,132.01,130.48,129.30,128.79,127.30,127.13,126.53,125.49,110.03,105.85,102.29,34.39,34.32,23.65,23.52.HRMS(m/z):cacld for C 33 H 30 O 9 S 2 [M-H] - 633.12585,found 633.12317.
GL16 yield 69%; mp 190.4-190.4; a pale yellow powder; 1 H NMR(500MHz,Chloroform-d)δ13.20(s,1H),8.53–8.49(m,2H),8.43–8.39(m,2H),8.22(d,J＝20.4Hz,2H),7.95–7.90(m,2H),7.66–7.61(m,1H),7.58(dd,J＝8.3,6.6Hz,2H),7.31(s,1H),6.79(s,1H). 13 C NMR(126MHz,Chloroform-d)δ182.54,166.03,154.56,154.14,146.75,138.96,137.63,133.79,133.52,133.24,133.17,132.95,132.89,132.61,130.16,129.43,129.30,128.92,128.64,128.01,126.64,124.84,123.32,123.25,121.15,121.08,110.54,106.04,102.76.HRMS(m/z):cacld for C 31 H 14 F 12 O 9 S 2 [M-H] - 820.98148,found 820.97913.
GL17 yield 77%; mp 181.8-183.1; a pale yellow powder; 1 H NMR(500MHz,Chloroform-d)δ12.91(s,1H),8.24(dd,J＝8.3,0.9Hz,1H),8.06(dd,J＝8.3,0.9Hz,1H),7.93–7.86(m,3H),7.78(d,J＝1.7Hz,1H),7.73(ddd,J＝8.3,1.8,0.8Hz,1H),7.64–7.58(m,2H),7.57–7.53(m,2H),7.21(s,1H),6.74(s,1H). 13 C NMR(126MHz,Chloroform-d)δ182.50,165.80,154.63,153.88,147.08,138.98,137.39,137.21,137.12,136.64,136.37,134.91,134.45,132.82,132.53,131.72,130.24,129.71,129.68,129.37,129.01,128.98,126.58,125.32,124.20,124.17,123.75,123.72,123.32,121.22,110.18,105.97,102.32.HRMS(m/z):cacld for C 29 H 14 Cl 2 F 6 O 9 S 2 [M-H] - 752.92877,found 752.92651.
GL18 yield 60%; mp 191.9-191.9; a pale yellow powder; 1 H NMR(500MHz,DMSO-d 6 )δ13.22(s,1H),8.22–8.14(m,2H),7.77–7.72(m,2H),7.70–7.64(m,3H),7.61(dd,J＝8.3,6.7Hz,2H),7.46(dd,J＝8.3,2.8Hz,4H),7.38(s,1H),7.24(s,1H),2.44(d,J＝6.3Hz,6H). 13 C NMR(126MHz,Chloroform-d)δ182.68,165.48,154.93,153.70,147.59,146.15,145.50,133.52,132.61,131.72,130.47,129.81,129.62,129.31,128.67,128.61,126.54,125.49,110.01,105.85,102.19,21.82,21.81.HRMS(m/z):cacld for C 29 H 22 O 9 S 2 [M-H] - 577.06325,found 577.06116.
GL19 yield 69%; mp 244.1-244.1; a pale yellow powder; 1 H NMR(500MHz,DMSO-d 6 )δ13.28(s,1H),8.21(dd,J＝3.8,1.7Hz,1H),8.19–8.14(m,2H),7.99(dd,J＝4.5,1.9Hz,1H),7.94–7.87(m,2H),7.81(d,J＝8.5Hz,1H),7.76(dt,J＝8.6,1.6Hz,1H),7.69–7.64(m,1H),7.63–7.58(m,2H),7.35(d,J＝3.0Hz,1H),7.24(d,J＝4.5Hz,1H). 13 C NMR(126MHz,DMSO-d 6 )δ183.05,165.62,154.51,154.10,146.35,135.59,134.95,134.09,133.71,133.49,133.28,132.80,132.08,131.99,131.48,130.92,130.44,129.85,129.66,127.44,125.08,110.44,106.18,102.86.HRMS(m/z):cacld for C 27 H 14 Br 2 Cl 2 O 9 S 2 [M-H] - 774.77298,found 774.77075.
