CN114129570B - Application of oxazolidinone compound in preparation of anti-coronavirus drugs - Google Patents
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Abstract
The invention discloses an application of an oxazolidinone compound in preparing an anti-coronavirus drug, wherein the anti-coronavirus drug contains the oxazolidinone compound as an active ingredient, and the oxazolidinone compound is a coronavirus 3CL protease inhibitor. The invention uses fluorescent probe method to test the enzyme activity of oxazolidinone compound in general formula I, which proves that it has inhibiting activity to coronavirus 3CL proteinase, and can be used as a potential medicine for treating and preventing SARS virus infection.
Description
Technical Field
The invention relates to an anti-coronavirus compound, in particular to a coronavirus 3CL protease inhibitor and application thereof.
Background
Isolation of human coronaviruses from 1965 to date, a total of 7 human coronaviruses were found to be pathogenic to humans. Coronaviruses have caused three major epidemic situations in humans over the last 20 years: SARS epidemic (SARS-CoV virus) originating in Guangdong in China, and middle east respiratory syndrome epidemic (MERS-CoV virus) originating in Saint Arabidopsis in 2012, and pneumonia epidemic (SARS-CoV-2 virus) of new coronavirus infection which is still spreading at present. Vaccine and drug development against coronaviruses has become a hotspot for research at home and abroad.
After the coronavirus is infected into host cells, with the help of the host cells, the genetic material RNA of the coronavirus is firstly translated and expressed to form two polyprotein precursors (pp 1a and pp1 ab), and the polyprotein precursors are subjected to intramolecular cleavage under the action of 3CL protease and PL protease to generate a plurality of non-structural proteins, and the 3CL protease is at least responsible for cleavage of 11 sites and is extremely important for virus replication, so the coronavirus is also called main protease, and the protease has no homologous protein in human body, and gene sequence analysis shows that the protease is relatively conserved, and the 3CL proteases of SARS-CoV and SARS-CoV-2 are highly similar, so the coronavirus has become ideal targets for antiviral drug development.
The coronavirus 3CL protease inhibitors reported in the literature are mainly divided into peptide inhibitors and non-peptide inhibitors, and the non-peptide inhibitors mainly comprise heterocyclic esters, flavonoids, pyrazoles, isatins (indoles) and macrocyclic compounds. The medicinal safety of these compounds is not yet known. The occurrence time of the new coronavirus is short, and related inhibitors are rarely reported so far. Oxazolidinone compounds are widely used as antibacterial drugs and anticoagulants, the safety of the oxazolidinone compounds is verified, but the oxazolidinone compounds are not reported as coronavirus 3CL protease inhibitors in the literature.
Disclosure of Invention
The invention aims to provide a novel oxazolidinone coronavirus 3CL protease inhibitor, which has a certain inhibition effect on coronavirus 3CL protease, and the oxazolidinone structure exists in various marketed medicines, and the related medicinal safety is verified.
The technical scheme of the invention comprises the following steps:
the application of an oxazolidinone compound in preparing an anti-coronavirus drug comprises the oxazolidinone compound as an active ingredient, wherein the oxazolidinone compound is a coronavirus 3CL protease inhibitor;
the oxazolidinone compound is a compound with a structure shown in a general formula I, an optical isomer, a solvate or pharmaceutically acceptable salt thereof;
in the formula I, R is H or halogen;
x is CH 2 Or c=o;
ar is a substituted or unsubstituted aryl group, the substituents on said aryl group being selected from trifluoromethyl, halogen, C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy or nitro.
The invention uses novel coronavirus (SARS-COV-2) as model, based on three-dimensional SARS-COV-23CL proteaseThe structure is designed according to the reported action modes of the small molecule N3 and the 3CL protease, and small molecule inhibitors, natural products, metal binding inhibitors and antiviral drugs approved by FDA obtained from the existing protease inhibitors are virtually screened to obtain the compounds which can inhibit the novel coronavirus 3CL protease. Then, a commercially available 3CL is used Pro The inhibitor screening kit is used for enzyme activity inhibition experiments, and the oxazolidinone compounds with inhibition effect on SARS-COV-23CL protease activity are screened out, so that candidate small molecules are provided for drug development of targeting SARS-COV-23CL protease.
The oxazolidinone target compound of the general formula I is obtained by the reaction of sulfonyl chloride and linezolid or rivaroxaban amine, and the synthetic route is as follows:
preferably, the coronavirus is any one of SARS-CoV, MERS-CoV, or SARS-CoV-2.
Preferably, the aryl group is phenyl or 8-quinolinyl.
Preferably, ar is phenyl, p-tolyl, p-methoxyphenyl, p-fluorophenyl, p-trifluoromethylphenyl, p-chlorophenyl, m-fluorophenyl, m-trifluoromethylphenyl, m-nitrophenyl, or o-trifluoromethylphenyl.
Preferably, the R substituent is a hydrogen or fluorine atom.
Preferably, the oxazolidinone compound is the following compound, optical isomer, solvate or pharmaceutically acceptable salt thereof;
preferably, the oxazolidinone compounds of formula I include optical isomers, solvates or pharmaceutically acceptable salts thereof.
In the anti-coronavirus drug, the active ingredient is an oxazolidone single compound or a mixture of the general formula I.
The invention also provides a pharmaceutical composition comprising one or more compounds of formula (I) and one or more pharmaceutically acceptable carriers. Preferably, the one or more pharmaceutically acceptable carriers are inert, non-toxic carriers, wherein the inert, non-toxic carriers can be selected according to the knowledge of those skilled in the art, including pharmaceutically used diluents, binders, disintegrants, lubricants, glidants, and the like, such as starch, gelatin, crospovidone, magnesium stearate, and colloidal silicon dioxide, and the like.
The coronavirus 3CL protease inhibitor screened by utilizing the oxazolidone structure in the antibacterial drug linezolid and the anticoagulant drug rivaroxaban on the market has more reliable related medicinal safety and clear impurity source compared with similar inhibitors reported in the literature.
