A bis-thiazole-containing amide derivative, a preparation method and application thereof

Abstract

This application discloses a method for preparing amide derivatives containing bisthiazole according to general formula III in the field of organic chemistry, wherein the substituent R1 is phenyl, substituted phenyl, thiazolyl, cyclopropyl, or an alkyl group of 1 to 3 carbons; or R2 is an alkyl group of 1 to 3 carbons. The compounds provided in this application possess potent antibacterial activity against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA), and they show broad application prospects in treating infectious diseases caused by these bacteria. Furthermore, these compounds can be used in combination with other antibacterial active substances to further enhance antibacterial effects or broaden the antibacterial spectrum, providing a more effective means of treating complex infections.

Description

Technical Field

[0001] This invention relates to the field of organic chemistry, specifically to an amide derivative containing bithiazole, its preparation method, and its application. Background Technology

[0002] The discovery of antibiotics has gradually brought the harm caused by bacterial infectious diseases under control. However, with the widespread use of antibiotics, various forms of antibiotic abuse have also emerged. This has not only led to the emergence of drug-resistant bacteria but also made the treatment of infectious diseases more difficult, resulting in increased morbidity and mortality rates. This poses a serious challenge to global healthcare and poses a threat to people's health and lives, and has become one of the major global health problems. Therefore, the development of new antibacterial drugs with low resistance, significant efficacy, and high safety is urgently needed. Summary of the Invention

[0003] This invention utilizes medicinal chemistry and drug design theories to design and synthesize a series of novel amide derivatives containing bithiazoles for antibacterial activity studies. Results show that some target compounds exhibit excellent antibacterial activity against both Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA), with particularly significant activity against MRSA, far superior to the control drug.

[0004] The main objective of this invention is to provide amide derivatives containing bithiazole, with the structure shown in general formula III:

[0005]

[0006] Wherein, R1 is a phenyl or substituted phenyl or thiazolyl or cyclopropyl or an alkyl group of 1 to 3 carbons; or R2 is an alkyl group of 1 to 3 carbons.

[0007] Synthetic route of the amide derivative containing bithiazole:

[0008]

[0009] Based on the above synthetic route, the method for preparing the amide derivative containing bithiazole includes the following steps:

[0010] S1. Preparation of Intermediate I: Dibenzothiazole disulfide, 1,2-dichloroethane, aminothiazolic acid and triethylamine were added sequentially to a reaction flask and stirred at 10-15°C. After stirring, triethyl phosphite or a dehydrating agent was added and reacted. After thin-layer chromatography, the mixture was filtered to obtain a crude product. The crude product was recrystallized to obtain a pale yellow powder, which is Intermediate I.

[0011] S2. Preparation of intermediate II: Boc-glycine, reagent A and dichloromethane were placed in a reaction flask and reacted at 0-40℃. Then, substituted thiazol-2-amine was added and the reaction was continued with stirring. After the reaction was completed, the mixture was filtered, the solvent was concentrated, and then trifluoroacetic acid and dichloromethane were added. The reaction was completed at 5-10℃. The solvent was then concentrated to obtain intermediate II.

[0012] The reagent A is selected from the combination of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole; or the combination of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole and 4-dimethylaminopyridine; or the combination of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine;

[0013] S3. Preparation of Compound III: Intermediate I, Intermediate II, triethylamine and tetrahydrofuran were placed in a reaction flask and stirred at 0-20°C until the reaction was complete. The solvent was concentrated and purified by thin-layer chromatography using silica gel plates to obtain Compound III.

[0014] Furthermore, the dehydrating agent is selected from concentrated sulfuric acid, concentrated phosphoric acid, or triphenylphosphine.

[0015] The amide derivatives containing dithiazole provided in this invention represent a novel class of compounds with potential antibacterial activity. Their antibacterial spectrum includes Staphylococcus aureus, Escherichia coli, methicillin-resistant Staphylococcus aureus (MRSA), and fluoroquinolone-resistant Escherichia coli (FREC), showing broad application prospects in treating infectious diseases caused by these bacteria. Furthermore, these compounds can be used in combination with other antibacterial active substances to further enhance antibacterial efficacy or broaden the antibacterial spectrum, providing a more effective means of treating complex infections.

[0016] The specific compounds shown below exhibit significant antibacterial effects against two common pathogens: Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA).

