Thiazole compound, synthetic method thereof and application of thiazole compound in preparation of anti-mycobacterium abscessus medicine

Abstract

The invention discloses a thiazole compound and a new application of the thiazole compound in preparation of a mycobacterium abscessus mycothiol disulfide reductase inhibitor and a mycobacterium abscessus resisting medicine. According to the invention, a compound capable of targeting mycobacterium abscessus mycothiol disulfide reductase and inhibiting the enzymatic activity of the mycobacterium abscessus mycothiol disulfide reductase is screened and synthesized, and meanwhile, the compound has mycobacterium abscessus resisting activity. According to the present invention, the anti-mycobacterium abscessus effect of the compound is semi-quantitatively determined by using the paper diffusion method, the thiazole compound can form the significant inhibition zone on the plate so as to show the anti-mycobacterium abscessus activity, and the synthesized thiazole compound can be used as the inhibitor of the mycobacterium abscessus branched mercaptan disulfide reductase, and can be used for the preparation of the anti-mycobacterium abscessus. And the compound is expected to be developed into a novel anti-mycobacterium abscessus medicine, and has an important application value.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and in particular relates to the use of thiazole compounds as inhibitors of Mycobacterium abscessus mycothiol disulfide reductase in the preparation of anti-Mycobacterium abscessus drugs. Background Art

[0002] Infections caused by nontuberculous mycobacteria (NTM) have increased significantly worldwide, and their infection rates have exceeded those of Mycobacterium tuberculosis in developed countries. Mycobacterium abscessus (Mab) is the most common pathogenic, rapidly growing NTM in the world. Due to its high drug resistance and invasiveness, it has become the focus of clinical and basic research in recent years as a highly drug-resistant opportunistic pathogen. Currently, there are no highly effective and targeted anti-Mab drugs, so the search for new potential drug targets is expected to treat Mab infection from the source. According to genotyping, Mab can be further divided into abscessus, Massimo, and Bolai subspecies. Among them, the abscessus subspecies carries the erm(41) gene, which mediates macrolide antibiotic resistance, significantly increasing the difficulty of clinical treatment. Epidemiological data show that the incidence of infection with this bacterium has increased significantly in chronic lung disease and immunosuppressed populations, and it has become one of the important pathogens of nosocomial infection.

[0003] Mycothiol (MSH) is a low-molecular-weight thiol unique to high-GC-content actinomycetes. It is a functional equivalent of glutathione (GSH) in host cells and plays an important role in the regulation of reactive oxygen and nitrogen species by Mabs. MSH plays a central role in bacterial redox homeostasis and is a key factor for the survival of mycobacteria under oxidative stress in host macrophages. The unique structure of MSH also determines its functional diversity. Its inositol group provides hydrophilicity, while the sulfhydryl (-SH) group of the cysteine ​​residue acts as an active site for redox reactions. In addition, the biosynthetic pathway of MSH is completely independent of the host cell's GSH pathway, providing a potential target for the development of specific antimicrobial drugs. Mycothiol disulfide reductase (Mtr) is a key enzyme that catalyzes the regeneration of MSH. It reduces mycothiol disulfide (MSSM) to MSH, which is crucial for Mycobacterium abscessus to maintain the stability of the MSH pool and subsequently affect its redox homeostasis. In recent years, MSH and Mtr have been regarded as hot targets for the development of anti-mycobacterial drugs. Summary of the Invention

[0004] This study screened and synthesized thiazole compounds through extensive experimental design. These compounds inhibit the growth of Mycobacterium abscessus and target mycobacterium disulfide reductase, inhibiting its activity and thus exerting an antibacterial effect. A series of derivative compounds were synthesized by structural derivatization based on the thiazole core of compound 1. Among them, thiazole compounds 2, 4, and 5 exhibited anti-Mycobacterium abscessus activity, and 2-5 showed in vitro inhibition of mycobacterium disulfide reductase activity.

