A benzothiazole-coupled hydroxamic acid compound, and a preparation method and application thereof

Abstract

The application relates to the field of medicine, in particular to a benzothiazole-coupled hydroxamic acid compound containing formula (I) and application thereof in preparation of a bacterial biofilm inhibitor. The benzothiazole-coupled hydroxamic acid compound is subjected to in-vivo and in-vitro pharmacodynamic verification, and most of the obtained compounds have bacterial biofilm inhibition activity, can be used for preparing an antibiofilm agent, and has the potential to be developed into an antibacterial drug. Formula (I).

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, and specifically relates to a class of benzothiazole-coupled isohydroxamic acid compounds, their preparation methods, and applications. Background Technology

[0002] The discovery of antibiotics revolutionized the course of medicine, significantly reducing the harm caused by microbial infections. However, in recent decades, the overuse of antibiotics, along with social and economic factors, has accelerated the spread of drug-resistant bacteria, leading to the emergence of multidrug-resistant "superbugs" that render current antimicrobial treatments ineffective. Currently, at least 700,000 people worldwide die annually from antimicrobial resistance (AMR). The World Health Organization predicts that without new and better treatments, this number could rise to 10 million by 2050. The frequent occurrence of cellular resistance compels the continuous development of antibiotics with new structures and targets; however, the development of new antibiotics requires enormous time, human, and material resources, posing a significant threat to human health and property.

[0003] Bacterial evolution has led to various resistance mechanisms against antibiotics, including reduced drug uptake, altered drug targets, drug inactivation, and activation of drug efflux pumps. These mechanisms cause traditional antibiotics to lose their original antibacterial efficiency, resulting in treatment failure. Biofilm formation is one of the main mechanisms by which bacteria resist antibiotics. Research over the past three decades has shown that bacteria utilize biofilms and quorum sensing to enhance their colony defenses. Biofilms, composed of extracellular polymers secreted by bacteria, form a natural barrier that allows them to evade the immune system and reduce antibiotic uptake, making them difficult to kill. Furthermore, bacteria regulate biofilm formation and growth through quorum sensing, further enhancing their ability to cope with harsh environments. Currently, there are no effective drugs targeting these resistance mechanisms. Compared to traditional antibiotics, biofilm and quorum sensing inhibitors can effectively weaken bacterial resistance, broadly enhance the killing effect of existing antibiotics on resistant bacteria, and are less likely to induce resistance because they do not threaten bacterial survival. Therefore, researching novel anti-biofilm and quorum sensing drugs is of great significance in overcoming antibiotic resistance.

[0004] The benzothiazole skeleton has good biofilm inhibitory activity. Therefore, based on the benzothiazole structure, this invention has invented a class of highly efficient and stable benzothiazole-coupled hydroxamic acid compounds. These compounds or their pharmaceutically acceptable salts can be used as potential anti-biofilm drugs and antibiotic potentiators to improve the clinical antibacterial treatment effect. Summary of the Invention

[0005] To overcome the shortcomings and deficiencies of the prior art, this invention provides a class of benzothiazole-coupled hydroxamic acid compounds. These compounds have stable chemical structures and, as demonstrated by activity experiments, possess anti-biofilm and quorum sensing effects, showing potential for development as antibiotic potentiators.

[0006] In one aspect, the present invention provides a benzothiazole-coupled isohydroxamic acid compound of formula (I) or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof:

[0007]

[0008] Equation (I)

[0009] Where R1 is a substituent group.

[0010] L is one of the following structures:

[0011] .

[0012] Preferably, the compound is selected from:

[0013] Table 1. Structure and Nomenclature of Compounds

[0014]

[0015] The present invention also provides a method for preparing the aforementioned benzothiazole-coupled hydroxamic acid compound, comprising the following steps:

[0016] (1.1) 2-aminobenzothiazoles with different substitutions, di-tert-butyl dicarbonate and triethylamine were reacted in a solvent. After the reaction was completed, the reaction solution was purified to obtain compound 1a-1m.