GL20 yield 66%; mp 199.6-199.6; a pale yellow powder; 1 H NMR(500MHz,DMSO-d 6 )δ13.30(s,1H),8.22–8.17(m,2H),8.11(ddd,J＝16.0,6.6,2.4Hz,2H),7.95(ddd,J＝8.8,4.4,2.4Hz,1H),7.87(ddd,J＝8.7,4.3,2.4Hz,1H),7.74(td,J＝8.8,3.0Hz,2H),7.70–7.66(m,1H),7.62(dd,J＝8.3,6.6Hz,2H),7.49(s,1H),7.28(s,1H). 13 C NMR(126MHz,Chloroform-d)δ182.61,165.79,163.16,162.81,161.08,160.75,154.77,153.95,147.06,133.30,133.27,132.81,131.90,131.70,131.67,131.59,130.28,129.47,129.39(d,J＝2.1Hz),129.26,129.19,126.60,125.14,123.11,122.96,122.72,122.57,117.74,117.56,117.52,117.34,110.32,105.97,102.46.HRMS(m/z):cacld for C 27 H 14 Cl 2 F 2 O 9 S 2 [M-H] - 652.93516,found 652.93292.
GL21 yield 72%; mp 215.5-215.6; a golden yellow powder; 1 H NMR(500MHz,DMSO-d 6 )δ13.26(s,1H),8.19–8.15(m,2H),8.10(dd,J＝9.0,5.6Hz,1H),7.99–7.93(m,2H),7.77(dd,J＝8.7,2.6Hz,1H),7.69–7.64(m,1H),7.60(dd,J＝8.3,6.8Hz,2H),7.55(ddd,J＝8.9,7.9,2.6Hz,1H),7.41(ddd,J＝9.0,7.9,2.6Hz,1H),7.33(s,1H),7.25(s,1H). 13 C NMR(126MHz,DMSO-d 6 )δ182.48,166.49,165.93,165.03,163.88,153.96,153.50,145.92,134.56,134.47,134.30,134.20,133.57,132.69,130.84,129.87,129.09,128.80,126.86,124.50,120.63,120.42,120.03,119.82,115.76,115.58,115.15,114.97,109.77,105.60,102.03.HRMS(m/z):cacld for C 27 H 14 Cl 2 F 2 O 9 S 2 [M-H] - 652.93516,found 652.93292.
GL22 yield 75%; mp 230.9-231.2; a pale yellow powder; 1 H NMR(500MHz,DMSO-d 6 )δ13.31(s,1H),8.53(t,J＝1.2Hz,1H),8.43(d,J＝2.1Hz,1H),8.21–8.16(m,2H),8.10–8.05(m,3H),7.98(dd,J＝8.6,2.1Hz,1H),7.70–7.65(m,1H),7.64–7.58(m,2H),7.45(s,1H),7.29(s,1H). 13 C NMR(126MHz,DMSO-d 6 )δ183.00,165.72,154.38,154.35,148.63,148.57,146.18,142.56,141.77,133.95,133.46,133.35,133.26,130.38,129.70,127.44,127.18,126.32,125.73,125.58,125.14,110.78,106.27,103.51.HRMS(m/z):cacld for C 27 H 14 Cl 2 N 2 O 13 S 2 [M-H] - 706.92416,found 706.92218.