[0005] The present invention aims to molecularly dock small molecules from an online library with the enzyme's three-dimensional structure based on the crystal structure of Mycobacterium abscessus branched thiol disulfide reductase. By studying their interaction patterns, highly ranked candidate compounds were synthesized. Thiazole compound 1 exhibited moderate anti-Mycobacterium abscessus activity and targeted mycothiol disulfide reductase. Its derivatives 2-5 also exhibited varying degrees of anti-Mycobacterium abscessus activity and mycothiol disulfide reductase inhibition, suggesting their potential use as antibacterial agents and inhibitors of Mycobacterium abscessus branched thiol disulfide reductase.

[0006] The Mycobacterium abscessus mycothiol disulfide reductase inhibitors screened by the present invention have the following general structural formula of thiazole compounds:

[0007]

[0008] Wherein R1 includes: halogen, alkyl or halogen-substituted alkyl; R2 includes phenyl or alkoxy-substituted phenyl.

[0009] As a preferred embodiment, the Mycobacterium abscessus mycothiol disulfide reductase inhibitor is characterized in that the thiazole compound includes the following compounds:

[0010]

[0011] The present invention screened and found that the synthesized thiazole compounds have anti-Mycobacterium abscessus activity and can bind to and effectively inhibit the activity of Mycobacterium abscessus mycothiol disulfide reductase. Therefore, the present invention has shown that the synthesized thiazole compounds can bind to and effectively inhibit the activity of mycothiol disulfide reductase, thereby exerting antibacterial activity against Mycobacterium abscessus. Therefore, the thiazole compounds and their derivatives of the present invention can be used to prepare anti-Mycobacterium abscessus drugs and Mycobacterium abscessus mycothiol disulfide reductase inhibitors.

[0012] As a preferred embodiment, the thiazole compounds and their derivatives synthesized by the present invention are prepared into inorganic acid salts or organic acid salts. As a preferred embodiment, the thiazole compounds and their derivatives are prepared into tablets, granules, capsules, pills, powders, oral solutions, and injections with pharmaceutically acceptable carriers.

[0013] Beneficial Effects:

[0014] The present invention has found that thiazole compounds can effectively inhibit the activity of thiol disulfide reductase of Mycobacterium abscessus Mycobacterium abscessus Figure 14 ), and the susceptibility test of thiazole compounds to inhibit Mycobacterium abscessus was determined as follows Figure 15 These results demonstrate that thiazole compounds can bind to and effectively inhibit the activity of mycothiol disulfide reductase in Mycobacterium abscessus, thereby exerting anti-Mycobacterium abscessus effects. Mycobacterium abscessus is the most common non-tuberculosis mycobacterium in clinical practice, and its drug resistance has become a major public health and safety issue. Therefore, the present invention has important clinical significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 It is the structural formula of thiazole compound 1 to 5.

[0016] Figure 2 This is a synthetic route for thiazole compounds.

[0017] Figure 3 For compound 1 1 H-NMR.

[0018] Figure 4 For compound 1 13 C-NMR.

[0019] Figure 5 1H-NMR of compound 1.

[0020] Figure 6 is the 13C-NMR of compound 1.

[0021] Figure 7 1H-NMR of compound 1.

[0022] Figure 8 is the 13C-NMR of compound 1.

[0023] Figure 9 1H-NMR of compound 1.

[0024] Figure 10 is the 13C-NMR of compound 1.

[0025] Figure 11 1H-NMR of compound 1.

[0026] Figure 12 is the 13C-NMR of compound 1.

[0027] Figure 13 This is the principle equation for the reaction catalyzed by Mycobacterium disulfide reductase of Mycobacterium abscessus in the mycobacterium.

[0028] Figure 14 is the relative inhibition rate of thiazole compounds on the activity of Mycobacterium abscessus mycothiol disulfide reductase.

[0029] Figure 15 The results are for in vitro susceptibility test of thiazole compounds against Mycobacterium abscessus (ATCC 19977). DETAILED DESCRIPTION

[0030] Through extensive experimental screening, the present invention discovered that thiazole compounds have good antibacterial activity against Mycobacterium abscessus and target the mycothiol disulfide reductase of Mycobacterium abscessus to inhibit its enzymatic activity. The present invention is further described below with reference to specific embodiments, but these embodiments should not be construed as limiting the present invention.