[0017] (1.2) Compound 1a-1m, ethyl bromoacetate and sodium hydride were placed in a solvent and reacted at 0°C. The resulting reaction solution was purified to obtain compound 2a-2m.

[0018] (1.3) Compound 2a-2m and sodium hydroxide aqueous solution were placed in a solvent and reacted at 50°C. The resulting reaction solution was purified to obtain compound 3a-3m.

[0019] (1.4) Compounds 3a-3m, fatty amines or aromatic amine methyl esters, react with HATU and triethylamine in a solvent. The resulting reaction solution is purified to obtain an intermediate. The intermediate is then reacted in a dichloromethane solution of trifluoroacetic acid. The resulting reaction solution is purified to obtain compounds 4a-5a.

[0020] (1.5) Compounds 4a-5a were placed in methanol with hydroxylamine hydrochloride and potassium hydroxide. The resulting reaction solution was purified to obtain compounds JH1-JH27.

[0021] Its synthesis circuit is as follows:

[0022] .

[0023] Preferably, the reaction conditions are: (a) (Boc)₂O, Et₃N, DMAP, DCM, rt, 4 h; (b) Ethylbromoacetate, NaH, dry DMF, rt, 3 h; (c) NaOH, H₂O, MeOH, 40 °C, 6 h; (d) HAUT, Et₃N, dry DCM, 40 °C, 4 h; (e) CF₃COOH, DCM, 40 °C, 6 h; (f) NH₂OH . HCl, KOH, MeOH, 0.5 h.

[0024] The present invention also provides the use of the benzothiazole-coupled hydroxamic acid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug in the preparation of anti-biofilm drugs and antibiotic potentiators.

[0025] Preferably, the antibiofilm agent includes an antibiofilm agent against Pseudomonas aeruginosa.

[0026] Preferably, the antibiotic potentiator includes a ciprofloxacin potentiator.

[0027] The present invention also provides a pharmaceutical composition comprising the benzothiazole-coupled hydroxamic acid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof.

[0028] Preferably, the pharmaceutical composition further comprises ciprofloxacin.

[0029] Preferably, the weight ratio of benzothiazole coupled with hydroxamic acid compounds or their pharmaceutically acceptable salts, isomers, solvates or prodrugs to ciprofloxacin is 0.2-10.0:1, more preferably 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1.0:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1, and even more preferably 0.83:1.

[0030] Preferably, the drug or pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers or excipients.

[0031] Beneficial effects:

[0032] Starting from the bioactive benzothiazole structure, this study successfully synthesized a series of chemically stable benzothiazole-coupled hydroxamic acid compounds through structural optimization. The anti-biofilm inhibitory activity of these compounds against *Pseudomonas aeruginosa* was detected using crystal violet staining, and their antibiotic synergistic effects were evaluated in animal models. Experimental results showed that most compounds exhibited significant inhibitory effects on *P. aeruginosa* biofilm formation and effectively enhanced the antibacterial activity of ciprofloxacin. Attached Figure Description

[0033] Figure 1 To demonstrate the synergistic effect of compound JH2 on CIP. (A) Bacterial smear results of wound infection areas in mice in the Control group, CIP-only group, and JH2-CIP combination group. Each experiment was repeated 3 times; (B) Monitoring of mouse wound area, with wound area calculated using ImageJ; (C) Photographic monitoring of mouse wound infection areas; (D) Bacterial survival rate in mouse wound infection areas. . Detailed Implementation

[0034] Unless otherwise specified, all reagents used in the examples are commercially available.