GL23 yield 64%; mp 198.3-198.4; a pale yellow powder; 1 H NMR(500MHz,Chloroform-d)δ13.07(s,1H),8.06–7.94(m,4H),7.93–7.88(m,2H),7.65–7.59(m,1H),7.59–7.53(m,2H),7.40–7.33(m,4H),7.25(s,1H),6.77(s,1H). 13 C NMR(126MHz,Chloroform-d)δ182.63,165.71,154.82,153.88,153.48,147.26,134.56,132.94,132.76,131.10,130.85,130.32,129.36,126.57,125.23,121.24,121.18,120.77,120.66,119.17,119.11,110.23,105.93,102.42.HRMS(m/z):cacld for C 29 H 16 F 6 O 9 S 2 [M-H] - 685.00672,found 685.00421.
GL24 yield 63%; mp 213.7-213.7; a pale yellow powder; 1 H NMR(500MHz,DMSO-d 6 )δ13.27(s,1H),8.20–8.14(m,2H),8.06(dd,J＝9.9,1.8Hz,1H),7.95(dd,J＝9.8,1.8Hz,1H),7.77(dd,J＝8.5,7.1Hz,1H),7.74–7.69(m,2H),7.69–7.64(m,2H),7.60(dd,J＝8.3,6.7Hz,2H),7.45(s,1H),7.25(s,1H). 13 C NMR(126MHz,DMSO-d 6 )δ183.04,165.65,160.10,159.93,158.01,157.84,154.35,154.13,146.28,133.29,132.53,132.12,132.04,131.97,131.13,131.05,130.43,129.67,129.46,129.02,127.42,124.88,123.75,123.64,122.32,122.13,121.97,121.86,121.84,121.65,110.53,106.22,103.35.HRMS(m/z):cacld for C 27 H 14 Br 2 F 2 O 9 S 2 [M-H] - 742.83208,found 742.82941.
GL25 yield 70%; mp 170.1-170.3; a pale yellow powder; 1 H NMR(500MHz,Chloroform-d)δ13.06(s,1H),8.22(dt,J＝10.5,1.8Hz,2H),8.17(dt,J＝7.9,1.4Hz,1H),8.11(dt,J＝8.2,1.4Hz,1H),7.97(td,J＝8.3,7.7,1.4Hz,2H),7.93–7.89(m,2H),7.72(t,J＝7.9Hz,2H),7.65–7.60(m,1H),7.59–7.54(m,2H),7.28(s,1H),6.77(s,1H). 13 C NMR(126MHz,Chloroform-d)δ182.60,165.79,154.77,153.95,147.07,137.61,136.07,132.80,132.27,132.00,131.97,131.92,131.70,131.66,131.63,131.05,131.03,130.29,130.17,129.89,129.38,126.60,126.02,125.99,125.73,125.70,125.15,124.07,123.94,121.90,121.77,110.33,105.97,102.50.HRMS(m/z):cacld for C 29 H 16 F 6 O 9 S 2 [M-H] - 685.00672,found 685.00421.
GL26 yield 71%; mp 186.8-187.1; a pale yellow powder; 1 H NMR(500MHz,Chloroform-d)δ13.11(s,1H),8.14(t,J＝1.8Hz,1H),8.03(t,J＝1.9Hz,1H),7.94(td,J＝7.0,1.6Hz,3H),7.85(dddd,J＝7.5,4.3,1.9,1.0Hz,2H),7.78(ddd,J＝7.9,1.8,1.0Hz,1H),7.67–7.61(m,1H),7.61–7.55(m,2H),7.48(t,J＝8.0Hz,1H),7.43(t,J＝8.0Hz,1H),7.28(d,J＝7.5Hz,1H),6.79(s,1H). 13 CNMR(126MHz,Chloroform-d)δ182.62,165.70,154.92,153.88,147.04,138.10,138.08,137.48,136.44,132.74,131.47,131.33,130.67,130.55,130.35,129.35,127.14,127.07,126.59,125.22,123.20,122.92,110.30,105.96,102.49.HRMS(m/z):cacld for C 27 H 16 Br 2 O 9 S 2 [M-H] - 706.85093,found 706.84937.
