A pleuromutilin derivative containing a 2-thio-4-thiazolidinone side chain, and its preparation method and application

Abstract

The present invention discloses a pleuromutilin derivative containing a 2-thio-4-thiazolidinone side chain, and its preparation method and application. The preparation method is as follows: first, pleuromutilin and p-toluenesulfonyl chloride are added to methyl tert-butyl ether, sodium hydroxide solution is added dropwise with stirring, and the reaction is refluxed to obtain intermediate 1; then, 2-thio-4-thiazolidinone is added to acetonitrile, anhydrous potassium carbonate is added and stirred at room temperature for 20 minutes, and then intermediate 1 is added, and the reaction is stirred at room temperature for a certain time to obtain intermediate 2; finally, intermediate 2 and an acyl chloride with different group donors are added to dichloromethane, and under the catalysis of triethylamine, stirred at room temperature for a certain time to obtain a pleuromutilin derivative containing a 2-thio-4-thiazolidinone side chain. The present invention synthesizes a pleuromutilin derivative containing a 2-thio-4-thiazolidinone side chain with good antibacterial activity through a simple preparation process, with high yield, good antibacterial activity against drug-resistant bacteria, and good application prospects.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry, and particularly relates to a pleuromutilin derivative containing a 2-thio-4-thiazolidinone side chain, and a preparation method and application thereof. Background Art

[0002] Pleuromutilins are diterpenoids with antibacterial activity. They are tricyclic diterpenoids with a (5-6-8) tricyclic ring. These compounds inhibit bacterial protein synthesis at the ribosomal level, targeting the 23S RNA of the bacterial 50S ribosomal subunit, with a binding site within the V domain of the peptidyl transferase (PTC). Their ternary nucleus binds to the active pocket of the A site, while the side chain partially covers the P site where tRNA binds to the ribosome, achieving antibacterial activity by inhibiting bacterial protein synthesis. Pleuromutilins have a nucleus structure distinct from common clinical antibacterial drugs, making them less likely to develop cross-resistance with other structurally similar antibacterial agents. The ester side chain at C-14 of pleuromutilins is a prime site for chemical modification, and most studies on the C-14 side chain have focused on modifying the C-22 position while retaining the ester structure.

[0003] Thiazolidinone-type small molecule heterocyclic compounds, as a special type of potentially advantageous structural framework, have attracted the attention of researchers in the field of medicinal chemistry in recent years. 2-Thio-4-thiazolidinone, also known as rhodanine, has a wide range of pharmacological activities and has become a dominant structural framework in medicinal chemistry, widely used in the construction of new drug molecules. Its molecular structure is shown below:

[0004]

[0005] 2-Thio-4-thiazolidinone derivatives possess a wide range of pharmacological activities, including antibacterial, anticancer, anti-tuberculosis, and hypoglycemic properties. They also play an important role in the pharmaceutical and medical materials fields. They also exhibit inhibitory activity against various enzyme targets, such as hepatitis C virus NS5B polymerase, penicillin-binding protein (PBP), HIV-1 integrase, and RNA polymerase. The synthesis of rhodanine derivatives primarily involves the reaction of the active methylene group at the C-5 position. Furthermore, the acidic nature of the NH group allows for a wide range of substitutions at the N-3 position, significantly enhancing their antibacterial activity and bioavailability. Summary of the Invention

[0006] In response to the problems existing in the above-mentioned background technology, the present invention provides a pleuromutilin derivative containing a 2-thioxo-4-thiazolidinone side chain, a preparation method and application thereof. The synthesized pleuromutilin derivative containing a 2-thioxo-4-thiazolidinone side chain has good in vitro antibacterial activity and can be used to prevent and treat infectious diseases caused by bacteria in humans or animals.

[0007] In order to achieve the above object, the present invention adopts the following technical solutions:

[0008] A pleuromutilin derivative containing a 2-thio-4-thiazolidinone side chain, the molecular structure of the compound is shown in the following formula (I):

[0009]

[0010] In the formula, the R group is selected from any one of the following groups:

[0011]

[0012] The specific groups of the compound of the above structure are summarized in Table 1:

[0013] Table 1 Compound numbers and specific groups

[0014]

[0015]

[0016] The present invention further provides a pharmaceutically acceptable salt of a pleuromutilin derivative containing a 2-thioxo-4-thiazolidinone side chain.

[0017] The present invention further provides a method for preparing a pleuromutilin derivative containing a 2-thio-4-thiazolidinone side chain, comprising the following steps:

[0018] (1) Pleuromutilin and p-toluenesulfonyl chloride are added to methyl tert-butyl ether and mixed, and sodium hydroxide solution is added dropwise under stirring. After reflux reaction, the reaction product is cooled, washed, and dried to obtain intermediate 1 having the structure shown in formula (II);

[0019]

[0020] (2) adding 2-thioxo-4-thiazolidinone to acetonitrile, adding anhydrous potassium carbonate and stirring at room temperature for a certain period of time, then adding the intermediate 1, stirring at room temperature for a certain period of time, and after the reaction is completed, quenching, extracting, drying, and purifying the reaction product to obtain the intermediate 2 with the structure shown in formula (III);

[0021]

[0022] (3) adding the intermediate 2 and the group donor acyl chloride to dichloromethane, stirring and reacting at room temperature for a certain time under the catalysis of triethylamine, quenching after the reaction is completed, and extracting, drying, and purifying the reaction product to obtain a pleuromutilin derivative containing a 2-thioxo-4-thiazolidinone side chain as shown in formula (I);

[0023]

[0024] In the formula, the R group is selected from any one of the following groups:

[0025]

[0026] Furthermore, in step (1), the molar volume ratio of the pleuromutilin, p-toluenesulfonyl chloride, methyl tert-butyl ether and sodium hydroxide solution is 10-12 mmol: 10-12 mmol: 10-15 mL: 2.5-2.8 mL, and the concentration of the sodium hydroxide solution is 10 mol / L.

[0027] Furthermore, in step (2), the molar volume ratio of the intermediate 1, 2-thioxo-4-thiazolidinone, potassium carbonate and acetonitrile is 5-9 mmol: 5-6 mmol: 6-10 mmol: 30-35 mL.

[0028] Furthermore, in step (2), the quenching, extraction, drying and purification of the reaction product are as follows: the reactant is quenched with a saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, dried with anhydrous sodium sulfate, and purified by column chromatography according to a ratio of petroleum ether: ethyl acetate = 3:1 to 2:1.

[0029] Furthermore, in step (3), the molar volume ratio of the intermediate 2, the group donor acyl chloride, triethylamine and dichloromethane is 1-1.2 mmol: 1-1.5 mmol: 2-2.4 mmol: 5-7 mL.