[0017]

[0018]

[0019] Compound IIIv showed better inhibitory effects on S. aureus than the control drug oxacillin, compound IIIw showed comparable inhibitory effects on S. aureus to oxacillin, and compounds IIIh and IIIt showed inhibitory effects on S. aureus that were close to those of oxacillin.

[0020] Most of these compounds exhibit superior activity against MRSA compared to oxacillin. For example:

[0021]

[0022] etc.

[0023] In particular, compounds IIIh, IIIt, IIIv and IIIw showed antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) that was 20 to 60 times that of the control drug oxacillin. Detailed Implementation

[0024] The present invention will be further described below with reference to the embodiments. However, the present invention is not limited to the following embodiments. It is foreseeable that various changes may occur in the implementation when those skilled in the art combine it with the prior art.

[0025] This invention discloses an amide derivative containing bithiazole, with general structural formula III and a synthetic route as follows:

[0026]

[0027] The specific structures, relevant NMR data, and physicochemical properties of the amide derivatives containing dithiazole of this invention are as follows:

[0028]

[0029] Ⅲa: White solid, mp 124~126℃; 1 H NMR(400MHz, DMSO-d6)δ:12.19(s,1H),9.17(t,J=5.9Hz,1H),8.07(d,J=2.1Hz,1H),7.88-7.7 7(m,2H),7.67(d,J=8.4Hz,1H),7.43(s,2H),7.06(s,1H),4.13(d,J=5.7Hz,2H),3.84(s,3H). 13 C NMR(101MHz,DMSO-d6)δ:169.22,168.62,163.58,158.65,149.57,146.72,143.03 ,135.07,132.08,131.52,130.64,127.91,126.21,111.08,109.66,62.52,42.17.

[0030]

[0031] IIIb: White solid, mp 135~137℃; 1H NMR (400MHz, DMSO-d6) δ: 11.97 (s, 1H), 9.30 (t, J = 6.0Hz, 1H), 7.64 (s, 2H), 7.47-7.40 ( m,1H),7.30-7.20(m,4H),7.06(s,1H),4.14(d,J=5.7Hz,2H),3.84(s,3H),2.35(s,3H). 13 C NMR(101MHz,DMSO-d6)δ:169.78,168.65,163.79,157.61,149.42,149.08,142.65,135.89, 134.58,131.23,129.71,128.43,126.42,111.97,108.02,62.58(d,J=3.3Hz),42.26,21.10.

[0032]

[0033] IIIc: Oily, 1 H NMR(400MHz, DMSO-d6)δ:12.08(s,1H),9.27(d,J=6.1Hz,1H),7.61(d,J=33.2Hz,5H),7.3 2(t,J=7.6Hz,1H),7.15(d,J=9.1Hz,2H),4.21(d,J=6.3Hz,2H),3.91(s,3H),2.67(s,3H). 13 C NMR(101MHz,DMSO-d6)δ:169.64,168.64,165.11,163.76,158.46,149.51,142.81,13 8.48,134.43,129.23,129.08,126.93,123.43,109.05,108.83,62.62,42.31,21.56.

[0034]

[0035] IIId: White solid, mp 117~119℃; 1 H NMR(400MHz, DMSO-d6)δ:12.06(s,1H),9.24(t,J=6.0Hz,1H),7.69(d,J=7.9Hz,2H),7.62(s,2H), 7.53(s,1H),7.22(d,J=7.9Hz,2H),7.09(s,1H),4.15(d,J=5.8Hz,2H),3.86(s,3H),2.29(s,3H). 13C NMR (101MHz, DMSO-d6) δ: 169.53, 168.59, 163.69, 158.39, 149.46 (d, J = 8.5Hz), 142.83, 137.73, 131.82, 129.88 (d,J=4.0Hz),126.20,108.87(d,J=6.6Hz),108.38(d,J=5.0Hz),62.57(d,J=8.0Hz),42.23,21.24(d,J=1.7Hz).

[0036]

[0037] IIIe: Oily, 1 H NMR (400MHz, DMSO-d6) δ: 12.19 (s, 1H), 9.30 (t, J = 5.9Hz, 1H), 7.97 (dt, J = 8.6, 4.2Hz, 1H), 7.62 (d, J = 2.4Hz, 1H),7.57(s,2H),7.47-4.71(m,1H),7.37(t,J=7.0Hz,2H),7.16(s,1H),4.22(d,J=5.8Hz,2H),3.94(s,3H). 13 C NMR(101MHz,DMSO-d6)δ:169.45,168.68,163.72,157.96,149.47,142.98,142.83,130. 23(d,J=8.5Hz),129.68,125.40,116.81,116.59,113.48,113.35,109.17,62.61,42.23.