Drawings
FIG. 1 is a hydrogen nuclear magnetic resonance spectrum of a target compound I-11;
FIG. 2 is a high resolution mass spectrum of compound of interest I-11;
FIG. 3 is an IC of compounds I-11 and I-15 50 。
Detailed Description
Specific embodiments of the present invention are illustrated with reference to the following examples. These examples are intended to illustrate the invention and are not intended to limit the invention in any way.
The chemical reagent used was purchased from Shanghai Bai Shun Biotechnology Co. New coronavirus (SARS-CoV-2) 3CL protease (3 CL) Pro ) Inhibitor screening kits were purchased from Xiamen Lanboride Biotechnology Inc.
Compound structure characterization instrument: a Shanghai instrument electro-physical optics company WRS-3 melting point instrument (temperature uncorrected); agilent 1290ii+6545 mass spectrometer; bruker Avance Neo 500MHz nuclear magnetic resonance apparatus (DMSO as solvent, TMS as internal standard).
The embodiment of the invention adopts a multi-mark high-flux microplate detector (PE EnVision) to detect the fluorescence intensity.
Example 1 Synthesis of (R) -N- ((3- (3-fluoro-4-morpholinophenyl) -2-oxooxazolidin-5-yl) methyl) -4- (trifluoromethyl) benzenesulfonamide (I-1)
4-Trifluoromethylbenzenesulfonyl chloride (1 mmol,0.2446 g) and linezolid (1 mmol,0.2953 g) were placed in a reaction flask, dichloromethane (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added sequentially, and the reaction was stirred at room temperature for 5 hours and monitored by TLC (ethyl acetate: n-hexane 2:1) for completion. The reaction solution was washed with water 3 times, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.4597g of a white solid (compound I-1) in 91% yield. m.p.179.7-181.6 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:8.42(t,J＝5.0Hz,1H),8.01(dd,J＝7.5,22.5Hz,4H),7.49-7.46(m,1H),7.15(dd,J＝5.0,10.0Hz,1H),7.07(t,J＝7.5Hz,1H),4.74-4.69(m,1H),4.10-4.01(m,1H),3.75-3.72(m,5H),3.24-3.13(m,2H),2.96(t,J＝2.5Hz,4H)； 13 C NMR(125MHz,DMSO-d 6 )δ:154.6(d,J＝242.5Hz),153.8,144.4,135.6(d,J＝8.8Hz),133.3(d,J＝11.3Hz),132.3(t,J＝32.5Hz),127.5,126.5(t,J＝3.8Hz),123.5(t,J＝267.5Hz),119.3(d,J＝5.0Hz),114.0(d,J＝2.5Hz),106.6(d,J＝26.3Hz),71.2,66.2,50.7(d,J＝2.5Hz),46.8,45.2；HRMS,m/z calcd.for C 21 H 22 F 4 N 3 O 5 S[M+H] + :504.1211；found:504.1216。
Example 2 Synthesis of (R) -4-fluoro-N- ((3- (3-fluoro-4-morpholinophenyl) -2-oxooxazolidin-5-yl) methyl) benzenesulfonamide (I-2)
4-Fluorobenzenesulfonyl chloride (1 mmol,0.1946 g) and linezolid (1 mmol,0.2953 g) were placed in a reaction flask, dichloromethane (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added sequentially, and the reaction was stirred at room temperature for 5 hours, and completion of the reaction was monitored by TLC (ethyl acetate: n-hexane 2:1). The reaction solution is washed for 3 times withoutDried over sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.3577g of a white solid (compound I-2) in 79% yield. m.p.168.0-168.8 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:8.18(t,J＝5.0Hz,1H),7.90-7.87(m,2H),7.50-7.42(m,3H),7.16(dd,J＝5.0,10.0Hz,1H),7.07(t,J＝10.0Hz,1H),4.74-4.68(m,1H),4.08(t,J＝10.0Hz,1H),3.76-3.73(m,5H),3.18-3.07(m,2H),2.97(t,J＝5Hz,4H)； 13 C NMR(125MHz,DMSO-d 6 )δ:164.2(d,J＝248.8Hz),154.6(d,J＝242.5Hz),153.9,136.8(d,J＝3.8Hz),135.6(d,J＝8.8Hz),133.3(d,J＝11.3Hz),129.5(d,J＝8.8Hz),119.3(d,J＝3.8Hz),116.4(d,J＝22.5Hz),114.1(d,J＝2.5Hz),106.6(d,J＝25.0Hz),71.2,66.2,50.7(d,J＝2.5Hz),46.9,45.2；HRMS,m/z calcd.for C 20 H 22 F 2 N 3 O 5 S[M+H] + :454.1243；found:454.1248。
Example 3 Synthesis of (R) -N- ((3- (3-fluoro-4-morpholinophenyl) -2-oxooxazolidin-5-yl) methyl) -4-methylbenzenesulfonamide (I-3)
P-toluenesulfonyl chloride (1 mmol,0.1906 g) and linezolid (1 mmol,0.2953 g) were placed in a reaction flask, dichloromethane (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added sequentially, and the reaction was stirred at room temperature for 5 hours and monitored by TLC (ethyl acetate: n-hexane 2:1) for completion. The reaction solution was washed with water for 3 times, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.3512g of an off-white solid (compound I-3) in 78% yield. m.p.149.4-150.0 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:8.05(t,J＝7.5Hz,1H),7.70(d,J＝10.0Hz,2H),7.48(dt,J＝1.1,15.0Hz,1H),7.40(d,J＝10.0Hz,2H),7.16(dd,J＝5.0,10.0Hz,1H),7.07(t,J＝10.0Hz,1H),4.72-4.67(m,1H),4.08-4.01(m,1H),3.75-3.73(m,5H),3.13-3.03(m,2H),2.96(t,J＝5.0Hz,4H),2.38(s,3H)； 13 C NMR(125MHz,DMSO-d 6 )δ:154.6(d,J＝242.5Hz),153.9,142.9,137.5,135.6(d,J＝8.8Hz),133.4(d,J＝10.0Hz),129.7,126.5,119.3(d,J＝3.8Hz),114.1(d,J＝2.5Hz),106.6(d,J＝25.0Hz),71.2,66.2,50.7(d,J＝2.5Hz),46.9,45.1；HRMS,m/z calcd.for C 21 H 25 FN 3 O 5 S[M+H] + :450.1493；found:450.1497。