[0030] Furthermore, in step (3), the quenching, extraction, drying and purification methods of the reaction product are as follows: the reactant is quenched with a saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, dried with anhydrous sodium sulfate, and purified by column chromatography according to petroleum ether: ethyl acetate = 4:1 to 2:1.

[0031] The present invention further provides a use of a pleuromutilin derivative containing a 2-thio-4-thiazolidinone side chain or a pharmaceutically acceptable salt of the pleuromutilin derivative in the preparation of antibacterial drugs for treating infectious diseases.

[0032] The present invention further provides an antibacterial drug, which comprises the above-mentioned pleuromutilin derivative containing a 2-thio-4-thiazolidinone side chain and one or more pharmaceutically acceptable carriers, excipients or diluents for the pleuromutilin derivative;

[0033] Alternatively, the drug comprises a pharmaceutically acceptable salt of the above-mentioned pleuromutilin derivative and one or more pharmaceutically acceptable carriers, excipients or diluents for the salt.

[0034] Compared with the shortcomings and deficiencies of the prior art, the present invention has the following beneficial effects:

[0035] The present invention synthesizes a large number of novel pleuromutilin derivatives with 2-thioxo-4-thiazolidinone side chains through a simple preparation process with high yield. Screening for antibacterial activity reveals that these compounds have good in vitro antibacterial activity and are particularly suitable as novel antibacterial agents for preventing and treating bacterial infections in humans or animals, particularly against Gram-positive bacteria such as Staphylococcus aureus and Streptococci. They also exhibit excellent antibacterial activity against drug-resistant MRSA. Therefore, the pleuromutilin derivatives prepared by the present invention have promising application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 This is the nuclear magnetic resonance spectrum of the pleuromutilin derivative 4 containing a 2-thio-4-thiazolidinone side chain provided in an embodiment of the present invention;

[0037] Figure 2 This is the nuclear magnetic spectrum of the pleuromutilin derivative 8 containing a 2-thio-4-thiazolidinone side chain provided in an embodiment of the present invention;

[0038] Figure 3 1 is the bactericidal kinetic curve of the pleuromutilin derivative 19 containing a 2-thio-4-thiazolidinone side chain and tiamulin (T) against MRSA provided in an embodiment of the present invention. DETAILED DESCRIPTION

[0039] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0040] Example 1

[0041] Preparation of Intermediate 1:

[0042] 18.93 g (0.05 mol) of pleuromutilin and 11.22 g (0.05 mol) of p-toluenesulfonyl chloride were added to 50 mL of methyl tert-butyl ether, stirred evenly, and then 13.5 mL of 10 mol / L sodium hydroxide solution was slowly added dropwise. After the addition was complete, the mixture was heated to 58°C and refluxed. The mixture was stirred vigorously for 1 hour, resulting in the formation of a large amount of white solid. After the reaction was completed, 100 mL of 0-4°C ultrapure water was added and stirred vigorously. The white solid was then filtered and rinsed three times with 0-4°C ultrapure water. The white solid was then vacuum-dried at 55°C to obtain Intermediate 1 with the structure of Formula (II) in a 94% yield. This intermediate 1 can be used directly in the next step without purification.

[0043]

[0044] Example 2

[0045] Preparation of intermediate 2:

[0046] 0.67 g (5 mmol) of 2-thioxo-4-thiazolidinone was added to 30 mL of acetonitrile, and 0.83 g (6 mmol) of anhydrous potassium carbonate was added with stirring at room temperature. After stirring for 20 min, 2.66 g (5 mmol) of intermediate 1 was added and the reaction was stirred at room temperature for 4 to 5 h. After the reaction was completed, the reaction was quenched with a saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and purified by column chromatography with petroleum ether: ethyl acetate = 2:1 to obtain intermediate 2 with a structure represented by formula (III) in a yield of 73%.

[0047]

[0048] 1 H NMR (400MHz, CDCl3) δ6.39 (dd, J=17.4, 11.0Hz, 1H), 5.74 (d, J=8.5Hz, 1H), 5.32-5 .24(m,1H),5.17(dd,J=17.4,1.6Hz,1H),4.15-3.90(m,4H),3.33(d,J=6.4Hz,1H) ,2.31-2.14(m,3H),2.12-2.02(m,2H),1.78-1.71(m,1H),1.70-1.46(m,5H),1.39 (d,J=22.4Hz,5H),1.18-1.05(m,4H),0.85(d,J=7.0Hz,3H),0.71(d,J=7.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.12,200.41,186.71,165.87,138.97,117.49,74.78,71.15,58.23,45.62,44.61,44.17,4 2.04,40.26,36.86,36.68,36.18,34.65,30.57,27.02,26.48,25.01,17.04,15.01,11.72.HRMS(ESI):calcd[M+Na] + for C 25 H 35 NO5S2516.1848,found,516.1838.

[0049] Example 3

[0050] Preparation of pleuromutilin derivatives 1 to 28 containing 2-thio-4-thiazolidinone side chain:

[0051] 1 mmol of the intermediate 2 prepared in Example 2 was dissolved in 6 mL of dichloromethane, 2 mmol of triethylamine was added, and 1.1 mmol of different group donor acyl chlorides were added with stirring at room temperature. The reaction was stirred at room temperature for 2 h, quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1 to 2:1). After concentration, the target compounds 1 to 28 were obtained.

[0052] Among them, the group donor acyl chlorides in the above reaction process are: cyclopropanecarbonyl chloride, cyclobutanecarbonyl chloride, cyclopentanecarbonyl chloride, cyclohexanecarbonyl chloride, hexanecarbonyl chloride, octanoyl chloride, n-butyryl chloride, p-chlorobenzoyl chloride, o-chlorobenzoyl chloride, 2,4,6-trichlorobenzoyl chloride, 2,2-dimethylbutyryl chloride, benzoyl chloride, o-methylbenzoyl chloride, m-methylbenzoyl chloride, p-methylbenzoyl chloride, m-chlorobenzoyl chloride, 2-thiophenecarbonyl chloride, isovaleryl chloride, pivaloyl chloride, 2-ethylhexanecarbonyl chloride, 3,3-dimethylbutyryl chloride, p-fluorobenzoyl chloride, 3-fluorobenzoyl chloride, o-bromobenzoyl chloride, m-bromobenzoyl chloride, o-fluorobenzoyl chloride, 3-methoxybenzoyl chloride, and 2,4-dichlorobenzoyl chloride.