[0035] Example 1: 5-(2-(benzo[ d Preparation of methyl thiazol-2-ylamino)acetamido)valerate (intermediate 4a)

[0036] Step 1: Benzo[ d Preparation of thiazol-2-ylcarbamate tert-butyl ester (intermediate 1a)

[0037]

[0038] 2-Aminobenzothiazole (0.150 g, 0.001 mol) was dissolved in dichloromethane, followed by the addition of triethylamine (0.211 ml, 0.0015 mol) and DMAP (0.012 g, 0.0001 mol). The mixture was stirred at room temperature, and then (Boc)₂O (0.275 ml, 0.0012 mol) was added dropwise. After the solvent addition was complete, the reaction was continued for approximately 4 h before termination. The residual organic solvent in the reaction system was removed, and the mixture was recrystallized from petroleum ether / ethyl acetate (200 / 20 v / v). The crystals were filtered under reduced pressure to give intermediate 1a as a grayish-white solid, 0.195 g, with a yield of 78.04%. 1 H NMR (400 MHz, DMSO- d 6) d 11.74 (s, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.70 – 7.63 (m, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.28 – 7.22(m, 1H), 1.51 (d, J = 2.1 Hz, 9H). 13 C NMR (101 MHz, DMSO) d 160.05, 153.41, 149.53, 132.56, 126.46, 123.61, 121.89, 120.61, 82.28, 28.31.1b-1m are prepared by the same method as 1a.

[0039] Step Two: N -(benzo[ d ]thiazol-2-yl)- N Preparation of ethyl 2-(tert-butoxycarbonyl)glycine (intermediate 2a)

[0040]

[0041] Intermediate 1a (0.250 g, 0.0001 mol) was placed in a 50 mL two-necked flask and dissolved in an appropriate amount of anhydrous DMF. Sodium hydride (0.048 g, 0.0015 mol) was added at 0 °C and stirred for 30 min. Then, ethyl bromoacetate (0.167 mL, 0.0015 mol) was added dropwise, and the reaction was continued for approximately 2 h. The reaction was then quenched with a small amount of ice water. The mixture was extracted with 100 mL × 3 ethyl acetate solutions, and the organic phases were combined. The solutions were then washed with 100 mL × 3 saturated NH4Cl solution and 100 mL × 3 saturated NaCl solution until a neutral aqueous layer emerged. After thorough drying with MgSO4, the mixture was filtered to remove the solvent. The residue was purified by rapid chromatography (petroleum ether-ethyl acetate = 200 / 20 v / v) to give intermediate 2a as a white solid, 0.201 g, yield: 60.01%. 1 H NMR (400 MHz, Chloroform- d ) d 7.77 (dd, J = 8.3, 5.0 Hz, 2H), 7.40 (s, 1H), 7.32 – 7.26 (m,1H), 4.99 (d, J = 2.8 Hz, 2H), 4.26 (dq, J= 6.9, 4.3, 2.8 Hz, 2H), 1.60 (s, 9H), 1.30 (dd, J = 4.5, 2.7 Hz, 3H). 13 C NMR (101 MHz, CDCl3) d 169.12, 160.52, 148.80, 133.67, 133.41, 125.78, 123.51, 121.20, 120.82, 77.24, 52.31, 48.10, 28.08.2b-2m are prepared by the same method as 2a.

[0042] Step 3: N -(benzo[ d ]thiazol-2-yl)- N Preparation of -(tert-Butoxycarbonyl)glycine (intermediate 3a)

[0043]

[0044] Intermediate 2a (0.336 g, 0.001 mol) was dissolved in methanol, and a 2 N sodium hydroxide aqueous solution (containing 0.002 mol of sodium hydroxide) was added. The reaction was terminated by stirring at 50 °C for 4 h. The methanol was removed, and the pH was adjusted to 5 with 1 mol / L HCl. A solid precipitated out, was filtered under reduced pressure, and dried under vacuum to obtain intermediate 3a as a white solid of 0.219 g, yield: 71.11%. 1 H NMR (400 MHz, DMSO-) d 6) d 7.89 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.37 (t, J =7.7 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 4.49 (s, 2H), 1.49 (s, 9H). 13 C NMR (101MHz, DMSO) d 169.95, 169.09, 160.79, 148.80, 133.32, 126.59, 124.18, 121.91, 121.23, 82.92, 52.75, 48.33, 28.03.3b-3m are prepared by the same method as 3a.