[0038]

[0039] IIIf: White solid, mp 202~203℃; 1 H NMR(400MHz, DMSO-d6)δ:12.12(s,1H),9.19(t,J=5.9Hz,1H),7.74(s,1H),7.69-7.58(m,2 H),7.53-7.41(m,3H),7.14-7.10(m,1H),7.08(s,1H),4.15(d,J=5.8Hz,2H),3.86(s,3H). 13C NMR (101MHz, DMSO-d6) δ: 169.39, 168.66, 164.22, 163.64, 161.80, 158.55, 149.55, 148.01 (d, J = 2.7Hz), 142.93, 136.86 (d, J = 8.2Hz) ,131.35(d,J=8.3Hz),122.24(d,J=2.7Hz),115.07(d,J=21.0Hz),112.81(d,J=22.9Hz),110.50,109.34,62.56(d,J=4.6Hz),42.22.

[0040]

[0041] IIIg: White solid, mp 140~142℃. 1 H NMR (400MHz, DMSO-d6) δ: 12.08 (s, 1H), 9.21 (t, J = 6.0Hz, 1H), 7.87-7.82 (m, 2H), 7.60 (s, 1H),7.54(s,2H),7.24(t,J=8.9Hz,2H),7.08(s,1H),4.14(d,J=5.8Hz,2H),3.85(s,3H). 13 C NMR(101MHz,DMSO-d6)δ:169.48,168.62,163.69,163.49,161.06,158.57,149.51,148.33,142.86,131.1 1(d,J=3.1Hz),128.29(d,J=8.3Hz),116.15(d,J=21.6Hz),109.62–108.43(m),62.58(d,J=3.9Hz),42.23.

[0042]

[0043] IIIh: White solid, mp 232~234℃. 1 H NMR(400MHz, DMSO-d6)δ:12.12(s,1H),9.21(t,J=5.9Hz,1H),7.96-7.82(m,1H),7.53-7.45(m, 3H, ArH), 7.33-7.28 (m, 1H), 7.16-7.10 (m, 1H), 7.07 (s, 1H), 4.15 (d, J = 5.9Hz, 2H), 3.85 (s, 3H). 13C NMR (101MHz, DMSO-d6) δ: 169.42, 168.67, 163.66, 161.18 (d, J = 12.9Hz), 16 0.77(d,J=12.6Hz),158.67(d,J=12.8Hz),158.02,149.54,142.92,142.16 (d,J=2.3Hz),130.89(m,J=9.3,4.7Hz),119.06(m,J=11.8,3.7Hz),112.90 ,109.21(d,J=11.6Hz),105.15(d,J=10.4Hz),62.55(d,J=11.8Hz),42.22.

[0044]

[0045] IIIi: White solid, mp 124~125℃; 1 H NMR (400MHz, DMSO-d6) δ: 12.00 (s, 1H), 9.30 (t, J = 6.0Hz, 1H, 7.61 (s, 2H), 7.53 (d, J=8.1Hz,2H),7.38-7.31(m,2H),7.05(s,1H),4.14(d,J=5.8Hz,2H),3.84(s,3H). 13 C NMR(101MHz,DMSO-d6)δ:169.79,168.74,163.87,157.74,149.30,145.90,142.53,133.25 ,131.54(d,J=6.9Hz),130.72,130.13,127.92,113.82,108.18,62.62(d,J=3.0Hz),42.24.

[0046]

[0047] Ⅲj: White solid, mp 131~132℃; 1 H NMR (400MHz, DMSO-d6) δ: 12.18 (d, J = 5.6Hz,

[0048] 1H),9.29–9.12(m,1H),7.90–7.89(m,1H),7.79(d,J=4.8Hz,2H),7.46-7.40(m,3H),7 .37(dd,J=7.9,2.0Hz,1H),7.08(d,J=9.5Hz,1H),4.14(t,J=7.1Hz,2H),3.86(s,3H). 13CNMR(101MHz,DMSO-d6)δ:169.27,168.61,163.60,158.53,149.57,147.70,143.0 1,136.52,134.10,131.23,128.11,125.93,124.70,110.54,109.61,62.53,42.19.