[0053] The synthetic route is shown below:

[0054]

[0055] Pleuromutilin derivative 1

[0056] 1 H NMR (400MHz, CDCl3) δ6.96 (d, J=1.7Hz, 1H), 6.39 (dd, J=17.4, 11.0Hz, 1H), 5 .72(d,J=8.5Hz,1H),5.33-5.25(m,1H),5.15(d,J=17.4Hz,1H),3.90(t,J=2 .1Hz,2H),3.48-3.23(m,2H),2.44-2.17(m,7H),2.09-1.93(m,4H),1.77-1. 24(m,11H),1.18-1.05(m,4H),0.85(d,J=6.9Hz,3H),0.69(d,J=7.0Hz,3H). 13C NMR (101MHz, CDCl3) δ217.21,172.30,167.00,160.40,153.71,139.04,117.45,103.04,74.81,70.48,58.33,45.64,44.80,44.15, 42.05,38.13,36.92,36.73,36.21,34.67,30.61,27.05,26.65,25.45,25.04,18.60,16.96,15.02,11.70.HRMS(ESI):calcd[M+Na] + for C 30 H 41 NO6S2 598.2267,found,598.2247.

[0057] Pleuromutilin derivative 2

[0058] 1 H NMR (400MHz, CDCl3) δ6.94 (s, 1H), 6.41 (dd, J = 17.4, 11.0Hz, 1H), 5.73 (d, J =8.4Hz,1H),5.29(d,J=10.7Hz,1H),5.16(d,J=17.4Hz,1H),3.91(t,J=2.0H z,2H),3.33(d,J=6.4Hz,1H),2.52(t,J=7.5Hz,2H),2.34-1.98(m,5H),1.77 -1.26(m,17H),1.19-1.06(m,4H),0.96-0.80(m,6H),0.69(d,J=6.8Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.21,170.71,167.02,160.49,153.59,139.07,117.49,103.11,74.84,70.50,58.35,45.67,44.82,44.18,42.08, 36.95,36.76,36.24,34.69,34.39,31.41,30.63,27.08,26.65,25.07,24.55,22.53,17.00,15.05,14.15,11.73.HRMS(ESI):calcd[M+Na] + for C 31 H 45 NO6S2614.2580,found,614.2546.

[0059] Pleuromutilin derivative 3

[0060] 1 H NMR (400MHz, CDCl3) δ6.94 (s, 1H), 6.41 (dd, J = 17.4, 11.0Hz, 1H), 5.73 (d, J = 8.5 Hz,1H),5.29(d,J=11.0Hz,1H),5.16(d,J=17.4Hz,1H),3.91(s,2H),3.33(d,J= 6.2Hz,1H),2.51(t,J=7.3Hz,2H),2.35-2.03(m,5H),1.80-1.30(m,13H),1.17- 1.06(m,4H),1.00(t,J=7.4Hz,3H),0.85(d,J=6.9Hz,3H),0.70(d,J=6.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.20,170.51,167.01,160.50,153.57,139.08,117.47,103.11,74.83,70.49,58.35,45.67,44.82,44. 18,42.08,36.94,36.75,36.24,34.69,30.63,27.07,26.66,25.06,18.39,16.99,15.04,13.83,11.72.HRMS(ESI):calcd[M+Na] + for C 29 H 41 NO6S2586.2267,found,586.2249.

[0061] Pleuromutilin derivative 4

[0062] 1 H NMR (400MHz, CDCl3) δ6.93(s,1H),6.40(dd,J=17.5,11.0Hz,1H),5.72(d,J=8.4Hz,1H),5.31-5.26(m,1H),5.15(dd,J=17.5,1.6Hz,1H),3.90(d,J=2. 3Hz,2H),3.37-3.27(m,1H),2.52(t,J=7.6Hz,2H),2.33-1.97(m,5H),1.76 -1.26(m,21H),1.17-1.03(m,4H),0.94-0.82(m,6H),0.69(d,J=7.0Hz,3H). 13C NMR (101MHz, CDCl3) δ217.16,170.68,166.99,160.47,153.57,139.07,1 17.45,103.08,74.82,70.48,58.33,45.65,44.80,44.16,42.06,36.93, 36.74,36.23,34.67,34.41,31.83,30.62,29.20,29.11,27.06,26.66,2 5.05,24.84,22.81,16.98,15.03,14.31,11.71.HRMS(ESI):calcd[M+Na] + forC 33 H 49 NO6S2642.2893,found,642.2863.

[0063] The NMR spectrum of its pleuromutilin derivative is as follows Figure 1 shown.

[0064] Pleuromutilin derivative 5

[0065] 1 H NMR (400MHz, CDCl3) δ6.92(s,1H),6.40(dd,J=17.4,11.0Hz,1H),5.73(d,J=8.4Hz,1H),5.29(d,J=11.0Hz,1H),5.15(d,J=17.4Hz,1H),3.91( t,2H),3.33(s,1H),2.36-2.11(m,3H),2.09-1.97(m,3H),1.84-1.32(m ,11H),1.18-0.97(m,8H),0.85(d,J=6.9Hz,3H),0.70(d,J=6.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.20,171.94,166.99,160.41,153.57,139.05,117.45,103.13,74.81,70.47,58.33,45.65,44.78,44. 15,42.06,36.93,36.73,36.22,34.67,30.61,27.05,26.64,25.04,16.97,15.03,13.11,11.71,9.96.HRMS(ESI):calcd[M+Na] + for C 29 H 39 NO6S2584.2111,found,584.2108.

[0066] Pleuromutilin derivative 6

[0067] 1 H NMR (400MHz, CDCl3) δ6.95 (s, 1H), 6.41 (dd, J = 17.4, 11.0Hz, 1H), 5.73 (d, J = 8.4 Hz,1H),5.30(d,J=11.1Hz,1H),5.16(d,J=17.4Hz,1H),3.92(t,J=2.1Hz,2H),3. 33(d,J=6.4Hz,1H),3.02-2.85(m,1H),2.37-2.14(m,3H),2.09-1.88(m,6H),1.7 8-1.26(m,15H),1.21-1.04(m,4H),0.86(d,J=6.8Hz,3H),0.70(d,J=6.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.23,173.74,167.06,160.36,153.87,139.07,117.53,103.06,74.86,70.50,58.37,45.68,44.85,44.19, 43.97,42.09,36.96,36.79,36.25,34.70,30.64,30.28,27.08,26.67,26.12,25.08,17.01,15.06,11.74.HRMS(ESI):calcd[M+Na] + forC 31 H 43 NO6S2612.2424,found,612.2352.