[0031] The experimental materials of the following examples are:

[0032] Thiazole compounds and BnMS-TNB were synthesized in our laboratory. NADPH was purchased from Shanghai Yuanye Biotechnology Co., Ltd. MabMtr protein was expressed and purified in our laboratory. Thiourea, bromopropane, acetonitrile, (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), N,N-diisopropylethylamine, and N,N-dimethylformamide were all commercially available chemical reagents.

[0033] Example 1 Synthesis of Thiazole Compounds

[0034] (1) Synthesis of 4-(4-chlorophenyl)thiazol-2-amine (Intermediate Ⅰ-1)

[0035]

[0036] 4-Chloro-2'-bromoacetophenone (500 mg, 2.14 mmol) was dissolved in 10 mL of ethanol. Thiourea (195.6 mg, 2.57 mmol) was added and the reaction temperature was raised to 70°C for 3 h. The reaction mixture was brought to room temperature. After TLC monitoring, the reaction solution was slowly poured into 40 mL of ice water to dilute the mixture, resulting in the precipitation of a white solid. The filter cake was then filtered, washed with water, and dried to afford Intermediate I-1 as a white solid (340 mg, 76%). 1 H NMR (500MHz, CDCl3) δ7.74-7.66(m,2H),7.37-7.31(m,2H),6.71(s,1H),5.06(s,2H).

[0037] (2) Synthesis of 4-(4-methylphenyl)thiazol-2-amine (Intermediate Ⅰ-2)

[0038]

[0039] The synthesis method was the same as that of intermediate Ⅰ-1, except that 4-methyl-2'-bromoacetophenone was used to replace 4-chloro-2'-bromoacetophenone to obtain white solid intermediate Ⅰ-2 (210 mg, 49%). 1 H NMR (500MHz, CDCl3) δ7.70(d,J=7.9Hz,2H),6.91(d,J=7.9Hz,2H),6.59(s,1H),5.10(s,2H),3.83(s,3H).

[0040] (3) Synthesis of 4-(4-fluorophenyl)thiazol-2-amine (Intermediate Ⅰ-3)

[0041]

[0042] The synthesis method is the same as that of intermediate Ⅰ-1, except that 4-fluoro-2'-bromoacetophenone is used to replace 4-chloro-2'-bromoacetophenone to obtain white solid intermediate Ⅰ-3 (300 mg, 68%). 1 H NMR (500MHz, CDCl3) δ7.77-7.69 (m, 2H), 7.06 (t, J = 8.7Hz, 2H), 6.65 (s, 1H), 5.11 (s, 2H).

[0043] (4) Synthesis of 4-(4-(trifluoromethyl)phenyl)thiazol-2-amine (Intermediate Ⅰ-4)

[0044]

[0045] The synthesis method was the same as that of intermediate Ⅰ-1, except that 2-bromo-1-(4-(trifluoromethyl)phenyl)ethanone was used to replace 4-chloro-2'-bromoacetophenone to obtain white solid intermediate Ⅰ-4 (250 mg, 54%). 1 H NMR (500MHz, CDCl3) δ7.88 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H), 6.84 (s, 1H), 5.09 (s, 2H).

[0046] (5) Synthesis of methyl 3-propoxybenzoate (Intermediate II)

[0047]

[0048] Methyl 3-hydroxybenzoate (1 g, 6.57 mmol) was dissolved in 20 mL of acetonitrile. Potassium hydroxide (44 mg, 7.89 mmol) and bromopropane (720 mg, 7.89 mmol) were added. The reaction mixture was heated to 60°C and stirred for 12 hours. The reaction was monitored by TLC. The mixture was then diluted with water and extracted three times with ethyl acetate and saturated sodium chloride. The organic phases were combined and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded Intermediate II (0.8 g, 64%) as a clear oil. This product was used directly in the next step without purification. 1 H NMR (400MHz, CDCl3) δ7.59 (d, J = 7.7Hz, 1H), 7.55-7.51 (m, 1H), 7.30 (d, J = 15.9Hz, 1H), 7.06 (dd, J = 8.3 ,2.7Hz,1H),3.92(t,J=6.6Hz,2H),3.88(d,J=1.4Hz,3H),1.79(h,J=7.1Hz,2H),1.02(t,J=7.5Hz,3H).