Example 4 Synthesis of (R) -N- ((3- (3-fluoro-4-morpholinophenyl) -2-oxooxazolidin-5-yl) methyl) benzenesulfonamide (I-4)
Benzenesulfonyl chloride (1 mmol,0.1766 g) and linezolid (1 mmol,0.2953 g) were placed in a reaction flask, dichloromethane (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added sequentially, and the reaction was stirred at room temperature for 5 hours and monitored by TLC (ethyl acetate: n-hexane 2:1) for completion. The reaction solution was washed with water for 3 times, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.3995g of a white solid (compound I-4) in 92% yield. m.p.157.8-159.3 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:8.15(t,J＝7.5Hz,1H),7.84-7.82(m,2H),7.68-7.64(m,3H),7.49(dd,J＝2.5,15.0Hz,1H),7.16(dd,J＝2.1,15.0Hz,1H),7.07(t,J＝10.0Hz,1H),4.73-4.69(m,1H),4.08(t,J＝10.0Hz,1H),3.78-3.73(m,5H),3.16-3.06(m,2H),2.97-2.95(m,4H)； 13 C NMR(125MHz,DMSO-d 6 )δ:154.6(d,J＝242.5Hz),153.9,140.3,135.6(d,J＝8.8Hz),133.4(d,J＝10.0Hz),132.6,129.3,126.5,119.3(d,J＝3.8Hz),114.1(d,J＝3.8Hz),106.6(d,J＝26.3Hz),71.2,66.2,50.7(d,J＝2.5Hz),46.9,45.2；HRMS,m/z calcd.for C 20 H 23 FN 3 O 5 S[M+H] + :436.1337；found:436.1342。
Example 5 Synthesis of (R) -N- ((2-oxo-3- (4- (3-oxomorpholinyl) phenyl) oxazolidin-5-yl) methyl) -4- (trifluoromethyl) benzenesulfonamide (I-5)
4-Trifluoromethylbenzenesulfonyl chloride (1 mmol,0.2446 g) and rivaroxaban amine (1 mmol,0.2913 g) were placed in a reaction vesselTo the flask, dichloromethane (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added successively, and the reaction was stirred at room temperature for 5 hours, and monitored by TLC (ethyl acetate: n-hexane 2:1) for completion. The reaction solution was washed with water 3 times, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.3661g of a white solid (compound I-5) in 73% yield. m.p.171.3-172.1 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:8.43(t,J＝10.0Hz,1H),8.02(q,J＝10.0Hz,4H),7.55(d,J＝10.0Hz,2H),7.42(d,J＝5.0Hz,2H),4.76-4.71(m,1H),4.20(s,2H),4.13(t,J＝7.5Hz,1H),3.98(t,J＝5.0Hz,2H),3.81-3.78(m,1H),3.72(t,J＝5.0Hz,2H),3.26-3.14(m,2H)； 13 C NMR(125MHz,DMSO-d 6 )δ:166.0,153.9,144.4,137.1,136.5,132.3(q,J＝32.1Hz),127.5,126.6(q,J＝3.8Hz),126.0,123.5(q,J＝271.3Hz),118.3,71.2,67.8,63.5,49.1,46.8,45.2；HRMS,m/z calcd.for C 21 H 21 F 3 N 3 O 6 S[M+H] + :500.1098；found:500.1103。
Example 6 Synthesis of (R) -4-fluoro-N- ((2-oxo-3- (4- (3-oxomorpholino) phenyl) oxazolidin-5-yl) methyl) benzenesulfonamide (I-6)
4-Fluorobenzenesulfonyl chloride (1 mmol,0.1946 g) and rivaroxaban amine (1 mmol,0.2913 g) were placed in a reaction flask, dichloromethane (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added successively, and the reaction was stirred at room temperature for 5 hours, and monitored by TLC (ethyl acetate: n-hexane 2:1) to complete the reaction. The reaction solution was washed with water 3 times, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.3878g of a white solid (compound I-6) in 86% yield. m.p.176.2-177.6 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:8.20(t,J＝7.5Hz,1H),7.89(t,J＝5.0Hz,2H),7.57-7.54(m,2H),7.47-7.40(m,4H),4.75-4.70(m,1H),4.20(s,2H),4.13(t,J＝10.0Hz,1H),3.98-3.96(m,2H),3.82-3.80(m,1H),3.72(t,J＝5.0Hz,2H),3.20-3.09(m,2H)； 13 C NMR(125MHz,DMSO-d 6 )δ:166.0,164.2(d,J＝248.8Hz),154.0,137.1,136.8(d,J＝3.8Hz),136.5,129.5(d,J＝10.0Hz),126.0,118.3,116.5(d,J＝22.5Hz),71.2,67.8,63.5,49.1,46.9,45.2；HRMS,m/z calcd.for C 20 H 21 FN 3 O 6 S[M+H] + :450.1130；found:450.1135。
EXAMPLE 7 Synthesis of (R) -4-methyl-N- ((2-oxo-3- (4- (3-oxomorpholin) phenyl) oxazolidin-5-yl) methyl) benzenesulfonamide (I-7)
4-Partosyl chloride (1 mmol,0.1906 g) and rivaroxaban amine (1 mmol,0.2913 g) were placed in a reaction flask, dichloromethane (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added successively, and the reaction was stirred at room temperature for 5 hours, and monitored by TLC (ethyl acetate: n-hexane 2:1) for completion. The reaction solution was washed with water 3 times, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.3869g of a white solid (compound I-7) in a yield of 87%. m.p.173.1-174.2 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:8.06(t,J＝7.5Hz,1H),7.71(d,J＝5.0Hz,2H),7.56-7.53(m,2H),7.43-7.39(m,4H),4.74-4.69(m,1H),4.20(s,2H),4.11(t,J＝10.0Hz,1H),3.98-3.96(m,2H),3.81-3.78(m,1H),3.72(t,J＝5.0Hz,2H),3.15-3.04(m,2H),2.38(s,3H)； 13 C NMR(125MHz,DMSO-d 6 )δ:166.0,154.0,142.9,137.5,137.1,136.5,129.7,126.5,126.0,118.3,71.2,67.8,63.5,49.1,46.9,45.2,21.0；HRMS,m/z calcd.for C 21 H 24 N 3 O 6 S[M+H] + :446.1380；found:446.1385。