[0068] Pleuromutilin derivative 7

[0069] 1 H NMR (400MHz, CDCl3) δ6.94 (s, 1H), 6.40 (dd, J = 17.3, 11.0Hz, 1H), 5.72 (d, J = 8. 4Hz,1H),5.29(d,J=8.5Hz,1H),5.15(d,J=17.4Hz,1H),3.98-3.84(m,2H),3.33 (d,J=6.4Hz,1H),2.61-2.44(m,1H),2.32-2.15(m,3H),2.08-1.97(m,4H),1.83 -1.25(m,19H),1.17-1.04(m,4H),0.84(d,J=6.9Hz,3H),0.69(d,J=6.8Hz,3H).13 C NMR (101MHz, CDCl3) δ217.21,172.87,167.01,160.32,153.77,139.04,117.46,102.97,74.81,70.46,58.33,45.64,44.79,44.15,43. 33,42.05,36.91,36.74,36.21,34.66,30.60,29.02,27.04,26.66,25.82,25.48,25.04,16.97,15.02,11.70.HRMS(ESI):calcd[M+Na] + for C 32 H 45 NO6S2626.2580,found,626.2556.

[0070] Pleuromutilin derivative 8

[0071] 1 H NMR(400MHz, CDCl3)δ8.11(d,J=8.3Hz,2H),7.47(d,J=8.2Hz,2H),7.10(s,1H), 6.41(dd,J=17.4,11.0Hz,1H),5.74(d,J=8.4Hz,1H),5.32-5.25(m,1H),5.14(d, J=17.4Hz,1H),4.03-3.85(m,2H),3.32(d,J=6.5Hz,1H),2.37-2.04(m,5H),1.7 8-1.30(m,11H),1.17-1.02(m,4H),0.85(d,J=6.9Hz,3H),0.71(d,J=6.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.19,166.97,162.82,160.92,153.39,140.87,139.07,131.91,129.31,127.26,117.49,103.67,74.82,70.55,5 8.34,45.66,44.82,44.18,42.09,36.93,36.77,36.25,34.69,30.62,27.07,26.66,25.06,17.01,15.06,11.72.HRMS(ESI):calcd[M+Na] + forC 32 H 38 ClNO6S2654.1721,found,654.1710.

[0072] The NMR spectrum of its pleuromutilin derivative is as follows Figure 2 shown.

[0073] Pleuromutilin derivative 9

[0074] 1 H NMR (400MHz, CDCl3) δ7.26-7.00(m,3H),6.26(dd,J=17.2,11.0Hz,1H),5.59(d,J=8.2Hz,1H),5.15-4.93(m,2H),3.80(t,2H),3.17(d,J=6.5Hz, 1H),2.25-2.01(m,3H),1.98-1.81(m,2H),1.66-1.41(m,4H),1.36-1.15 (m,7H),1.02-0.89(m,4H),0.71(d,J=7.1Hz,3H),0.55(d,J=7.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.20,167.01,161.34,160.79,152.71,139.01,137.36,133.31,130.95,128.46,117.54,103.73,74.85,70.59,5 8.35,45.68,44.86,44.17,42.09,36.94,36.71,36.23,34.71,30.64,27.07,26.55,25.07,17.02,15.06,11.74.HRMS(ESI):calcd[M+Na] + for C 32 H 36 Cl3NO6S2722.0941,found,722.0918.

[0075] Pleuromutilin derivative 10

[0076] 1H NMR (400MHz, CDCl3) δ8.14 (dd, J=8.1, 1.5Hz, 1H), 7.47 (td, J=7.5, 1.4Hz, 1H), 7.35-7.28 (m, 2H) ,7.05(s,1H),6.42(dd,J=17.4,11.0Hz,1H),5.74(d,J=8.4Hz,1H),5.30(d,J=1.5Hz,1H),5.13(d d,J=17.4,1.6Hz,1H),4.03-3.86(m,2H),3.32(d,J=6.5Hz,1H),2.65(s,3H),2.34-2.16(m,3H), 2.09-1.99(m,2H),1.78-1.31(m,11H),1.09(s,4H),0.85(d,J=6.9Hz,3H),0.71(d,J=6.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.22,167.04,164.03,160.64,153.75,141.98,13 9.02,133.41,132.24,131.64,127.61,126.19,117.50,103.60,74.81,70. 48,58.33,45.65,44.79,44.15,42.07,36.93,36.80,36.22,34.68,30.61, 27.04,26.59,25.05,22.22,17.00,15.05,11.73.HRMS(ESI):calcd[M+Na] + forC 33 H 41 NO6S2 634.2267,found,634.2234.

[0077] Pleuromutilin derivative 11

[0078] 1 H NMR (400MHz, CDCl3) δ6.91 (s, 1H), 6.48-6.35 (m, 1H), 5.72 (d, J = 8.5Hz, 1H ),5.30(d,J=11.1Hz,1H),5.16(d,J=17.4Hz,1H),3.99-3.84(m,2H),3.33( d,J=6.4Hz,1H),2.33-2.16(m,3H),2.07-2.02(m,2H),1.79-1.29(m,13H) ,1.27(s,6H),1.16-1.06(m,4H),0.96-0.82(m,6H),0.69(d,J=6.9Hz,3H).13 C NMR (101MHz, CDCl3) δ217.21,175.09,167.12,160.28,154.05,139.05,117.55,103.16,74.84,70.49,58.36,45.67,44.89,44.20,43. 48,42.09,36.95,36.81,36.24,34.70,33.50,30.64,27.07,26.69,25.07,24.75,17.01,15.04,11.73,9.55.HRMS(ESI):calcd[M+Na] + for C 31 H 45 NO6S2 614.2580,found,614.2535.

[0079] Pleuromutilin derivative 12

[0080] 1 H NMR (400MHz, CDCl3) δ8.17(d,J=7.4Hz,2H),7.63(t,J=7.3Hz,1H),7.49(t,J=7.7Hz,2H),7.09(d,J =0.9Hz,1H),6.41(dd,J=17.4,11.0Hz,1H),5.73(d,J=8.4Hz,1H),5.28(d,J=11.0Hz,1H),5.13(d, J=17.4Hz,1H),4.03-3.87(m,2H),3.31(d,J=6.3Hz,1H),2.33-2.15(m,3H),2.10-2.00(m,2H),1.7 9-1.45(m,6H),1.44-1.31(m,5H),1.14-1.04(m,4H),0.84(d,J=6.9Hz,3H),0.71(d,J=6.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.18,166.97,163.64,160.69,153.64,139.04,134.23,130.53,128.86,128.78,117.45,103.57,74.79,70.51,5 8.32,45.64,44.79,44.15,42.07,36.92,36.77,36.22,34.66,30.60,27.04,26.63,25.04,16.97,15.03,11.69.HRMS(ESI):calcd[M+Na] + for C 32 H39 NO6S2598.2291,found,598.2272.