[0049]

[0050] IIIk: White solid, mp 134~136℃; 1 H NMR (400MHz, DMSO-d6) δ: 12.08 (s, 1H), 9.21 (t, J = 6.0Hz, 1H), 7.81 (d, J = 8.5Hz, 2H), 7.66 (s,1H),7.53(s,2H),7.49-7.43(m,2H),7.07(s,1H),4.14(d,J=5.8Hz,2H),3.85(s,3H). 13 C NMR(101MHz,DMSO-d6)δ:169.44,168.65,163.69,158.63,149.48,148.09 ,142.84,133.33,132.89,129.33,127.96,109.91,109.10,62.60,42.22.

[0051]

[0052] IIIl: White solid, mp 144~146℃; 1 H NMR (400MHz, DMSO-d6) δ: 12.19 (s, 1H), 9.17 (s, 1H), 8.07 (d, J = 2.1Hz, 1H), 7.85-7.78 (m, 2H),7.67(d,J=8.4Hz,1H),7.43(s,2H),7.06(s,1H),4.13(d,J=5.7Hz,2H),3.84(s,3H). 13 C NMR(101MHz,DMSO-d6)δ:169.22,168.62,163.58,158.65,149.57,146.72,143.03 ,135.07,132.08,131.52,130.64,127.91,126.21,111.08,109.66,62.52,42.17.

[0053]

[0054] Ⅲm: White solid, mp 124~126℃; 1 H NMR(400MHz, DMSO-d6)δ:12.02(s,1H),9.33(d,J=6.0Hz,1H),7.75(d,J=8.0Hz,1H),7.66(s,2H),7.59(dd,J=7.7,1 .8Hz,1H),7.54-7.43(m,2H),7.35(dt,J=7.8,3.9Hz,1H),7.09(d,J=4.3Hz,1H),4.18(d,J=5.9Hz,2H),3.89(s,3H). 13 C NMR(101MHz,DMSO-d6)δ:169.85,168.77,163.84,157.78,149.41,147.62,142.62 ,135.62,133.86,131.83,130.45,128.37,121.87,113.50,107.90,62.63,42.30.

[0055]

[0056] Ⅲn: White solid, mp 134~135℃; 1 H NMR(400MHz, DMSO-d6)δ:12.17(s,1H),9.17(t,J=5.9Hz,1H),8.04(t,J=1.9Hz,1H),7.82(dt,J=7.7,1.3Hz,1H ),7.77(s,1H),7.50(dd,J=8.1,2.0Hz,1H),7.47-7.34(m,3H),7.07(s,1H),4.13(d,J=5.8Hz,2H),3.84(s,3H). 13 C NMR(101MHz,DMSO-d6)δ:169.26,168.59,163.60,158.52,149.56,147.58,143.00 ,136.74,131.50,131.00,128.82,125.05,122.70,110.51,109.66,62.54,42.18.

[0057]

[0058] IIIo: White solid, mp 140~142℃; 1H NMR(400MHz, DMSO-d6)δ:12.11(s,1H),9.22(t,J=6.0Hz,1H),7.77–7.72(m,2H), 7.67(s,1H),7.62–7.52(m,4H),7.08(s,1H),4.15(d,J=5.7Hz,2H),3.85(s,3H). 13 C NMR(101MHz,DMSO-d6)δ:169.44,168.66,163.68,158.64,149.50,148.14,142. 88,133.69,132.23,128.26,121.50,109.97,109.12,62.58(d,J=4.6Hz),42.22.

[0059]

[0060] IIIp: White solid, mp 100~102℃; 1 H NMR(400MHz, DMSO-d6)δ:11.88(s,1H),9.35(d,J=5.9Hz,1H),7.76(s,2H),7.68(s,1H),7.56- 7.51(m,3H),7.12(d,J=3.5Hz,1H),4.19(d,J=5.8Hz,2H),3.90(d,J=3.6Hz,3H),2.47(s,3H). 13 C NMR(101MHz,DMSO-d6)δ:170.83,169.87,168.60,163.83,154.92,149.39,143.3 7,142.57,133.84,132.00,130.55,122.91,121.28,107.60,62.62,42.21,12.04.