Example 8 Synthesis of (R) -N- ((2-oxo-3- (4- (3-oxomorpholinyl) phenyl) oxazolidin-5-yl) methyl) benzenesulfonamide (I-8)
Sulfonyl chloride (1 mmol,0.1766 g) and rivaroxaban amine (1 mmol,0.2913 g) were placed in a reaction flask, dichloromethane (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added sequentially, and the mixture was stirred at room temperature for 5 hours, TLThe reaction was monitored for completion by C (ethyl acetate: n-hexane 2:1). The reaction solution was washed with water for 3 times, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.3892g of a white solid (compound I-8) in a yield of 90%. m.p.158.5-159.3 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:8.16(t,J＝7.5Hz,1H),7.83(d,J＝10.0Hz,2H),7.68-7.54(m,5H),7.43-7.40(m,2H),4.75-4.70(m,1H),4.20(s,2H),4.12(t,J＝7.5Hz,1H),3.98-3.96(m,2H),3.83-3.79(m,1H),3.72(t,J＝5.0Hz,2H),3.18-3.08(m,2H)； 13 C NMR(125MHz,DMSO-d 6 )δ:166.0,154.0,140.4,137.1,136.5,132.6,129.3,126.5,126.0,118.3,71.2,67.8,63.5,49.1,46.9,45.2；HRMS,m/z calcd.for C 20 H 22 N 3 O 6 S[M+H] + :432.1224；found:432.1231。
Example 9 Synthesis of (R) -N- ((3- (3-fluoro-4-morpholinophenyl) -2-oxooxazolidin-5-yl) methyl) quinoline-8-sulfonamide (I-9)
8-quinoline sulfonyl chloride (1 mmol,0.2277 g) and linezolid (1 mmol,0.2953 g) were placed in a reaction flask, dichloromethane (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added sequentially, and the reaction was stirred at room temperature for 5 hours and monitored by TLC (ethyl acetate: n-hexane 2:1) to complete the reaction. The reaction solution was washed 3 times with water, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.4657g of a white solid (compound I-9) in 96% yield. m.p.100.2-100.8 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:9.04-9.03(m,1H),8.52-8.50(m,1H),8.34-8.27(m,2H),7.77-7.65(m,3H),7.35-7.32(m,1H),7.04-7.00(m,2H),4.71-4.66(m,1H),3.98(t,J＝7.5Hz,1H),3.76-3.73(m,5H),3.34-3.25(m,2H),2.96(t,J＝5.0Hz,4H)； 13 C NMR(125MHz,DMSO-d 6 )δ:154.5(d,J＝241.3Hz),153.7,151.3,142.6,137.0,136.6,135.5(d,J＝8.8Hz),133.7,133.3(d,J＝10.0Hz),130.5,128.6,125.7,122.5,119.2(d,J＝5.0Hz),113.9(d,J＝3.8Hz),106.5(d,J＝25.0Hz),71.3,66.2,50.7(d,J＝2.5Hz),46.8,45.5；HRMS,m/z calcd.for C 23 H 24 FN 4 O 5 S[M+H] + :487.1446；found:487.1451。
Example 10 Synthesis of (R) -N- ((2-oxo-3- (4- (3-oxomorpholinyl) phenyl) oxazolidin-5-yl) methyl) quinoline-8-sulfonamide (I-10)
8-quinoline sulfonyl chloride (1 mmol,0.2277 g) and rivaroxaban amine (1 mmol,0.2913 g) were placed in a reaction flask, dichloromethane (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added sequentially, and the reaction was stirred at room temperature for 5 hours, and monitored by TLC (ethyl acetate: n-hexane 2:1) for completion. The reaction solution was washed with water for 3 times, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.3614g of a white solid (compound I-10) in 75% yield. m.p.222.4-224.1 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:8.96(dd,J＝1.7,4.2Hz,1H),8.43(dd,J＝1.7,8.4Hz,1H),8.26(dd,J＝1.2,7.3Hz,1H),8.20(dd,J＝1.2,8.3Hz,1H),7.69-7.64(m,2H),7.59(q,J＝4.2Hz,1H),7.36-7.28(m,4H),4.65-4.60(m,1H),4.13(s,2H),3.95(t,J＝10.0Hz,1H),3.91-3.89(m,2H),3.72(dd,J＝5.0,10.0Hz,1H),3.64(t,J＝5.0Hz,2H),3.26-3.18(m,2H)； 13 C NMR(125MHz,DMSO-d 6 )δ:166.0,153.8,151.3,142.6,137.1,137.0,136.6,136.4,133.7,130.5,128.6,125.9,125.7,122.5,118.1,71.3,67.8,63.5,49.1,46.8,45.5；HRMS,m/z calcd.for C 23 H 23 N 4 O 6 S[M+H] + :483.1333；found:483.1337。
EXAMPLE 11 Synthesis of (R) -3-fluoro-N- ((3- (3-fluoro-4-morpholinophenyl) -2-oxooxazolidin-5-yl) methyl) benzenesulfonamide (I-11)
m-Fluorobenzenesulfonyl chloride (1 mmol,0.1946 g) and linezolid (1 mmol,0.2953 g) were placed in a reaction flask, dichloromethane (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added sequentially, and the mixture was stirred at room temperature for 5 hours and reacted by TLC (acetic acid)Ethyl ester: n-hexane 2:1) monitored the reaction was complete. The reaction solution was washed 3 times with water, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.4273g of a white solid (compound I-11) in 94% yield. m.p.166.4-166.8 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:8.27(t,J＝7.5Hz,1H),7.70-7.61(m,3H),7.56-7.51(m,1H),7.48(dd,J＝5.0,15.0Hz,1H),7.16(dd,J＝5.0,10.0Hz,1H),7.07(t,J＝10.0Hz,1H),4.74-4.69(m,1H),4.08(t,J＝10.0Hz,1H),3.76-3.73(m,5H),3.22-3.11(m,2H),2.97(t,J＝5Hz,4H)； 13 C NMR(125MHz,DMSO-d 6 )δ:161.8(d,J＝246.3Hz),154.6(d,J＝242.5Hz),153.9,142.5(d,J＝6.3Hz),135.6(d,J＝8.8Hz),133.3(d,J＝11.3Hz),131.7(d,J＝7.5Hz),122.7(d,J＝3.8Hz),119.8(d,J＝20.0Hz),119.3(d,J＝3.8Hz),114.1(d,J＝2.5Hz),113.6(d,J＝23.8Hz),106.6(d,J＝26.3Hz),71.2,66.2,50.7(d,J＝2.5Hz),46.9,45.2；HRMS,m/z calcd.for C 20 H 22 F 2 N 3 O 5 S[M+H] + :454.1243；found:454.1247。