[0081] Pleuromutilin derivative 13

[0082] 1 H NMR (400MHz, CDCl3) δ8.00(d,J=8.0Hz,2H),7.23(d,J=8.0Hz,2H),7.03(s,1H),6.36(dd, J=17.4,11.0Hz,1H),5.68(d,J=8.4Hz,1H),5.23(d,J=10.9Hz,1H),5.08(d,J=17.2Hz,1H ),3.96-3.80(m,2H),3.26(d,J=6.5Hz,1H),2.38(s,3H),2.29-2.09(m,3H),2.00-1.93(m ,2H),1.73-1.25(m,11H),1.10-0.98(m,4H),0.79(d,J=7.0Hz,3H),0.65(d,J=6.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.23,167.04,163.72,160.57,153.80,145.20,139.04,130.62,129.62,126.03,117.53,103.48,74.85,70.52,58.3 7,45.68,44.83,44.19,42.10,36.96,36.82,36.25,34.70,30.65,27.07,26.63,25.08,22.06,17.01,15.07,11.73.HRMS(ESI):calcd[M+Na] + for C 33 H 41 NO6S2 634.2267,found,634.2256.

[0083] Pleuromutilin derivative 14

[0084] 1H NMR (400MHz, CDCl3) δ8.15(t,J=1.9Hz,1H),8.05(dt,J=7.8,1.3Hz,1H),7.64-7.59(m,1H),7.44( t,J=7.9Hz,1H),7.10(s,1H),6.42(dd,J=17.4,11.0Hz,1H),5.74(d,J=8.5Hz,1H),5.29(d,J=10.7 Hz,1H),5.14(d,J=17.4Hz,1H),4.01-3.87(m,2H),3.32(d,J=6.5Hz,1H),2.32-2.17(m,3H),2.11 -2.03(m,2H),1.78-1.31(m,11H),1.15-1.04(m,4H),0.85(d,J=7.0Hz,3H),0.72(d,J=7.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.17,166.96,162.47,161.02,153.29,139.08,1 35.11,134.29,130.56,130.51,130.24,128.66,117.49,103.71,74.82, 70.57,58.35,45.67,44.82,44.19,42.10,36.94,36.76,36.26,34.69,3 0.63,27.08,26.65,25.07,17.02,15.07,11.72.HRMS(ESI):calcd[M+Na] + for C 32 H 38 ClNO6S2654.1721,found,654.1710.

[0085] Pleuromutilin derivative 15

[0086] 1H NMR (400MHz, CDCl3) δ7.97(d,J=3.7Hz,1H),7.68(d,J=4.9Hz,1H),7.16(t,J=4.4Hz,1H),7.0 6(s,1H),6.41(dd,J=17.4,11.0Hz,1H),5.73(d,J=8.5Hz,1H),5.29(d,J=6.6Hz,1H),5.14(d d,J=17.4,1.5Hz,1H),4.03-3.84(m,2H),3.32(d,J=6.4Hz,1H),2.33-2.16(m,3H),2.09-1.9 8(m,2H),1.76-1.31(m,11H),1.17-1.04(m,4H),0.85(d,J=7.0Hz,3H),0.71(d,J=7.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.21,167.00,160.77,159.11,153.22,139.03,135.51,134.55,131.98,128.41,117.51,103.67,74.82,70.53,5 8.35,45.66,44.83,44.17,42.08,36.95,36.77,36.23,34.69,30.63,27.06,26.63,25.06,17.01,15.06,11.72.HRMS(ESI):calcd[M+Na] + for C 30 H 37 NO6S3626.1675,found,626.1658.

[0087] Pleuromutilin derivative 16

[0088] 1 H NMR (400MHz, CDCl3) δ6.95 (s, 1H), 6.40 (dd, J = 17.4, 11.0Hz, 1H), 5.73 (d, J = 8.5Hz ,1H),5.33-5.25(m,1H),5.16(dd,J=17.4,1.6Hz,1H),3.91(s,2H),3.33(s,1H),2. 41(d,J=7.1Hz,2H),2.31-2.16(m,3H),2.10-2.03(m,2H),1.80-1.31(m,12H),1.1 7-1.08(m,4H),1.01(d,J=6.7Hz,6H),0.85(d,J=7.0Hz,3H),0.69(d,J=7.0Hz,3H). 13C NMR (101MHz, CDCl3) δ217.19,169.91,167.01,160.48,153.55,139.06,117.47,103.08,74.82,70.47,58.33,45.65,44.81,44.16, 43.32,42.06,36.92,36.73,36.23,34.68,30.62,27.06,26.66,25.85,25.05,22.61,16.98,15.03,11.72.HRMS(ESI):calcd[M+Na] + forC 30 H 43 NO6S2600.2424,found,600.2429.

[0089] Pleuromutilin derivative 17

[0090] 1 H NMR (400MHz, CDCl3) δ6.94 (s, 1H), 6.41 (dd, J = 17.4, 11.0Hz, 1H), 5.73 (d, J = 8 .4Hz,1H),5.31(d,J=1.5Hz,1H),5.16(dd,J=17.4,1.6Hz,1H),3.92(s,2H),3. 33(t,J=7.7Hz,1H),2.41(s,2H),2.32-2.16(m,3H),2.12-1.99(m,2H),1.77-1 .28(m,11H),1.17-1.00(m,13H),0.85(d,J=7.0Hz,3H),0.69(d,J=7.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.19,169.12,167.05,160.44,153.54,139.05,117.51,103.16,74.83,70.47,58.34,47.77,45.66,44.83, 44.18,42.07,36.93,36.75,36.23,34.69,31.32,30.63,29.82,27.07,26.67,25.06,17.01,15.04,11.73.HRMS(ESI):calcd[M+Na] + forC 30 H 43 NO6S2600.2424,found,600.2415.

[0091] Pleuromutilin derivative 18

[0092] 1 H NMR (400MHz, CDCl3) δ6.97 (s, 1H), 6.41 (dd, J = 17.4, 11.0Hz, 1H), 5.73 (d, J = 8. 4Hz,1H),5.30(d,J=11.1Hz,1H),5.16(dd,J=17.4,1.4Hz,1H),3.92(s,2H),3. 33(d,J=6.5Hz,1H),2.53-2.45(m,1H),2.34-2.16(m,3H),2.09-1.98(m,2H),1 .80-1.22(m,19H),1.19-1.06(m,4H),0.98-0.83(m,9H),0.70(d,J=7.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.21,173.35,167.09,160.33,153.77,139.03,1 17.55,103.00,74.84,70.48,58.35,47.50,45.67,44.87,44.18,42.08, 36.94,36.79,36.23,34.69,31.68,30.63,29.77,27.07,26.67,25.49,2 5.06,22.87,17.01,15.03,14.21,12.04,11.74.HRMS(ESI):calcd[M+Na] + forC 38 H 49 NO6S2642.2893,found,642.2871.