[0045] Step 4: 5-(2-(benzo[ dPreparation of methyl thiazol-2-ylamino)acetamido)valerate (intermediate 4a)

[0046]

[0047] Intermediate 3a (0.308 g, 0.001 mol) was dissolved in DMF, and 2-(7-azabenzotriazole)- N,N, N',N '-Tetramethylurea hexafluorophosphate (HATU, 0.571 g, 0.0015 mol) and triethylamine (0.277 ml, 0.002 mol) were reacted at room temperature with stirring for 30 min. Then, methyl 5-aminovalerate hydrochloride (0.251 g, 0.0015 mol) was added, and the reaction was terminated after 6 h. The mixture was extracted with 30 ml × 3 ethyl acetate, and washed with 30 ml × 3 saturated NaHCO3 solution, 30 ml × 3 saturated NH4Cl solution, and 100 ml × 3 saturated NaCl solution, respectively, until the aqueous layer was neutral. The combined organic phases were thoroughly dried with MgSO4 and filtered to remove the solvent, yielding an oily liquid. The oily liquid was then placed in a 2 mol solution of trifluoroacetic acid in dichloromethane and reacted at room temperature with stirring for 30 min, and the reaction was terminated. The pH was adjusted to 7 with 1 mol / L NaOH, and the mixture was extracted with 100 ml × 3 ethyl acetate solutions. The organic phases were then combined and washed with 100 ml × 3 saturated NH4Cl solution and 100 ml × 3 saturated NaCl solution until the aqueous layer was neutral. After thorough drying with MgSO4, the mixture was filtered to remove the solvent. The residue was purified by rapid chromatography (petroleum ether-ethyl acetate = 40 / 80 v / v) to give intermediate 4a as a white solid, 0.201 g, yield: 62.51%. 1 H NMR (400 MHz, DMSO-) d 6) d 8.24 (d, J = 6.0 Hz, 1H), 8.02 (d, J = 6.0 Hz, 1H), 7.66 (dd, J = 7.9, 1.9 Hz, 1H), 7.37 (dd, J = 8.1, 1.9 Hz, 1H), 7.28 – 7.15 (m, 1H), 7.02(dt, J = 9.3, 4.6 Hz, 1H), 4.08 – 3.90 (m, 2H), 3.56 (d, J = 2.0 Hz, 3H), 3.09(q, J= 6.3, 5.6 Hz, 2H), 2.29 (td, J = 7.4, 2.0 Hz, 2H), 1.60 – 1.47 (m, 2H), 1.41 (p, J = 7.1 Hz, 2H). 13 C NMR (101 MHz, DMSO) d 173.73, 169.00, 166.67, 152.63, 131.10, 125.93, 121.53, 121.39, 118.56, 51.64, 47.06, 38.54, 33.36, 28.93, 22.24. 4b-5a are prepared by the same method as 4a.

[0048] Example 2: N -hydroxy-4-(2-(benzo[ d Thiazol-2-yl)amino)acetamido)butyramide (compound JH1)

[0049] Hydroxylamine hydrochloride (1.389 g, 0.02 mol) and potassium hydroxide (1.28 g, 0.024 mol) were reacted in methanol for 30 min. The filtrate was collected by vacuum filtration, and reactant 4a (0.161 g, 0.0005 mol) was added. The reaction was continued for another 30 min. After the reaction was completed, the pH of the reaction solution was adjusted to 7 with dilute hydrochloric acid, and ice water was added to the reaction solution to precipitate a solid. If no solid precipitated, the reaction solution was concentrated under reduced pressure until a solid precipitated. The precipitated solid was filtered and washed with water. The solid was stirred overnight with methanol-ethyl acetate (1 / 20 v / v) and filtered to obtain product JH1 as a white solid, 0.105 g, yield: 65.22%. 1 H NMR (400 MHz, DMSO- d 6) d 10.33 (s, 1H), 8.67 (s, 1H), 8.22 (d, J = 6.0 Hz, 1H), 8.01 (d, J = 6.2Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.03 (t, J = 7.7 Hz, 1H), 3.99 (d, J= 5.3 Hz, 2H), 3.08 (q, J = 6.7 Hz, 2H), 1.94 (t, J = 7.4 Hz, 2H), 1.44 (m, 4H). 13 C NMR (101 MHz, DMSO) d 169.43, 168.92,166.68, 152.65, 131.10, 125.95, 121.52, 121.40, 118.58, 47.05, 38.77, 32.39,29.14, 23.03.HRMS (ESI) of compoundJH1: calcd. for C 14 H 19 N4O3S [M + H] + =323.1173, found [M + H] + =323.1165.