EXAMPLE 12 Synthesis of (R) -3-fluoro-N- ((2-oxo-3- (4- (3-oxomorpholin) phenyl) oxazolidin-5-yl) methyl) benzenesulfonamide (I-12)
M-fluorobenzenesulfonyl chloride (1 mmol,0.1946 g) and rivaroxaban amine (1 mmol,0.2913 g) were placed in a reaction flask, dichloromethane (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added successively, and the reaction was stirred at room temperature for 5 hours, and monitored by TLC (ethyl acetate: n-hexane 2:1) for completion. The reaction solution was washed with water 3 times, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.3720g of a white solid (compound I-12) in a yield of 83%. m.p.172.9-173.6 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:8.29(t,J＝5.0Hz,1H),7.70-7.61(m,3H),7.56-7.50(m,3H),7.43-7.40(m,2H),4.75-4.71(m,1H),4.20(s,2H),4.13(t,J＝10.0Hz,1H),3.98-3.96(m,2H),3.80(dd,J＝5.0,10.0Hz,1H),3.72(t,J＝5.0Hz,2H),3.24-3.12(m,2H)； 13 C NMR(125MHz,DMSO-d 6 )δ:166.0,161.8(d,J＝246.3Hz),154.0,142.5(d,J＝6.3Hz),137.1,136.5,131.7(d,J＝7.5Hz),126.0,122.7(d,J＝10.0Hz),119.8(d,J＝20.0Hz),118.3,113.6(d,J＝23.8Hz),71.2,67.8,63.5,49.1,46.9,45.2；HRMS,m/z calcd.for C 20 H 21 FN 3 O 6 S[M+H] + :450.1130；found:450.1134。
EXAMPLE 13 Synthesis of (R) -N- ((3- (3-fluoro-4-morpholinophenyl) -2-oxooxazolidin-5-yl) methyl) -3-nitrobenzenesulfonamide (I-13)
M-nitrobenzenesulfonyl chloride (1 mmol,0.2216 g) and linezolid (1 mmol,0.2953 g) were placed in a reaction flask, dichloromethane (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added successively, and the reaction was stirred at room temperature for 5 hours, and completion of the reaction was monitored by TLC (ethyl acetate: n-hexane 2:1). The reaction solution was washed with water 3 times, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.4265g of a yellow solid (compound I-13) in 89% yield. m.p.179.3-179.7 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:8.56-8.46(m,3H),8.24-8.22(m,1H),7.90(t,J＝7.5Hz,1H),7.45(dd,J＝5.0,15.0Hz,1H),7.13(dd,J＝5.0,10.0Hz,1H),7.05(t,J＝7.5Hz,1H),4.74-4.69(m,1H),4.07(t,J＝7.5Hz,1H),3.75-3.70(m,5H),3.28-3.17(m,2H),2.96(t,J＝5.0Hz,4H)； 13 C NMR(125MHz,DMSO-d 6 )δ:154.6(d,J＝242.5Hz),153.8,148.0,142.1,135.6(d,J＝8.8Hz),133.3(d,J＝10.0Hz),132.5,131.4,127.2,121.4,119.3(d,J＝5.0Hz),114.0(d,J＝3.8Hz),106.6(d,J＝26.3Hz),71.1,66.2,50.7(d,J＝2.5Hz),46.9,45.2；HRMS,m/z calcd.for C 20 H 22 FN 4 O 7 S[M+H] + :481.1188；found:481.1193。
EXAMPLE 14 Synthesis of (R) -3-nitro-N- ((2-oxo-3- (4- (3-oxomorpholin) phenyl) oxazolidin-5-yl) methyl) benzenesulfonamide (I-14)
M-nitrobenzenesulfonyl chloride (1 mmol,0.2216 g) and rivaroxaban amine (1 mmol,0.2913 g) were placed in a reaction flask, methylene chloride (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added successively, and the reaction was stirred at room temperature for 5 hours, and completion of the reaction was monitored by TLC (ethyl acetate: n-hexane 2:1). The reaction solution was washed with water for 3 times, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.3924g of a pale yellow solid (compound I-14) in 82% yield. m.p.137.7-138.8 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:8.49(t,J＝1.9Hz,1H),8.45(t,J＝5.0Hz,1H),8.41-8.39(m,1H),8.17-8.15(m,1H),7.83(t,J＝7.5Hz,1H),7.47-7.44(m,2H),7.35-7.32(m,2H),4.68-4.63(m,1H),4.13(s,2H),4.05(t,J＝7.5Hz,1H),3.90(t,J＝5.0Hz,2H),3.70(dd,J＝5.0,10.0Hz,1H),3.65(t,J＝5.0Hz,2H),3.22-3.10(m,2H)； 13 C NMR(125MHz,DMSO-d 6 )δ:166.0,153.9,148.0,142.1,137.1,136.4,132.5,131.4,127.2,126.0,121.4,118.2,71.1,67.8,63.5,49.1,46.8,45.2；HRMS,m/z calcd.for C 20 H 21 N 4 O 8 S[M+H] + :477.1075；found:477.1080。
EXAMPLE 15 Synthesis of (R) -N- ((3- (3-fluoro-4-morpholinophenyl) -2-oxooxazolidin-5-yl) methyl) -3- (trifluoromethyl) benzenesulfonamide (I-15)