[0061]

[0062] Ⅲq: White solid, mp 159~161℃. 1 H NMR(400MHz, DMSO-d6)δ:12.00(s,1H),9.24(t,J=6.0Hz,1H),7.91–7.83(m,1H),7.63(s,1H),7.57(s,2H ),7.33(t,J=7.8Hz,1H),7.12(d,J=8.6Hz,2H),7.04(t,J=7.5Hz,1H),4.18(d,J=5.9Hz,2H),3.89(s,6H). 13C NMR(101MHz,DMSO-d6)δ:169.59,168.53,163.73,156.99,156.94,149.52,145.32,14 2.80,129.55,129.41,122.89,121.02,112.64,112.13,108.80,62.61,55.88,42.29.

[0063]

[0064] IIIr: White solid, mp 114~115℃. 1 H NMR(400MHz, DMSO-d6)δ:12.31–12.09(m,1H),9.29(t,J=5.8Hz,1H),7.62(s,1H),7.40(d,J=7.8Hz,2H) ,7.30(t,J=7.8Hz,1H),7.14(s,1H),6.94-6.78(m,1H),4.18(d,J=5.8Hz,2H),3.89(s,3H),3.76(s,3H). 13 C NMR(101MHz,DMSO-d6)δ:170.18,168.40,162.78,160.05,158.24,149.22,148.17,139.93,135.88 ,130.32,118.52,114.19,111.34,109.77,109.33,62.79(d,J=4.3Hz),55.42(d,J=4.2Hz),42.24.

[0065]

[0066] IIIs: White solid, mp 221~222℃; 1 H NMR(400MHz, DMSO-d6)δ:12.02(s,1H),9.22(t,J=6.0Hz,1H),7.73(d,J=8.5Hz,2H),7.59(s,2H), 7.45(s,1H),7.08(s,1H),6.97(d,J=8.8Hz,2H),4.13(d,J=5.8Hz,2H),3.85(s,3H),3.76(s,3H). 13C NMR(101MHz,DMSO-d6)δ:169.49,168.53,163.66,159.49,158.32,149.51,149.22,142.82 ,127.60,127.29,114.65,108.90,107.28,62.57(d,J=4.5Hz),55.59(d,J=4.3Hz),42.22.

[0067]

[0068] Ⅲt: Yellow solid, mp 132~134℃; 1 H NMR(400MHz, DMSO-d6)δ:12.07(s,1H),9.17(t,J=5.9Hz,1H),7.90(d,J=8.0Hz,1H),7.75-7.69(m, 2H),7.60-7.53(m,1H),7.53(s,1H),7.39(s,2H),7.04(s,1H),4.13(d,J=5.8Hz,2H),3.83(s,3H). 13 C NMR(101MHz,DMSO-d6)δ:169.28,168.67,163.60,158.27,149.59,148.96,145.28,143. 02,133.20,131.42,129.92,128.66,124.58,112.77,109.61,62.52(d,J=1.9Hz),42.14.

[0069]

[0070] IIIu: Yellow solid, mp 165~167℃; 1 H NMR(400MHz, DMSO-d6)δ:12.20(s,1H),9.18(t,J=6.0Hz,1H),8.61(t,J=2.0Hz,1H),8.24(d,J=7.8Hz,1H),8.15(dd, J=8.3,2.4Hz,1H),7.88(s,1H),7.70(t,J=8.0Hz,1H),7.39(s,2H),7.06(s,1H),4.13(d,J=5.8Hz,2H),3.84(s,3H). 13C NMR(101MHz,DMSO-d6)δ:169.31,168.65,163.73,158.81,149.42,148.73,146.88 ,142.86,135.91,132.30,130.98,122.91,120.58,111.53,109.70,60.31,42.18.

[0071]

[0072] IIIv: White solid, mp 182~184℃; 1 H NMR(400MHz, DMSO-d6)δ:12.28(s,1H),9.20(t,J=5.8Hz,1H),7.91(d,J=3.4Hz,1H),7.83(d,J=3.9H z,1H),7.78(d,J=3.3Hz,1H),7.48(s,2H),7.08(d,J=3.9Hz,1H),4.16(d,J=5.8Hz,2H),3.88(s,3H). 13 C NMR (101MHz, DMSO-d6) δ: 169.34, 168.82, 163.65, 162.33, 159.00, 149.55, 144.35, 143.54, 142.96, 120.93, 111.81, 109.42, 62.58, 42.21.