[0093] Pleuromutilin derivative 19

[0094] 1 H NMR (400MHz, CDCl3) δ6.92(s,1H),6.49-6.35(m,1H),5.72(d,J=8.7Hz,1H),5.30(d,J=11.1Hz,1H),5.16(d,J=17.4Hz,1H),4.00-3.82(m,2 H),3.33(s,1H),2.35-2.18(m,3H),2.10-1.99(m,2H),1.75-1.32(m,20H),1.18-1.03(m,4H),0.85(d,J=7.1Hz,3H),0.70(d,J=6.4Hz,3H). 13C NMR (101MHz, CDCl3) δ217.19,175.54,167.09,160.28,154.04,139.04,117.54,103.19,74.82,70.48,58.35,45.66,44.87,44. 19,42.08,39.52,36.94,36.81,36.24,34.69,30.63,27.27,27.07,26.69,25.06,17.01,15.04,11.73.HRMS(ESI):calcd[M+Na] + for C 31 H 45 NO6S2614.2580,found,614.2542.

[0095] Pleuromutilin derivative 20

[0096] 1 H NMR (400MHz, CDCl3) δ8.25-8.15(m,2H),7.21-7.11(m,2H),7.09(s,1H),6.48-6.3 6(m,1H),5.74(d,J=8.5Hz,1H),5.30(d,J=1.6Hz,1H),5.14(dd,J=17.5,1.6Hz,1H) ,4.04-3.86(m,2H),3.33(d,J=6.5Hz,1H),2.36-2.14(m,3H),2.12-1.99(m,2H),1 .79-1.26(m,11H),1.15-1.03(m,4H),0.85(d,J=7.0Hz,3H),0.71(d,J=7.0Hz,3H). 13 C NMR(101MHz, CDCl3)δ217.05,166.77,166.37(d,J=256.1Hz),162.46,160.63,153.24,138.8 0,133.00(d,J=9.6Hz),129.98(d,J=9.4Hz),125.69(d,J=3.1Hz),124.81(d,J=3.1Hz),117.2 9,115.96(d,J=22.1Hz),103.41,74.59,70.29,58.11,45.43,44.56,43.93,41.86,36.70,36 .55,36.00,34.46,30.39,26.83,26.39,24.82,16.78,14.82,11.50.HRMS(ESI):calcd[M+Na] + for C32 H 38 FNO6S2638.2016,found,638.2012.

[0097] Pleuromutilin derivative 21

[0098] 1 H NMR (400MHz, CDCl3) δ7.97 (dt, J=7.7, 1.3Hz, 1H), 7.90-7.81 (m, 1H), 7.52-7.44 (m, 1H), 7.41-7.3 1(m,1H),7.10(s,1H),6.42(dd,J=17.4,11.0Hz,1H),5.74(d,J=8.4Hz,1H),5.30(d,J=1.5Hz,1H) ,5.14(dd,J=17.4,1.5Hz,1H),4.03-3.86(m,2H),3.32(t,J=7.3Hz,1H),2.37-2.15(m,3H),2.09- 1.98(m,2H),1.79-1.31(m,11H),1.17-1.05(m,4H),0.85(d,J=7.0Hz,3H),0.71(d,J=6.9Hz,3H). 13 C NMR(101MHz, CDCl3)δ217.21,166.96,162.80(d,J=247.9Hz),162.54(d,J=3.3Hz),160.99,1 53.31,139.05,130.92(d,J=7.6Hz),130.60(d,J=7.8Hz),126.31(d,J=3.2Hz),121.41(d,J=2 1.2Hz),117.51,117.28,103.70,74.81,70.54,58.33,45.66,44.80,44.17,42.08,36.93,36 .75,36.24,34.69,30.62,27.06,26.62,25.06,17.01,15.05,11.73.HRMS(ESI):calcd[M+Na] + forC 32 H 38 FNO6S2 638.2016,found,638.2008.

[0099] Pleuromutilin derivative 22

[0100] 1H NMR (400MHz, CDCl3) δ8.08-8.01(m,1H),7.72(dt,J=6.7,1.3Hz,1H),7.45-7.37(m,2H),7. 14(s,1H),6.41(dd,J=17.5,11.0Hz,1H),5.73(d,J=8.4Hz,1H),5.27(d,J=1.6Hz,1H),5.1 3(dd,J=17.4,1.6Hz,1H),4.02-3.87(m,2H),3.32(s,1H),2.37-2.17(m,3H),2.12-1.96(m ,2H),1.76-1.32(m,11H),1.18-1.04(m,4H),0.84(d,J=7.1Hz,3H),0.70(d,J=6.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.21,166.98,162.41,160.87,153.22,139.02,1 35.11,133.93,132.45,129.99,127.57,123.10,117.50,103.72,74.79, 70.50,58.32,45.64,44.78,44.14,42.06,36.92,36.76,36.21,34.67,3 0.60,27.04,26.59,25.04,17.01,15.05,11.72.HRMS(ESI):calcd[M+Na] + for C 32 H 38 BrNO6S2698.1216,found,698.1207.

[0101] Pleuromutilin derivative 23

[0102] 1H NMR(400MHz, CDCl3)δ8.31(t,J=1.8Hz,1H),8.10(dt,J=7.8,1.3Hz,1H),7.79-7.75(m,1H),7.38(t ,J=7.9Hz,1H),7.11(s,1H),6.42(dd,J=17.4,11.0Hz,1H),5.74(d,J=8.4Hz,1H),5.31(d,J=1.6Hz, 1H),5.14(dd,J=17.5,1.6Hz,1H),4.02-3.87(m,2H),3.33(d,J=6.5Hz,1H),2.38-2.15(m,3H),2.1 0-1.99(m,2H),1.80-1.26(m,11H),1.19-1.04(m,4H),0.85(d,J=7.0Hz,3H),0.72(d,J=7.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.27,166.98,162.33,161.03,153.25,139.03,1 37.21,133.40,130.72,130.48,129.11,122.96,117.54,103.72,74.82, 70.56,58.34,45.67,44.78,44.17,42.09,36.94,36.75,36.23,34.69,3 0.62,27.07,26.62,25.06,17.03,15.07,11.74.HRMS(ESI):calcd[M+H] + for C 32 H 38 BrNO6S2,676.1396,found,676.1344.