[0049] (6) Synthesis of 3-propoxybenzoic acid (Intermediate III)

[0050]

[0051] Intermediate II (880 mg, 4.2 mmol) was dissolved in 6 mL of methanol. 2 mL of 2M sodium hydroxide was added with stirring. The reaction was heated to 40°C and stirred for 3 h. After completion of the reaction, the pH was adjusted to 2-3 with 1M hydrochloric acid. Extraction was performed with ethyl acetate, followed by washing with saturated sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford Intermediate III as a white solid (705 mg, 94%). The product was carried forward to the next step without purification. 1 H NMR (400MHz, DMSO) δ7.52(t,J=7.6,1.3Hz,1H),7.43(t,J=2.1Hz,1H),7.39(t,J=7.9Hz,1 H),7.18-7.14(m,1H),3.94(t,J=6.5Hz,2H),1.72(h,J=7.1Hz,2H),0.97(t,J=7.4Hz,3H).

[0052] (7) Synthesis of N-(4-(4-chlorophenyl)thiazol-2-yl)-3-propoxybenzamide (Compound 1)

[0053]

[0054] Intermediate III (43.5 mg, 0.24 mmol) was dissolved in 1 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (107.5 mg, 0.84 mmol) and (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (108.6 mg, 0.28 mmol) were added. After stirring at room temperature for 2 minutes, Intermediate I-1 (50 mg, 0.24 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction as monitored by TLC, the reaction solution was diluted with four times the amount of water, extracted three times with ethyl acetate, washed with saturated sodium chloride, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was separated and purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain the final product, Compound 1, as a white solid (35 mg, 33%). 1 H NMR(500MHz, CDCl3)δ10.00(s,1H),7.75-7.67(m,2H),7.47-7.40(m,2H),7.39-7.32(m,3H),7.17(s,1H ),7.10(dd,J=8.1,2.5Hz,1H),3.96(t,J=6.5Hz,2H),1.84(q,J=7.0Hz,2H),1.06(td,J=7.3,4.1Hz,3H); 13 C NMR (101MHz, CDCl3) δ164.76,159.61,158.49,148.99,133.84,133.08,132.66, 129.97,128.89,127.29,119.97,118.95,112.89,108.41,69.81,22.53,10.54.

[0055] (8) Synthesis of N-(4-(4-methylphenyl)thiazol-2-yl)-3-propoxybenzamide (Compound 2)

[0056]

[0057] The synthesis method was the same as step (7) for compound 1, except that intermediate Ⅰ-2 replaced intermediate Ⅰ-1 to obtain white solid compound 2 (35 mg, 33%). 1H NMR (500MHz, CDCl3) δ9.71 (s, 1H), 7.72 (d, J = 7.8Hz, 2H), 7.50 (t, J = 2.0Hz, 1H), 7.48-7.45 (m, 1H), 7.40 (t, J = 7.9Hz, 1H), 7. 22(d,J=7.9Hz,2H),7.13(d,J=6.5Hz,2H),3.99(t,J=6.5Hz,2H),2.38(s,3H),1.85(h,J=7.0Hz,2H),1.06(t,J=7.4Hz,3H); 13 C NMR (101MHz, CDCl3) δ164.62,159.61,158.14,150.20,137.96,133.19,131.48,129.94 ,129.44,125.95,119.96,118.97,112.84,107.33,69.79,53.48,22.52,21.28,10.53.

[0058] (9) Synthesis of N-(4-(4-chlorophenyl)thiazol-2-yl)-3,5-dimethoxybenzamide (Compound 3)

[0059]

[0060] The synthesis method was the same as that of compound 1 in step (7), except that intermediate III was replaced by 3,5-dimethoxybenzoic acid to obtain compound 3 (35 mg, 33%) as a white solid. 1 H NMR (500MHz, CDCl3) δ10.82 (s, 1H), 7.61 (d, J = 8.4Hz, 2H), 7.27 (d, J = 6.1Hz, 2H), 6.91 (d, J = 2.2Hz, 2H), 6.53 (t, J = 2.2Hz, 1H), 3.76 (s, 6H); 13 C NMR (101MHz, CDCl3) δ164.07,159.93,157.85,148.05,132.85,132.74,131.49,127.73,126.21,107.43,104.28,104.02,54.54.