[0073]

[0074] IIIw: White solid, mp 126~128℃; 1 H NMR (400MHz, DMSO-d6) δ: 11.76 (s, 1H), 9.23 (t, J = 6.0Hz, 1H), 7.74 (s, 2H), 7.05 (s, 1H), 6.81 (s, 1H), 4. 06(d,J=5.9Hz,2H),3.83(s,3H),1.92(t,J=4.8Hz,1H),0.86–0.82(m,2H),0.66(dd,J=4.9,2.1Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ:169.68,168.26,163.69,157.84,152.71,149.40,142.65,10 8.29,108.04,106.44,106.27,62.56(d,J=18.9Hz),42.15,12.22(d,J=10.0Hz),7.89.

[0075]

[0076] Ⅲx: White solid, mp 125~127℃; 1 H NMR (400MHz, DMSO-d6) δ: 11.70 (s, 1H), 9.31 (t, J = 6.1Hz, 1H), 8.03 (s, 2H), 7.06 (s, 1H), 6. 83(s,1H),4.08(d,J=6.1Hz,2H),3.84(s,3H),2.57(d,J=7.6Hz,2H),1.15(t,J=7.5Hz,3H). 13 C NMR (101MHz, DMSO-d6) δ: 170.14, 168.44, 163.88, 158.04, 152.64, 149.34, 142.49, 107.81, 107.00, 62.64, 42.25, 24.35, 13.76.

[0077]

[0078] Ⅲy: White solid, mp 154~155℃; 1 H NMR (400MHz, DMSO-d6) δ: 11.70 (s, 1H), 9.36 (t, J = 6.1Hz, 1H), 8.09 (s, 2H ) ,7.10(s,1H),6.84(s,1H),4.12(d,J=6.1Hz,2H),3.87(s,3H),2.24(s,3H). 13 C NMR (101MHz, DMSO-d6) δ: 170.29, 168.42, 164.00, 157.91, 149.26, 146.44, 142.41, 109.04, 106.87, 62.68, 42.25, 16.68.

[0079] The following examples illustrate the specific preparation method of the amide derivative containing bithiazole of the present invention.

[0080] Example 1: Preparation of compound IIIh

[0081] 13.5 mmol of dibenzothiazole disulfide, 30 mL of 1,2-dichloroethane, 10 mmol of aminothiazic acid, and 10 mmol of triethylamine were added sequentially to a reaction flask. The mixture was stirred at 15 °C for 1.5 h, and then 6.75 mmol of triphenylphosphine was added and reacted for another 6 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the mixture was filtered to obtain the crude product. Recrystallization yielded a pale yellow powder, which is intermediate I.

[0082] Weigh 3 mmol of Boc-glycine, 3.5 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 3.5 mmol of 1-hydroxybenzotriazole, and 5 mL of dichloromethane into a reaction flask. React at 20 °C for 5 min. Then add 2 mmol of 4-(2,4-difluorophenyl)thiazole-2-amine and continue stirring for 6 h. After the reaction is complete, filter and concentrate the solvent. Then add 12 mmol of trifluoroacetic acid and 5 mL of dichloromethane into the reaction flask and react at 5 °C for 2 h. After the reaction is complete, concentrate the solvent to obtain intermediate II.

[0083] 1 mmol of intermediate I, 2 mmol of intermediate II, 3 mmol of triethylamine and 15 mL of tetrahydrofuran were weighed into a reaction flask and stirred at 5 °C for 8 h. After the reaction was completed, the solvent was concentrated and purified by thin-layer chromatography on silica gel plate to obtain compound III.

[0084] Example 2: Preparation of compound Ⅲt

[0085] 13.5 mmol of dibenzothiazole disulfide, 30 mL of 1,2-dichloroethane, 10 mmol of aminothiazic acid, and 10 mmol of triethylamine were added sequentially to a reaction flask. The mixture was stirred at 10 °C for 1.5 h, and then 6.75 mmol of concentrated phosphoric acid was added and reacted for 4 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the mixture was filtered to obtain the crude product. Recrystallization yielded a pale yellow powder, which is intermediate I.

[0086] Weigh 3 mmol of Boc-glycine, 3.5 mmol of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 3 mmol of N,N-diisopropylethylamine, and 5 mL of dichloromethane into a reaction flask. React at 15 °C for 5 min. Then add 2 mmol of 4-(2-nitrophenyl)thiazole-2-amine and continue stirring for 6 h. After the reaction is complete, filter and concentrate the solvent. Then add 12 mmol of trifluoroacetic acid and 5 mL of dichloromethane into the reaction flask and react at 8 °C for 2 h. After the reaction is complete, concentrate the solvent to obtain intermediate II.