[0103] Pleuromutilin derivative 24

[0104] 1H NMR (400MHz, CDCl3) δ8.11-8.01(m,1H),7.55-7.48(m,2H),7.42-7.34(m,1H),7.14(s,1H) ,6.41(dd,J=17.5,11.0Hz,1H),5.73(d,J=8.4Hz,1H),5.29(d,J=1.5Hz,1H),5.13(dd,J=1 7.4,1.6Hz,1H),4.04-3.88(m,2H),3.31(d,J=6.5Hz,1H),2.34-2.14(m,3H),2.09-1.97(m ,2H),1.78-1.29(m,11H),1.17-1.05(m,4H),0.84(d,J=7.0Hz,3H),0.70(d,J=7.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.21,166.98,161.92,160.86,153.23,139.02,1 35.16,133.95,132.45,131.77,128.08,126.99,117.49,103.74,74.80, 70.50,58.32,45.65,44.78,44.14,42.07,36.92,36.76,36.21,34.68,3 0.61,27.04,26.58,25.04,17.00,15.05,11.72.HRMS(ESI):calcd[M+H] + for C 32 H 38 ClNO6S2 632.1901,found,632.1867.

[0105] Pleuromutilin derivative 25

[0106] 1H NMR (400MHz, CDCl3) δ8.04(d,J=8.5Hz,1H),7.54(d,J=2.0Hz,1H),7.36(dd,J=8.5,2.0Hz,1H) ,7.12(s,1H),6.41(dd,J=17.4,11.0Hz,1H),5.74(d,J=8.4Hz,1H),5.30(d,J=1.6Hz,1H),5.14 (dd,J=17.4,1.6Hz,1H),4.01-3.86(m,2H),3.32(t,J=7.4Hz,1H),2.34-2.14(m,3H),2.09-1. 98(m,2H),1.82-1.27(m,11H),1.18-1.04(m,4H),0.85(d,J=7.0Hz,3H),0.70(d,J=7.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.19,166.96,161.07,161.06,153.02,139.94,1 39.06,136.41,133.48,131.77,127.47,126.33,117.50,103.86,74.81, 70.54,58.33,45.66,44.81,44.16,42.08,36.92,36.76,36.23,34.69,3 0.61,27.06,26.62,25.06,17.02,15.06,11.73.HRMS(ESI):calcd[M+Na] + forC 32 H 37 Cl2NO6S2 688.1331,found,688.1309.

[0107] Pleuromutilin derivative 26

[0108] 1H NMR (400MHz, CDCl3) δ8.17-8.05(m,1H),7.61(dt,J=5.5,1.7Hz,1H),7.30-7.18(m,2H),7. 11(s,1H),6.41(dd,J=17.4,11.0Hz,1H),5.74(d,J=8.4Hz,1H),5.29(d,J=3.6Hz,1H),5.1 3(dd,J=17.4,1.5Hz,1H),4.03-3.86(m,2H),3.32(s,1H),2.34-2.16(m,3H),2.11-1.98(m ,2H),1.79-1.32(m,11H),1.17-1.06(m,4H),0.85(d,J=6.9Hz,3H),0.71(d,J=6.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.23, 167.00, 162.69 (d, J = 262.8Hz), 160.91 (d, J = 4.1Hz), 16 0.84,153.22,139.03,135.97(d,J=9.2Hz),132.76,124.44(d,J=3.9Hz),117.65,117. 50,117.43,103.82,74.81,70.51,58.34,45.66,44.80,44.15,42.08,36.94,36.77,36 .23,34.69,30.62,27.05,26.57,25.05,16.99,15.04,11.73.HRMS(ESI):calcd[M+Na] + for C 32 H 38 FNO6S2638.2016,found,638.2019.

[0109] Pleuromutilin derivative 27

[0110] 1H NMR (400MHz, CDCl3) δ8.06-7.94(m,2H),7.47-7.33(m,2H),7.10(d,J=0.8Hz,1H),6.42(dd, J=17.5,11.0Hz,1H),5.74(d,J=8.5Hz,1H),5.31(d,J=1.5Hz,1H),5.14(dd,J=17.4,1.5Hz,1 H),4.07-3.87(m,2H),3.33(d,J=6.6Hz,1H),2.43(s,3H),2.35-2.15(m,2H),2.12-1.97(m,2 H),1.86-1.29(m,11H),1.14(d,J=25.5Hz,4H),0.85(d,J=6.9Hz,3H),0.72(d,J=6.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.25,167.03,163.82,160.64,153.72,139.02,13 8.75,135.05,131.02,128.78,128.68,127.75,117.54,103.52,74.83,70. 50,58.35,45.66,44.80,44.16,42.09,36.95,36.80,36.23,34.70,30.63, 27.06,26.61,25.06,21.53,17.02,15.06,11.74.HRMS(ESI):calcd[M+Na] + forC 33 H 41 NO6S2634.2267,found,634.2226.

[0111] Pleuromutilin derivative 28

[0112] 1H NMR (400MHz, CDCl3) δ7.83-7.74(m,1H),7.66(t,J=2.0Hz,1H),7.46-7.35(m,1H),7.21-7.13(m, 1H),7.09(s,1H),6.41(dd,J=17.5,11.0Hz,1H),5.74(d,J=8.4Hz,1H),5.30(d,J=1.5Hz,1H),5.1 4(dd,J=17.4,1.5Hz,1H),4.04-3.77(m,5H),3.32(d,J=6.7Hz,1H),2.36-2.14(m,3H),2.12-1.97 (m,2H),1.75-1.30(m,11H),1.13(d,J=25.1Hz,4H),0.85(d,J=6.7Hz,3H),0.71(d,J=7.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ217.21,167.00,163.57,160.71,159.92,153.62,13 9.02,130.01,129.90,122.99,120.87,117.51,114.74,103.64,74.80,70. 51,58.33,55.78,45.65,44.80,44.16,42.07,36.93,36.78,36.22,34.68 ,30.61,27.04,26.61,25.05,17.01,15.05,11.72.HRMS(ESI):calcd[M+H] + for C 33 H 41 NO6S2 628.2397,found,628.2347.