[0061] (10) Synthesis of N-(4-(4-fluorophenyl)thiazol-2-yl)-3-propoxybenzamide (Compound 4)

[0062]

[0063] The synthesis method was the same as that of compound 1 in step (7), except that intermediate I-3 was used instead of intermediate I-1 to obtain white solid compound 4 (29 mg, 33%).1 H NMR (500 MHz, CDC13) δ 11.09 (s, 1H), 8.00-7.91 (m, 2H), 7.66-7.59 (m, 2H), 7.56-7.51 (m, 1H), 7.39 (s, 1H), 7.32-7.26 (m, 3H), 4.17 (t, J = 6.5 Hz, 2H), 2.10 (q, J = 7.0 Hz, 2H), 1.33 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDC13) δ 164.55, 159.67, 158.29, 149.02, 133.05, 130.04, 127.78 (d, J = 8.1 Hz), 120.01, 118.92, 115.81, 115.59, 112.94, 107.65, 69.83, 22.51, 10.51.

[0064] (11) Synthesis of N-(4-(4-(trifluoromethyl))thiazol-2-yl)-3-propoxybenzamide (Compound 5)

[0065]

[0066] Synthetic procedure same as Compound 1, intermediate 1-4 instead of intermediate 1-1 to give Compound 5 as a white solid (35 mg, 34%). 1 H NMR (500 MHz, CDC13) δ 9.90 (s, 1H), 7.94 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.51-7.45 (m, 2H), 7.40 (t, J = 7.9 Hz, 1H), 7.33 (s, 1H), 7.14 (dd, J = 8.2, 2.5 Hz, 1H), 3.99 (t, J = 6.5 Hz, 2H), 1.86 (h, J = 7.2 Hz, 2H), 1.08 (t, J = 7.4 Hz, 3H); 13 C NMR (126 MHz, CDC13) δ 164.55, 159.75, 158.42, 148.62, 137.43, 133.01, 130.07, 126.22, 125.74, 120.00, 118.91, 113.09, 109.88, 69.89, 53.40, 22.50, 10.46.

[0067] Example 2 Test of thiazole compounds to inhibit mycobacterial mycolic acid biosynthesis in Mycobacterium abscessus

[0068] The thiazole compounds were analyzed for their inhibitory effect on the activity of mycobacterial mycolic acid biosynthesis in Mycobacterium abscessus.

[0069] Tested compounds: Thiazole compounds 1 to 5 prepared in Example 1 above.

[0070] The principle equation of the BnMS-TNB reduction reaction catalyzed by Mycobacterium disulfide reductase MabMtr of Mycobacterium abscessus is as follows: Figure 13 :

[0071] In vivo, MSSM is reduced to MSH under the catalysis of Mtr, thereby maintaining redox homeostasis in mycobacteria. A limiting factor in MSH research is the low yield of MSH and its disulfide MSSM. Consequently, alternative substrates are often used in practical studies. BnMS-TNB is a commonly used alternative to disulfide MSSM in MSH research in recent years, primarily used to study the activity and function of MSH-related enzymes. It is a synthetic glycoside compound with 2-amino-2-deoxy-D-glucose (glucosamine) as the backbone, N-acetyl-L-cysteine ​​linked to the 2-amino position of glucosamine via an amide bond, and 5-thio-2-nitrobenzoic acid (TNB) as a reporter group. The TNB group is released during the enzymatic reaction, producing a yellow product that can be used to quantify enzyme activity using a colorimetric assay (measuring its absorbance at 412 nm).