[0087] 1 mmol of intermediate I, 2 mmol of intermediate II, 3 mmol of triethylamine and 15 mL of tetrahydrofuran were weighed into a reaction flask and stirred at 8 °C for 7 h. After the reaction was completed, the solvent was concentrated and purified by thin-layer chromatography on silica gel plate to obtain compound IIIt.

[0088] Example 3: Preparation of compound IIIv

[0089] 13.5 mmol of dibenzothiazole disulfide, 30 mL of 1,2-dichloroethane, 10 mmol of aminothiazic acid, and 10 mmol of triethylamine were added sequentially to a reaction flask. The mixture was stirred at 12 °C for 1.5 h, and then 6.75 mmol of triethyl phosphite was added and the reaction was carried out for 6 h. Thin-layer chromatography was used to monitor the reaction. After the reaction was completed, the mixture was filtered to obtain the crude product. Recrystallization yielded a pale yellow powder, which is intermediate I.

[0090] Weigh 3 mmol of Boc-glycine, 3.5 mmol of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 3 mmol of N,N-diisopropylethylamine, and 5 mL of dichloromethane into a reaction flask. React at 20 °C for 5 min. Then add 2 mmol of 4-(thiazol-2-yl)thiazol-2-amine and continue stirring for 7 h. After the reaction is complete, filter and concentrate the solvent. Then add 12 mmol of trifluoroacetic acid and 5 mL of dichloromethane into the reaction flask and react at 5 °C for 2 h. After the reaction is complete, concentrate the solvent to obtain intermediate II.

[0091] 1 mmol of intermediate I, 2 mmol of intermediate II, 3 mmol of triethylamine and 15 mL of tetrahydrofuran were weighed into a reaction flask and stirred at 10 °C for 5 h. After the reaction was completed, the solvent was concentrated and purified by thin-layer chromatography on silica gel plate to obtain compound IIIv.

[0092] Example 4: Preparation of compound IIIw

[0093] 13.5 mmol of dibenzothiazole disulfide, 30 mL of 1,2-dichloroethane, 10 mmol of aminothiazic acid, and 10 mmol of triethylamine were added sequentially to a reaction flask. The mixture was stirred at 10 °C for 1.5 h, and then 6.75 mmol of triethyl phosphite was added and the reaction was carried out for 4 h. Thin-layer chromatography was used to monitor the reaction. After the reaction was completed, the mixture was filtered to obtain the crude product. Recrystallization yielded a pale yellow powder, which is intermediate I.

[0094] Weigh 3 mmol of Boc-glycine, 3.5 mmol of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 3 mmol of N,N-diisopropylethylamine, and 5 mL of dichloromethane into a reaction flask. React at 25 °C for 5 min. Then add 2 mmol of 4-cyclopropylthiazol-2-amine and continue stirring for 6 h. After the reaction is complete, filter and concentrate the solvent. Then add 12 mmol of trifluoroacetic acid and 5 mL of dichloromethane into the reaction flask and react at 5 °C for 2 h. After the reaction is complete, concentrate the solvent to obtain intermediate II.

[0095] 1 mmol of intermediate I, 2 mmol of intermediate II, 3 mmol of triethylamine and 15 mL of tetrahydrofuran were weighed into a reaction flask and stirred at 8 °C for 6 h. After the reaction was completed, the solvent was concentrated and purified by thin-layer chromatography on silica gel plate to obtain compound IIIw.

[0096] Example 5: Preparation of compound IIIx

[0097] 13.5 mmol of dibenzothiazole disulfide, 30 mL of 1,2-dichloroethane, 10 mmol of aminothiazic acid, and 10 mmol of triethylamine were added sequentially to a reaction flask. The mixture was stirred at 10 °C for 1.5 h, and then 6.75 mmol of concentrated sulfuric acid was added and the reaction was carried out for 4 h. Thin-layer chromatography was used to monitor the reaction. After the reaction was completed, the mixture was filtered to obtain the crude product. Recrystallization yielded a pale yellow powder, which is intermediate I.

[0098] Weigh 3 mmol of Boc-glycine, 3.5 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 4 mmol of 1-hydroxybenzotriazole, 5 mmol of 4-dimethylaminopyridine, and 5 mL of dichloromethane into a reaction flask. React at 23 °C for 5 min. Then add 2 mmol of 4-ethylthiazole-2-amine and continue stirring for 6 h. After the reaction is complete, filter and concentrate the solvent. Then add 12 mmol of trifluoroacetic acid and 5 mL of dichloromethane into the reaction flask and react at 5 °C for 2 h. After the reaction is complete, concentrate the solvent to obtain intermediate II.