GL27 yield 74%; MP (mp)170.5 to 170.6; orange powder; 1 H NMR(500MHz,Chloroform-d)δ13.14(s,1H),7.94–7.90(m,2H),7.65–7.60(m,1H),7.57(dd,J＝8.3,6.6Hz,2H),7.53(ddd,J＝5.2,2.3,1.0Hz,2H),7.48(ddd,J＝4.9,2.3,1.1Hz,2H),7.25(s,1H),7.18(dddd,J＝8.3,6.0,4.7,2.4Hz,2H),6.78(s,1H). 13 C NMR(126MHz,Chloroform-d)δ182.58,165.84,163.74,163.64,163.55,161.70,161.61,161.52,154.83,153.99,146.84,139.33,139.26,139.19,137.72,137.65,137.58,132.83,130.26,129.38,126.61,124.96,112.61,112.55,112.44,112.37,112.30,112.19,112.13,111.04,110.85,110.65,110.40,110.22,110.02,106.01,102.43.HRMS(m/z):cacld for C 27 H 14 F 4 O 9 S 2 [M-H] - 620.99426,found 620.99109.
GL28 yield 67%; mp 174.0-174.0; a pale yellow powder; 1 H NMR(500MHz,Chloroform-d)δ12.96(s,1H),7.96–7.88(m,3H),7.83(ddd,J＝9.5,7.7,5.9Hz,1H),7.63–7.59(m,1H),7.56(dd,J＝8.4,6.6Hz,2H),7.24(s,1H),7.05(tdd,J＝10.4,5.1,2.6Hz,2H),6.99(ddt,J＝10.7,7.8,2.6Hz,2H),6.74(s,1H). 13 C NMR(126MHz,Chloroform-d)δ182.59,168.51,168.42,167.99,167.91,166.43,166.34,165.93,165.84,165.71,162.00,161.92,161.89,161.81,159.89,159.82,159.79,159.72,154.68,153.84,147.09,133.22,133.13,132.76,132.64,132.56,130.29,129.35,126.56,125.32,121.67,121.64,121.56,121.53,119.85,119.81,119.74,119.71,112.52,112.49,112.34,112.31,111.93,111.91,111.76,111.73,110.19,106.69,106.49,106.48,106.29,106.18,105.98,105.91,105.78,102.54.HRMS(m/z):cacld for C 27 H 14 F 4 O 9 S 2 [M-H] - 620.99426,found 620.99146.GL29 yield 77%; mp 199.7-199.8; a pale yellow powder; 1 H NMR(500MHz,DMSO-d 6 )δ13.27(s,1H),8.18–8.14(m,3H),8.08(ddd,J＝8.3,6.7,1.7Hz,1H),7.78(ddt,J＝8.1,6.1,2.0Hz,2H),7.69–7.64(m,1H),7.61(dd,J＝8.3,6.7Hz,2H),7.52–7.42(m,3H),7.25(s,1H). 13 C NMR(126MHz,DMSO-d 6 )δ177.73,160.77,150.23,148.94,142.41,132.56,131.25,130.81,130.66,129.94,127.47,126.59,125.53,124.51,123.07,122.55,121.75,120.64,116.64,116.41,105.10,101.11,96.64.HRMS(m/z):cacld for C 27 H 14 Cl 2 F 2 O 9 S 2 [M-H] - 652.93516,found 652.93280.
GL30 yield 57%; mp 183.9-184.3; a pale yellow powder; 1 H NMR(500MHz,Chloroform-d)δ12.89(s,1H),8.14–8.09(m,1H),7.99–7.95(m,1H),7.90–7.86(m,2H),7.84–7.80(m,1H),7.70–7.65(m,1H),7.62–7.58(m,1H),7.57–7.49(m,4H),7.44–7.34(m,2H),7.19(s,1H),6.72(s,1H). 13 C NMR(126MHz,Chloroform-d)δ182.54,165.50,154.98,153.74,147.32,137.47,136.02,135.61,135.46,135.42,134.62,132.63,132.27,131.41,130.39,129.30,127.77,127.27,126.53,125.44,121.53,121.29,109.88,105.91,101.53.HRMS(m/z):cacld for C 27 H 16 Br 2 O 9 S 2 [M-H] - 706.85093,found 706.84827.