M-trifluoromethanesulfonyl chloride (1 mmol,0.2446 g) and linezolid (1 mmol,0.2953 g) were placed in a reaction flask, dichloromethane (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added sequentially, and the reaction was stirred at room temperature for 5 hours and monitored by TLC (ethyl acetate: n-hexane 2:1) to complete the reaction. The reaction solution was washed 3 times with water, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.3846g of a white solid (compound I-15) in a yield of 76%. m.p.137.8-138.7 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:8.38(t,J＝7.5Hz,1H),8.13(t,J＝10.0Hz,2H),8.06(d,J＝5.0Hz,1H),7.87(t,J＝7.5Hz,1H),7.48(dd,J＝2.5,15.0Hz,1H),7.15(dd,J＝2.2,8.8Hz,1H),7.07(t,J＝10.0Hz,1H),4.74-4.69(m,1H),4.08(t,J＝7.5Hz,1H),3.75-3.72(m,5H),3.24-3.13(m,2H),2.96(t,J＝4.6Hz,4H)； 13 C NMR(125MHz,DMSO-d 6 )δ:154.6(d,J＝242.5Hz),153.9,141.7,135.6(d,J＝8.8Hz),133.3(d,J＝11.3Hz),131.0,130.6,130.0(q,J＝32.5Hz),129.4(q,J＝15.0Hz),123.5(q,J＝271.3Hz),123.1(q,J＝3.8Hz),119.3(d,J＝3.8Hz),114.1(d,J＝2.5Hz),106.6(d,J＝26.3Hz),71.2,66.2,50.7(d,J＝2.5Hz),46.9,45.2；HRMS,m/zcalcd.for C 21 H 22 F 4 N 3 O 5 S[M+H] + :504.1211；found:504.1215。
EXAMPLE 16 Synthesis of (R) -N- ((2-oxo-3- (4- (3-oxomorpholinyl) phenyl) oxazolidin-5-yl) methyl) -3- (trifluoromethyl) benzenesulfonamide (I-16)
M-trifluoromethylbenzenesulfonyl chloride (1 mmol,0.2446 g) and rivaroxaban amine (1 mmol,0.2913 g) were placed in a reaction flask, dichloromethane (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added successively, and the reaction was stirred at room temperature for 5 hours, and monitored by TLC (ethyl acetate: n-hexane 2:1) to complete the reaction. The reaction solution was washed with water for 3 times, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.4002g of a pale yellow solid (compound I-16) in 80% yield. m.p.158.4-159.5 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:8.40(t,J＝5.0Hz,1H),8.14(d,J＝5.0Hz,2H),8.06(d,J＝5.0Hz,1H),7.87(t,J＝7.5Hz,1H),7.56-7.53(m,2H),7.43-7.40(m,2H),4.76-4.72(m,1H),4.20(s,2H),4.14(t,J＝10.0Hz,1H),3.99-3.97(m,2H),3.80(dd,J＝5.0,10.0Hz,1H),3.72(t,J＝5.0Hz,2H),3.26-3.15(m,2H)； 13 C NMR(125MHz,DMSO-d 6 )δ:166.0,154.0,141.7,137.1,136.5,131.0,130.6,130.0(q,J＝32.5Hz),129.4(q,J＝3.8Hz),126.0,123.5(q,J＝271.3Hz),123.1(q,J＝3.8Hz),118.3,71.2,67.8,63.5,49.1,46.9,45.2；HRMS,m/z calcd.for C 21 H 21 F 3 N 3 O 6 S[M+H] + :500.1098；found:500.1103。
EXAMPLE 17 Synthesis of (R) -N- ((3- (3-fluoro-4-morpholinophenyl) -2-oxooxazolidin-5-yl) methyl) -4-methoxybenzenesulfonamide (I-17)
P-methoxybenzenesulfonyl chloride (1 mmol,0.2067 g) and linezolid (1 mmol,0.2953 g) were placed in a reaction flask, dichloromethane (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added successively, and the reaction was stirred at room temperature for 5 hours, and completion of the reaction was monitored by TLC (ethyl acetate: n-hexane 2:1). The reaction solution was washed with water 3 times, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.4342g of a white solid (compound I-17) in 93% yield. m.p.174.2-175.7 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:7.97(t,J＝5.0Hz,1H),7.77-7.74(m,2H),7.48(dd,J＝2.5,15.0Hz,1H),7.17-7.05(m,4H),4.73-4.68(m,1H),4.07(t,J＝10.0Hz,1H),3.84(s,3H),3.77-3.73(m,5H),3.12-3.02(m,2H),2.96(t,J＝5.0Hz,4H)； 13 C NMR(125MHz,DMSO-d 6 )δ:162.3,154.6(d,J＝242.5Hz),154.0,135.6(d,J＝8.8Hz),133.4(d,J＝10.0Hz),132.0,128.7,119.3(d,J＝3.8Hz),114.4,114.1(d,J＝2.5Hz),106.6(d,J＝26.3Hz),71.2,66.2,55.7,50.7(d,J＝3.8Hz),46.8,45.1；HRMS,m/z calcd.for C 21 H 25 FN 3 O 6 S[M+H] + :466.1443；found:466.1448。
EXAMPLE 18 Synthesis of (R) -4-methoxy-N- ((2-oxo-3- (4- (3-oxomorpholin) phenyl) oxazolidin-5-yl) methyl) benzenesulfonamide (I-18)
P-methoxybenzenesulfonyl chloride (1 mmol,0.2067 g) and rivaroxaban amine (1 mmol,0.2913 g) were placed in a reaction flask, dichloromethane (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added successively, and the reaction was stirred at room temperature for 5 hours, and completion of the reaction was monitored by TLC (ethyl acetate: n-hexane 2:1). Washing the reaction solution with water for 3 times, drying with anhydrous sodium sulfate, and separating and purifying by column chromatography (ethyl acetate: n-hexane 2:1) to obtain 0.4171g pale yellow solid (Compound I-18) in 90% yield. m.p.142.2-143.4 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:7.98(t,J＝5.0Hz,1H),7.77-7.74(m,2H),7.57-7.54(m,2H),7.43-7.40(m,2H),7.14-7.11(m,2H),4.74-4.70(m,1H),4.20(s,2H),4.12(t,J＝10.0Hz,1H),3.98-3.96(m,2H),3.84(s,3H),3.82-3.79(m,1H),3.72(t,J＝5.0Hz,2H),3.14-3.03(m,2H)； 13 C NMR(125MHz,DMSO-d 6 )δ:166.0,162.3,154.0,137.1,136.5,132.0,128.7,126.0,118.3,114.4,71.2,67.8,63.5,55.7,49.0,46.9,45.2；HRMS,m/zcalcd.for C 21 H 24 N 3 O 7 S[M+H] + :462.1329；found:462.1336。