[0099] 1 mmol of intermediate I, 2 mmol of intermediate II, 3 mmol of triethylamine and 15 mL of tetrahydrofuran were weighed into a reaction flask and stirred at 6 °C for 7 h. After the reaction was completed, the solvent was concentrated and purified by thin-layer chromatography on silica gel plate to obtain compound IIIx.

[0100] Antibacterial activity test

[0101] Using oxacillin as a control drug, the minimum inhibitory concentration (MIC) of the compound of formula III against Staphylococcus aureus, Escherichia coli, methicillin-resistant Staphylococcus aureus (MRSA), and fluoroquinolone-resistant Escherichia coli (FREC) was determined by microdilution method. The data are shown in Table 1.

[0102] Table 1

[0103]

[0104] The experimental results clearly demonstrate that the compounds of formula III protected by this invention possess potential antibacterial activity. Some compounds, such as compound IIIv, exhibit superior inhibitory activity against *S. aureus* compared to the control drug oxacillin; some compounds, such as compound IIIw, show inhibitory activity comparable to oxacillin; and some compounds, such as compounds IIIh and IIIt, show inhibitory activity close to that of oxacillin. Most compounds show superior activity against methicillin-resistant *S. aureus* (MRSA) compared to oxacillin, with some compounds exhibiting 20 to 60 times greater antibacterial activity against MRSA than oxacillin, such as compounds IIIh, IIIt, IIIv, and IIIw. These compounds demonstrate significant anti-MRSA activity. Their potential antibacterial activity can be used to treat infectious diseases caused by *S. aureus* and MRSA. They can also be used in combination with other antibacterial substances.

Claims

1. An amide derivative containing bithiazole, characterized in that, The amide derivative containing bithiazole is selected from any of the following compounds: Ⅲa: 、Ⅲb: 、 Ⅲe: 、Ⅲf: 、 Ⅲg: 、Ⅲh: 、 Ⅲi: 、Ⅲj: 、 Ⅲl： 、Ⅲm： 、 Ⅲn: 、Ⅲp: 、 Ⅲq： 、Ⅲr： 、 Ⅲs: 、Ⅲt: 、 Ⅲu: 、Ⅲv: 、 Ⅲw: 、Ⅲx: 。 2. The method for preparing the amide derivative containing bithiazole according to claim 1, characterized in that: The amide derivative containing bithiazole was prepared according to the following synthetic route: 。 3. The method for preparing the amide derivative containing bithiazole according to claim 2, characterized in that: Includes the following steps: S1. Preparation of Intermediate I: Dibenzothiazole disulfide, 1,2-dichloroethane, aminothiazolic acid and triethylamine were added sequentially to a reaction flask and stirred at 10~15 °C. After stirring, triethyl phosphite or a dehydrating agent was added and reacted. After thin-layer chromatography, the mixture was filtered to obtain a crude product. The crude product was recrystallized to obtain a light yellow powder, which is Intermediate I. S2. Preparation of intermediate II: Boc-glycine, reagent A and dichloromethane were placed in a reaction flask and reacted at 0~40 ℃. Then, substituted thiazol-2-amine was added and the reaction was continued with stirring. After the reaction was completed, the mixture was filtered, the solvent was concentrated, and then trifluoroacetic acid and dichloromethane were added. The reaction was completed at 5~10 ℃. The solvent was then concentrated to obtain intermediate II. The reagent A is selected from the combination of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole; or the combination of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole and 4-dimethylaminopyridine; or the combination of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine; S3. Preparation of Compound III: Intermediate I, Intermediate II, triethylamine and tetrahydrofuran were placed in a reaction flask and stirred at 0-20 °C until the reaction was complete. The solvent was concentrated and purified by thin-layer chromatography using silica gel plates to obtain Compound III.

4. The method for preparing the amide derivative containing bithiazole according to claim 3, characterized in that: The dehydrating agent is selected from one of concentrated sulfuric acid, concentrated phosphoric acid, or triphenylphosphine.

5. The use of the amide derivative containing bithiazole according to claim 1 in the preparation of a medicament for treating and / or preventing methicillin-resistant Staphylococcus aureus infections.

6. The use of the amide derivative containing bithiazole according to claim 1 in the preparation of a medicament for treating and / or preventing Staphylococcus aureus infections.

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