[0072]

[0073] The test method is as follows:

[0074] The enzyme activity reaction buffer is 100mM HEPES, 50mM NaCl, 0.05% bovine serum albumin (BSA), 0.01% Tween-20, pH 7.5, and the reaction system is 200μL. Containing 500nM MabMtr protein, the final concentration of BnMS-TNB is fixed at 100μM, and the final concentration of NADPH is fixed at 200μM. At 25°C, the increase in TNB absorbance at 412nm is monitored 30min after the start of the reaction. Each group of experiments is carried out in parallel 3 times. Data analysis was performed using GraphPad Prism 9 according to formula 1. The system with added inactivated enzyme was used as the blank control, the enzyme activity level without added compound was used as unit 1, and the enzyme activity level after adding compound was its relative value. The experimental results are shown in the figure below. Figure 14 As shown, thiazole compounds 1 to 5 have different levels of inhibitory effects on the inhibition of Mycobacterium abscessus mycothiol disulfide reductase.

[0075]

[0076] Example 3 Thiazole compounds have anti-Mycobacterium abscessus effects

[0077] Tested compounds: Thiazole compounds 1 to 5 synthesized in Example 1 above.

[0078] Assay method: First, prepare a double-layer plate. Pour 15 mL of 7H11 agar medium into a sterile Petri dish and let it solidify, serving as the bottom plate. Pour 10 mL of 7H9 agar medium into a sterile Petri dish and let it solidify, serving as the top plate. Mycobacterium abscessus (ATCC 19977) was inoculated into the liquid medium and cultured to the logarithmic growth phase. The bacterial solution concentration was adjusted to a McFarland turbidity of 0.5. A sterile cotton swab was used to evenly spread the bacterial solution onto the agar surface, ensuring uniform distribution. Then, using sterile tweezers, a 5 μL susceptibility paper disc (d = 5 mm) soaked in 3.2 mg / mL of the thiazole compound being tested was gently placed on the agar, pressing gently to ensure full contact. Azithromycin was used as a positive control, and ethambutol was used as a negative control. An appropriate distance was maintained between the discs to avoid cross-contamination. The Petri dish was incubated at 37°C for 2 days. Finally, the diameter of the inhibition zone was observed to evaluate the antibacterial effect of the compound.

[0079] like Figure 15 The positive drug azithromycin and compounds 1, 2, 4, and 5 showed good antibacterial activity.

[0080] The above description is merely a preferred embodiment of the present invention and should not be construed as limiting the scope of the present invention. Persons skilled in the art will readily appreciate that various equivalent modifications or alterations may be made based on the technical solutions and the description of the preferred embodiments of the present invention without departing from the principles of the present invention, and such modifications and alterations should also be considered within the scope of protection of the present invention.

Claims

1. A Mycobacterium abscessus mycothiol disulfide reductase inhibitor, characterized in that It has the following general structural formula of thiazole compounds: Wherein R1 includes: halogen, alkyl or halogen-substituted alkyl; R2 includes phenyl or alkoxy-substituted phenyl.

2. The Mycobacterium abscessus mycothiol disulfide reductase inhibitor according to claim 1, characterized in that Thiazoles include the following compounds:

3. The method for synthesizing the thiazole compound according to claim 2, characterized in that: The following steps are involved: (1) Synthesis of 4-(4-methylphenyl)thiazol-2-amine, intermediate Ⅰ-1 The raw material 4-methyl-2'-bromoacetophenone was dissolved in ethanol and thiourea was added. The reaction temperature was raised to 70-80°C for 1-3 hours. The reaction was brought to room temperature. After TLC monitoring, the reaction solution was slowly poured into ice water to dilute. A white solid precipitated and was filtered. The filter cake was washed with water and dried to obtain the product intermediate I-1. (2) Synthesis of 4-(4-chlorophenyl)thiazol-2-amine, intermediate Ⅰ-2 The synthesis method is the same as that of intermediate Ⅰ-1 in step (1), except that 4-chloro-2'-bromoacetophenone is substituted for 4-methyl-2'-bromoacetophenone to obtain white solid intermediate Ⅰ-2; (3) Synthesis of 4-(4-fluorophenyl)thiazol-2-amine, intermediate Ⅰ-3 The synthesis method is the same as that of intermediate Ⅰ-1 in step (1), except that 4-methyl-2'-bromoacetophenone is replaced by 4-fluoro-2'-bromoacetophenone to obtain white solid intermediate Ⅰ-3; (4) Synthesis of 4-(4-(trifluoromethyl)phenyl)thiazol-2-amine, Intermediate Ⅰ-4 The synthesis method is the same as that of intermediate Ⅰ-1 in step (1), except that 4-methyl-2'-bromoacetophenone is replaced by 2-bromo-1-(4-(trifluoromethyl)phenyl)ethanone to obtain white solid intermediate Ⅰ-4; (5) Synthesis of methyl 3-propoxybenzoate, intermediate II Dissolve the raw material, methyl 3-hydroxybenzoate, in acetonitrile. Add potassium hydroxide and bromopropane. Heat the reaction to 60-70°C and stir for 6-12 hours. Monitor the reaction by TLC. Then, dilute the reaction solution with water, extract three times with ethyl acetate, then with saturated sodium chloride. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain Intermediate II as a clear oil. (6) Synthesis of 3-propoxybenzoic acid, intermediate III Intermediate II was dissolved in methanol, and sodium hydroxide was added with stirring. The reaction temperature was raised to 40-50°C and stirred for 1-3 hours. After completion of the reaction monitored by TLC, the pH of the reaction solution was adjusted to 2-3 with 1M hydrochloric acid. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Intermediate III. (7) Synthesis of N-(4-(4-chlorophenyl)thiazol-2-yl)-3-propoxybenzamide, i.e., Compound 1 Intermediate III was dissolved in N,N-dimethylformamide, and N,N-diisopropylethylamine and (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were added. After stirring at room temperature, intermediate I-1 was added and stirred at room temperature for 1 to 3 hours. After the reaction was completed as monitored by TLC, water was added to dilute the reaction solution, and the mixture was extracted with ethyl acetate and washed with saturated sodium chloride. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was separated and purified by silica gel column chromatography to obtain the final product, compound 1.

4. The method for synthesizing the thiazole compound according to claim 2, wherein: The synthesis of N-(4-(4-methylphenyl)thiazol-2-yl)-3-propoxybenzamide, i.e., compound 2, comprises the following steps: Intermediate III was dissolved in N,N-dimethylformamide, and N,N-diisopropylethylamine and (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were added. After stirring at room temperature, intermediate I-2 was added and stirred at room temperature for 1 to 3 hours. The reaction was monitored by TLC. The reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated sodium chloride, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The final product, compound 2, was obtained by separation and purification by silica gel column chromatography.

5. The method for synthesizing the thiazole compound according to claim 3, characterized in that: The synthesis of N-(4-(4-chlorophenyl)thiazol-2-yl)-3,5-dimethoxybenzamide, i.e., compound 3, comprises the following steps: The synthesis method is the same as that of compound 1 in step (7) of claim 7, except that 3,5-dimethoxybenzoic acid is used as the raw material to replace intermediate III, and intermediate I-3 is used to replace intermediate I-1 to obtain white solid compound 3.

6. The method for synthesizing thiazole compounds according to claim 3, characterized in that: The synthesis of N-(4-(4-fluorophenyl)thiazol-2-yl)-3-propoxybenzamide, i.e., compound 4, comprises the following steps: The synthesis method is the same as that of compound 1 in step (7) of claim 7, except that intermediate I-4 is used instead of intermediate I-1 to obtain white solid compound 4.

7. The method for synthesizing thiazole compounds according to claim 3, characterized in that: Synthesis of N-(4-(4-(trifluoromethyl))thiazol-2-yl)-3-propoxybenzamide, Compound 5 The synthesis method is the same as that of compound 1 in step (7) of claim 7, except that intermediate I-5 is used instead of intermediate I-1 to obtain white solid compound 5.

8. Use of the thiazole compound and its derivatives and salts according to claim 1 or 2 in the preparation of a mycobacterium disulfide reductase inhibitor of Mycobacterium abscessus.

9. Use of the thiazole compound and its derivatives and salts according to claim 1 or 2 in the preparation of anti-Mycobacterium abscessus drugs.

10. The use according to claim 6 or 7, characterized in that: The thiazole compounds and their derivatives are prepared with pharmaceutically acceptable carriers into tablets, granules, capsules, pills, powders, oral solutions or injections.

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