EXAMPLE 19 Synthesis of (R) -N- ((3- (3-fluoro-4-morpholinophenyl) -2-oxooxazolidin-5-yl) methyl) -2- (trifluoromethyl) benzenesulfonamide (I-19)
O-trifluoromethylsulfonyl chloride (1 mmol,0.2446 g) and linezolid (1 mmol,0.2953 g) were placed in a reaction flask, dichloromethane (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added sequentially, and the reaction was stirred at room temperature for 5 hours, and monitored by TLC (ethyl acetate: n-hexane 2:1) for completion. The reaction solution was washed with water for 3 times, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.4376g of an off-white solid (compound I-19) in a yield of 87%. m.p.102.5-104.1 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:8.54(t,J＝7.5Hz,1H),8.11(d,J＝5.0Hz,1H),7.98(dd,J＝0.8,7.7Hz,1H),7.91-7.88(m,1H),7.84(t,J＝7.5Hz,1H),7.47(dd,J＝5.0,15.0Hz,1H),7.15(dd,J＝5.0,7.5Hz,1H),7.07(t,J＝10.0Hz,1H),4.76-4.71(m,1H),4.09(t,J＝10.0Hz,1H),3.79-3.73(m,5H),3.34-3.24(m,2H),2.97(t,J＝5.0Hz,4H)； 13 C NMR(125MHz,DMSO-d 6 )δ:154.6(d,J＝242.5Hz),153.9,139.5(d,J＝1.3Hz),135.6(d,J＝8.8Hz),133.4,133.36(d,J＝11.3Hz),133.0,129.8,128.5(q,J＝6.3Hz),126.1(q,J＝32.5Hz),122.9(q,J＝272.5Hz),119.3(d,J＝3.8Hz),114.1(d,J＝3.8Hz),106.6(d,J＝26.3Hz),71.2,66.2,50.7(d,J＝2.5Hz),46.9,45.5；HRMS,m/z calcd.for C 21 H 22 F 4 N 3 O 5 S[M+H] + :504.1211；found:504.1214。
EXAMPLE 20 Synthesis of (R) -N- ((2-oxo-3- (4- (3-oxomorpholinyl) phenyl) oxazolidin-5-yl) methyl) -2- (trifluoromethyl) benzenesulfonamide (I-20)
O-trifluoromethylbenzenesulfonyl chloride (1 mmol,0.2446 g) and rivaroxaban amine (1 mmol,0.2913 g) were placed in a reaction flask, dichloromethane (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added successively, and the reaction was stirred at room temperature for 5 hours, and monitored by TLC (ethyl acetate: n-hexane 2:1) to complete the reaction. The reaction solution was washed with water for 3 times, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.4652g of a white solid (compound I-20) in 93% yield. m.p.127.6-128.9 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:8.56(t,J＝7.5Hz,1H),8.11(d,J＝5.0Hz,1H),7.98(dd,J＝2.5,7.5Hz,1H),7.91-7.88(m,1H),7.84(t,J＝7.5Hz,1H),7.56-7.53(m,2H),7.43-7.40(m,2H),4.76-4.72(m,1H),4.20(s,2H),4.14(t,J＝10.0Hz,1H),3.99-3.97(m,2H),3.83(dd,J＝5.0,10.0Hz,1H),3.72(t,J＝5.0Hz,2H),3.26-3.15(m,2H)； 13 C NMR(125MHz,DMSO-d 6 )δ:166.0,153.9,139.5,137.1,136.5,133.4,133.0,129.8,128.5(q,J＝6.3Hz),126.1(q,J＝32.5Hz),126.0,122.9(q,J＝272.5Hz),118.3,71.2,67.8,63.5,49.1,46.9,45.5；HRMS,m/z calcd.for C 21 H 21 F 3 N 3 O 6 S[M+H] + :500.1098；found:500.1101。
EXAMPLE 21 Synthesis of (R) -4-chloro-N- ((3- (3-fluoro-4-morpholinophenyl) -2-oxooxazolidin-5-yl) methyl) benzenesulfonamide (I-21)
P-Chlornesulfonyl chloride (1 mmol,0.2111 g) and linezolid (1 mmol,0.2953 g) were placed in a reaction flask, followed by the addition of methylene chlorideAlkane (12 mL) and triethylamine (1.2 mmol,0.1214 g), were stirred at room temperature for 5 hours and monitored by TLC (ethyl acetate: n-hexane 2:1) for completion. The reaction solution was washed 3 times with water, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.4147g of a white solid (compound I-21) in 88% yield. m.p.181.2-182.9 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:8.25(t,J＝5.0Hz,1H),7.84-7.81(m,2H),7.69-7.66(m,2H),7.48(dd,J＝5.0,15.0Hz,1H),7.15(dd,J＝2.2,8.8Hz,1H),7.07(t,J＝7.5Hz,1H),4.71-4.68(m,1H),4.08(t,J＝10.0Hz,1H),3.75-3.72(m,5H),3.20-3.09(m,2H),2.96(t,J＝4.6Hz,4H)； 13 C NMR(125MHz,DMSO-d 6 )δ:154.6(d,J＝242.5Hz),153.9,139.3,137.5,135.6(d,J＝8.8Hz),133.3(d,J＝11.3Hz),129.5,128.5,119.3(d,J＝3.8Hz),114.1(d,J＝3.8Hz),106.6(d,J＝26.3Hz),71.2,66.2,50.7(d,J＝3.8Hz),46.9,45.2；HRMS,m/z calcd.for C 20 H 22 ClFN 3 O 5 S[M+H] + :470.0947；found:470.0951。
EXAMPLE 22 Synthesis of (R) -4-chloro-N- ((2-oxo-3- (4- (3-oxomorpholin) phenyl) oxazolidin-5-yl) methyl) benzenesulfonamide (I-22)
P-Chlornesulfonyl chloride (1 mmol,0.2111 g) and rivaroxaban amine (1 mmol,0.2913 g) were placed in a reaction flask, dichloromethane (12 mL) and triethylamine (1.2 mmol,0.1214 g) were added successively, and the reaction was stirred at room temperature for 5 hours, and completion of the reaction was monitored by TLC (ethyl acetate: n-hexane 2:1). The reaction solution was washed with water 3 times, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: n-hexane 2:1) to give 0.4254g of a white solid (compound I-22) in 91% yield. m.p.187.4-188.9 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ:8.19(t,J＝7.5Hz,1H),7.77-7.74(m,2H),7.62-7.60(m,2H),7.49-7.46(m,2H),7.35-7.33(m,2H),4.68-4.63(m,1H),4.12(s,2H),4.05(t,J＝7.5Hz,1H),3.90(t,J＝5.0Hz,2H),3.72(dd,J＝5.0,10.0Hz,1H),3.64(t,J＝5.0Hz,2H),3.13-3.02(m,2H)； 13 C NMR(125MHz,DMSO-d 6 )δ:166.0,154.0,139.3,137.5,137.1,136.5,129.5,128.5,126.0,118.3,71.2,67.8,63.5,49.1,46.9,45.2；HRMS,m/z calcd.For C 20 H 21 ClN 3 O 6 S[M+H] + :466.0834；found:466.0839。