[0113] Effect Test Example 1

[0114] The pleuromutilin derivatives 1 to 28 containing 2-thio-4-thiazolidinone side chains prepared in Example 3 were subjected to antibacterial tests:

[0115] The minimum inhibitory concentrations (MICs) of pleuromutilin derivatives 1 to 28 containing a 2-thio-4-thiazolidinone side chain against methicillin-resistant Staphylococcus aureus, Staphylococcus aureus (S. aureus-25923), Escherichia coli, Streptococcus agalactiae (S. agalactiae), and Streptococcus dysgalactiae (S. dysgalactiae-1) were determined by a two-fold dilution method. The results are shown in Table 2. The standard strains were purchased from ATCC, and the clinical strains were deposited at the Lanzhou Institute of Animal Husbandry and Veterinary Drugs, Chinese Academy of Agricultural Sciences.

[0116] Table 2 Minimum inhibitory concentration of pleuromutilin derivatives in vitro

[0117]

[0118]

[0119] As can be seen from Table 2, this type of pleuromutilin derivatives has good inhibitory effects on MRSA and S. aureus-25923. Among them, the pleuromutilin derivative 19 has the best antibacterial effect, and its MIC value is comparable to that of the control drug tiamulin, while its inhibitory effect on S. agalactiae and S. dysgalactiae-1 is better than that of tiamulin.

[0120] Effect Test Example 2

[0121] Study on the bactericidal kinetic curve of pleuromutilin derivatives:

[0122] According to the results of the MIC experiment, the truncated pleuromutilin derivative 19 with better activity was screened out, and its bactericidal kinetic curve against MRSA was studied. Preparation of drug solution: truncated pleuromutilin derivative 19 and tylosin (T) were prepared into drug solutions with concentrations of 1×MIC, 4×MIC, and 6×MIC, respectively; another bacterial growth tube was taken as the control group. 50μL of bacterial solution was added to tubes with different concentrations, mixed, and placed in a 37°C shaker for culture. Then, 100μL of samples were taken at 0, 2, 4, 6, 8, 12, and 24h, mixed, and then 100μL was taken from this 1mL and added to 900μL of normal saline; diluted in a 10-fold gradient in sequence. Take 100μL of bacterial solution with different dilution multiples and evenly spread it on the MHA culture medium, and make 3 parallels for each dilution concentration. The culture medium was placed in a 37°C constant temperature incubator for culture for 24h, after which the colonies were counted, and a curve was drawn based on the statistical results. The bactericidal kinetic curve is shown as follows. Figure 3As shown. Principle of colony count calculation: The number of colonies between 30-300 is considered an effective dilution. The formula for calculating the number of bacteria in the bacterial solution is: the number of viable bacteria per ml of the original bacterial solution = the average number of colonies on 3 replicate plates of the same dilution × dilution factor × 10. Repeat the experiment three or more times. Figure 3 As can be seen, each compound exhibited concentration-dependent effects. Compared with the control group, the pleuromutilin derivative 19 and the control drug at 1×MIC slowed down bacterial growth; at 4×MIC and 6×MIC, the pleuromutilin derivative 19 and the control drug had a bactericidal effect against MRSA.

[0123] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A pleuromutilin derivative containing a 2-thio-4-thiazolidinone side chain, characterized in that: The molecular structure of the compound is shown in the following formula (I): In the formula, the R group is selected from any one of the following groups:

2. A pharmaceutically acceptable salt of the pleuromutilin derivative containing a 2-thioxo-4-thiazolidinone side chain as claimed in claim 1.

3. A method for preparing a pleuromutilin derivative containing a 2-thioxo-4-thiazolidinone side chain as claimed in claim 1, characterized in that: The following steps are involved: (1) Pleuromutilin and p-toluenesulfonyl chloride are added to methyl tert-butyl ether and mixed, and sodium hydroxide solution is added dropwise under stirring. After reflux reaction, the reaction product is cooled, washed, and dried to obtain intermediate 1 having the structure shown in formula (II); (2) adding 2-thioxo-4-thiazolidinone to acetonitrile, adding anhydrous potassium carbonate and stirring at room temperature for a certain period of time, then adding the intermediate 1, stirring at room temperature for a certain period of time, and after the reaction is completed, quenching, extracting, drying, and purifying the reaction product to obtain the intermediate 2 with the structure shown in formula (III); (3) adding the intermediate 2 and the group donor acyl chloride to dichloromethane, stirring and reacting at room temperature for a certain time under the catalysis of triethylamine, quenching after the reaction is completed, and extracting, drying, and purifying the reaction product to obtain a pleuromutilin derivative containing a 2-thioxo-4-thiazolidinone side chain as shown in formula (I); In the formula, the R group is selected from any one of the following groups:

4. The preparation method according to claim 3, wherein In step (1), the molar volume ratio of the pleuromutilin, p-toluenesulfonyl chloride, methyl tert-butyl ether and sodium hydroxide solution is 10-12 mmol: 10-12 mmol: 10-15 mL: 2.5-2.8 mL, and the concentration of the sodium hydroxide solution is 10 mol / L.

5. The preparation method according to claim 3, wherein In step (2), the molar volume ratio of the intermediate 1, 2-thioxo-4-thiazolidinone, potassium carbonate and acetonitrile is 5-9 mmol: 5-6 mmol: 6-10 mmol: 30-35 mL.

6. The preparation method according to claim 3, wherein In step (2), the quenching, extraction, drying and purification of the reaction product are as follows: the reactant is quenched with a saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, dried with anhydrous sodium sulfate, and purified by column chromatography according to a ratio of petroleum ether: ethyl acetate = 3:1 to 2:

1.

7. The preparation method according to claim 3, wherein In step (3), the molar volume ratio of the intermediate 2, the group donor acyl chloride, triethylamine and dichloromethane is 1-1.2 mmol: 1-1.5 mmol: 2-2.4 mmol: 5-7 mL.

8. The preparation method according to claim 3, wherein The quenching, extraction, drying and purification methods of the reaction product are as follows: the reactant is quenched with a saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, dried with anhydrous sodium sulfate, and purified by column chromatography according to a ratio of petroleum ether to ethyl acetate of 4:1 to 2:

1.

9. Use of the pleuromutilin derivative containing a 2-thioxo-4-thiazolidinone side chain according to claim 1 or the pharmaceutically acceptable salt of the pleuromutilin derivative according to claim 2 in the preparation of antibacterial drugs for treating infectious diseases.

10. An antibacterial drug, characterized in that: The drug comprises the pleuromutilin derivative containing a 2-thio-4-thiazolidinone side chain according to claim 1 and one or more pharmaceutically acceptable carriers, excipients or diluents for the pleuromutilin derivative; Alternatively, the drug comprises a pharmaceutically acceptable salt of the pleuromutilin derivative according to claim 2 and one or more pharmaceutically acceptable carriers, excipients or diluents for the salt.

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