GL31 yield 59%; mp 168.5-168.9; a pale yellow powder; 1 H NMR(500MHz,DMSO-d 6 )δ13.48(s,1H),8.22–8.17(m,2H),7.70–7.64(m,1H),7.61(dd,J＝8.3,6.7Hz,2H),7.52(s,1H),7.26(s,1H),3.74(dq,J＝25.0,7.3Hz,4H),1.47(dt,J＝8.5,7.3Hz,6H). 13 C NMR(126MHz,Chloroform-d)δ182.84,165.69,154.14,153.74,147.67,132.69,130.37,129.33,126.57,125.49,109.89,105.78,102.11,48.33,47.63,8.39,8.12.HRMS(m/z):cacld for C 19 H 18 O 9 S 2 [M-H] - 453.03195,found 453.03012.
pharmacological experiments
Experimental materials
The apparatus used in the bioactivity assay comprises a Perkin Elmer multifunctional enzyme-labeled instrument; up>A ZW-A micro-oscillator; -20 ℃ celadon hal refrigerator (model: BC/BD-429 HEM); thermo Fisher pipette (specification: 2-2. Mu.l, 1-10. Mu.l, 10-100. Mu.l, 100-1000. Mu.l); WHB 96-well whole black cell culture plate; screening kit for neuraminidase inhibitor (Shanghai Biyun biotechnology Co., ltd., P0309) comprising neuraminidase detection buffer 10ml, neuraminidase 1ml, neuraminidase fluorogenic substrate 1ml, purified water 1.2ml; novel coronavirus Mpro/3CLpro inhibitor screening kit (enhanced) (Shanghai Biyunshigan Biotechnology Co., ltd. P0315S) comprising Assay Buffer 30ml,2019-nCoV Mpro/3CLpro 100. Mu.l, substrate 200. Mu.l, ebselen (10 mM) 20. Mu.l.
Experimental method
1. Screening of potential inhibitors of neuraminidase
a. Sample preparation:
samples to be tested were prepared as 10. Mu.M, 20. Mu.M, 30. Mu.M and 40. Mu.M, respectively, using 2% DMSO as solvent. Placing into a refrigerator at 4 ℃ for standby.
b. Determination of the samples:
according to the operation instructions of the neuraminidase kit, the steps are carried out: 70. Mu.l of buffer was added to each sample well, followed by addition of neuraminidase, the sample to be tested and ultrapure water in a total volume of 20. Mu.l, so that the total volume per well was 90. Mu.l. Shaking and stirring for about 1 minute. Incubation was carried out at 37℃for 2 min to allow the compound to interact well with neuraminidase. Mu.l neuraminidase fluorogenic substrate was added to each sample well. Shaking and stirring for about 1 minute. After incubation at 37℃for 30min, a fluorescence assay was performed. The excitation wavelength was 322nm and the emission wavelength was 450nm. The detection system settings are shown in table 2.
TABLE 2 neuraminidase inhibitor detection System
The inhibition rate of each sample can be calculated as follows:
inhibition rate (100%) = [1- (RFU) Sample group -RFU Blank group )/(RFU Enzyme value set -RFU Blank group )]×100％
2. Novel coronavirus M pro Screening of potential protease inhibitors
a. Sample preparation:
samples to be tested were prepared as 10. Mu.M, 20. Mu.M, 30. Mu.M and 40. Mu.M, respectively, using 2% DMSO as solvent. And (5) putting the mixture into a refrigerator at the temperature of 4 ℃ for cold storage and preservation, and keeping the mixture for standby.
b. Preparation of positive control:
the positive control inhibitor Ebselen provided in the kit was diluted to 10. Mu.M, 20. Mu.M, 30. Mu.M and 40. Mu.M at a concentration of 10mM (providing the initial concentration).
c. Determination of the samples:
according to novel coronavirus M pro The operation steps of the protease inhibitor screening kit instruction are to prepare a proper amount of detection reagent by referring to the table S-2. The detection system settings are shown in table 3.