EXAMPLE 23 target Compound pair SARS-CoV-23CL Pro Primary screening for inhibiting activity
SARS-CoV-2 3CL Pro The substrate of (2) is Mca-AVLQ ∈SGFR-K (Dnp) K, the substrate is 3CL Pro After specific shearing, MCA fluorescent group can be generated, the maximum excitation light of MCA is 320nm, the maximum emission wavelength is 405nm, and 3CL is detected by measuring the fluorescence intensity Pro Is a compound of formula (I).
SARS-CoV-2-3 CL of 0.2 mu M is selected Pro The series of compounds was initially screened at 20 μm substrate and 50 μm small molecule concentration (DMSO as a blank) and when different compounds were added to the enzymatic reaction mixture, the change in fluorescence value was calculated to evaluate the compound versus 3CL Pro Is effective in inhibiting the inhibition of the action of (a). The specific method comprises the following steps:
1. selecting an OptiPlate-384 micro-plate (black), wherein 41 mu L of a reaction system (20 mu L of a substrate and 20 mu L of an enzyme solution and 1 mu L of a small molecule, controlling the DMSO content) is adopted in each hole, and the buffer of the reaction solution is 50mM Tris-HCl pH 7.3 and contains 1mM EDTA;
2. incubating 20. Mu.L of 0.2. Mu.M enzyme with small molecules at 30 ℃ for 5-10min, rapidly adding 20. Mu.L of substrate and fully mixing (reaction final concentration of substrate 20. Mu.M);
3. measuring absorbance at 320nm excitation and 405nm emission, and continuously recording for about 10 min;
4. and (3) plotting the time and the increment value of the excitation light relative to 0 time, calculating the slope, and comparing the slope with the slope without adding the target compound to obtain the inhibition rate of the target compound to the enzyme activity.
Table 1: i-1 to I-22 (50. Mu.M) enzyme activity inhibition rate
As can be seen from Table 1, the compounds inhibit the activity of novel coronavirus 3CL protease to some extent, and the compound I-11 is effective against SARS-CoV-23CL Pro The inhibition effect of (C) is optimal, and the inhibition effect is I-2 and I-15 times. Furthermore, given the high similarity of coronavirus 3CL proteases reported in the literature, it is speculated that this class of compounds is also able to effectively inhibit the activity of other coronavirus 3C-like proteases, especially for SARS-CoV-1 and MERS-CoV.
EXAMPLE 24 target Compounds I-11 and I-15 pair SARS-CoV-23CL Pro Inhibition capability detection
1. mu.L of 0.2. Mu.M enzyme was mixed with 1. Mu.L of I-11 and I-15 (50. Mu.M, 25. Mu.M, 12.5. Mu.M, 6.25. Mu.M, 3.125. Mu.M, 1.56. Mu.M, 0.78. Mu.M, 0.39. Mu.M, 0.195. Mu.M, 0.098. Mu.M) at different final concentrations;
2. incubating at 30deg.C for 5-10min, rapidly adding 20 μL of short peptide substrate, and mixing well (final substrate reaction concentration 20 μM);
3. measuring absorbance at 320nm excitation and 405nm emission, and continuously recording for about 10 min;
4. by using GraphPad Prism5 software, the enzyme activity inhibition ability of the compound, IC, can be obtained by plotting the logarithmic value of the compound concentration as abscissa and the enzyme activity inhibition rate as ordinate as shown in FIG. 3 50 The values are shown in Table 2.
Table 2: i-11 and I-15 inhibit SARS-CoV-2-3 CL Pro Is of (2) 50 Value of
Claims (3)
1. The application of the oxazolidinone compound in preparing the anti-coronavirus medicament is characterized in that the anti-coronavirus medicament contains the oxazolidinone compound as an active ingredient, and the oxazolidinone compound is a coronavirus 3CL protease inhibitor;
the coronavirus is SARS-CoV-2;
the oxazolidinone compound is the following compound or pharmaceutically acceptable salt thereof;
2. the use according to claim 1, wherein the active ingredient is a single compound or a mixture of more than one of the oxazolidinones according to claim 1.
3. The use of claim 1, wherein said anti-coronavirus agent further comprises a pharmaceutically acceptable carrier.
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