TABLE 3 preparation method of detection reagent
In a 96-well plate, 93. Mu.l buffer solvent was added to the blank wells, and 93. Mu.l detection reagent was added to each of the remaining wells except the blank wells. The positive control drug Ebselen, the sample solvent and the sample to be tested were each added dropwise in an amount of 5. Mu.l according to the operating requirements. Shaking and stirring for 1 minute. Then 2. Mu.l of substrate was added quickly to each well. Shaking again for about 1 minute. Incubation at 37deg.C in darkness for 5min to allow the tested compound to react with M pro The proteases interact well and a subsequent fluorometric assay is performed. The excitation wavelength was 325nm and the emission wavelength was 393nm. The detection system settings are shown in table 4.
TABLE 4 novel coronavirus M pro Protease inhibitor detection system
The inhibition rate of each sample can be calculated as follows:
inhibition rate (100%) = (RFU 100% enzyme activity control -RFU Sample group )/(RFU 100% enzyme activity control -RFU Blank control )×100％
Experimental results
Through the operation of the pharmacological experiment, the neuraminidase NA and the novel coronavirus main protease M are respectively treated pro And (5) performing activity measurement to obtain an experimental result. And calculate IC 50 Values, most of which showed better enzyme inhibition activity. The results are summarized in Table 5.
TABLE 5 enzyme Activity measurement results
As can be seen from Table 5, in the screening process for NA inhibitors, the IC of the compounds GL03, GL08, GL09, GL15, GL25, GL31 50 The values are lower than those of baicalein, i.e. the compounds have certain inhibition effect, wherein GL31 (IC 50 = 25.53 μm) has the best inhibitory effect and has the potential to be a neuraminidase inhibitor.
Comparative M pro The screening results of inhibitors revealed that the compounds GL08, GL10, GL23 and GL29 were IC 50 The values were lower than those of baicalein, and IC of Compound GL10 50 The lowest value (IC) 50 =28.35 μm). That is, compound GL10 has the best inhibition of novel coronavirus M pro The protease is expected to become a new coronavirus M pro Potential inhibitors of proteases.
Claims (10)
1. A baicalein derivative, which is characterized by being a compound having the following general formula:
in the general formula, R is respectively:
2. the baicalein derivative according to claim 1, wherein the baicalein derivative is a compound of the following structural formula:
3. the preparation method of baicalein derivatives according to claim 1, wherein baicalein is used as a raw material, and the two hydroxyl groups of C6-OH and C7-OH are substituted by sulfonyloxy through electrophilic substitution reaction, and the reaction equation is as follows:
4. the method for preparing baicalein derivatives according to claim 3, wherein the reaction solvent of the electrophilic substitution reaction is anhydrous acetone after drying and dehydration.
5. The method for preparing baicalein derivatives according to claim 3, wherein the electrophilic substitution reaction is carried out under ice bath condition for 1 hr, quenching with ice water, and filtering.
6. The use of baicalein derivatives according to claim 1 or 2 in the preparation of influenza virus neuraminidase NA inhibitors.
7. The use of baicalein derivatives according to claim 6 for preparing influenza virus neuraminidase NA inhibitors, wherein the compound is: GL09, GL15, GL25, GL31.
8. Preparation of novel coronavirus main proteinase M by baicalein derivatives according to claim 1 or 2 pro Use of inhibitors.
9. The method for preparing novel coronavirus main proteinase M from baicalein derivatives according to claim 8 pro Use in an inhibitor, characterized in that the compound is: GL08, GL10, GL29.
10. The preparation of influenza virus neuraminidase NA inhibitor and novel coronavirus main protease M from baicalein derivatives according to claim 1 pro Use of inhibitors.
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