[0050] Example 3: N -hydroxy-5-(2-((6-methoxybenzo[ d Thiazol-2-yl)amino)acetamido)pentanamide (compound JH2)

[0051] Using 4b (0.176 g, 0.0005 mol) and hydroxylamine hydrochloride (1.389 g, 0.02 mol) as raw materials, the same method as compound JH1 was used to synthesize JH2 as a white solid of 0.141 g, with a yield of 80.57%. 1 H NMR (400 MHz, DMSO- d 6) d 10.34(t, J = 3.6 Hz, 1H), 8.75 – 8.57 (m, 1H), 8.00 (t, J = 6.8 Hz, 2H), 7.43 – 7.23(m, 2H), 6.82 (t, J = 7.1 Hz, 1H), 3.93 (d, J = 6.1 Hz, 2H), 3.73 (t, J = 4.0 Hz, 3H), 3.08 (q, J = 6.3 Hz, 2H), 1.94 (q, J = 6.9 Hz, 2H), 1.43 (m, 4H). 13C NMR (101MHz, DMSO) d 169.46, 168.96, 165.23, 154.94, 146.10, 131.83, 118.77, 113.48,106.07, 56.01, 47.11, 38.75, 32.38, 29.11, 23.03.HRMS (ESI) of compoundJH2:calcd. for C 15 H 21 N4O4S [M + H] + =353.1279, found [M + H] + =353.1275.

[0052] Example 4: N -hydroxy-5-(2-((5-methoxybenzo[ d Thiazol-2-yl)amino)acetamido)pentanamide (compound JH3)

[0053] Using 4c (0.175 g, 0.0005 mol) and hydroxylamine hydrochloride (1.389 g, 0.02 mol) as raw materials, the same method as compound JH1 was used to synthesize JH3, which was a grayish-white solid of 0.113 g, with a yield of 64.57%. 1 H NMR (400 MHz, DMSO- d 6) d 10.35(d, J = 4.4 Hz, 1H), 8.68 (s, 1H), 8.20 (t, J = 5.4 Hz, 1H), 8.00 (q, J = 5.4 Hz, 1H), 7.52 (dd, J = 8.7, 4.5 Hz, 1H), 6.98 (d, J = 4.0 Hz, 1H), 6.65 (t, J = 8.2, 3.6 Hz, 1H), 3.97 (t, J = 5.3 Hz, 2H), 3.75 (d, J = 4.7 Hz, 3H), 3.17 – 2.95 (m,2H), 2.08 – 1.76 (m, 2H), 1.68 – 1.24 (m, 4H). 13 C NMR (101 MHz, DMSO) d169.43,168.93, 165.42, 150.50, 141.92, 132.11, 122.24, 113.71, 108.51, 56.02, 47.06,38.78, 32.38, 29.15, 23.05.HRMS (ESI) of compoundJH3: calcd. for C 15 H 21 N4O4S [M+ H] + =353.1279, found [M + H] + =353.1276.

[0054] Example 5: N -hydroxy-5-(2-((4-methoxybenzo[ d [Thiazol-2-yl)amino)acetamido)pentanamide (compound JH4)

[0055] Using 4d (0.175 g, 0.0005 mol) and hydroxylamine hydrochloride (1.389 g, 0.02 mol) as raw materials, the same method as compound JH1 was used to synthesize JH4 as a white solid of 0.146 g, with a yield of 83.43%. 1 H NMR (400 MHz, DMSO- d 6) d 10.33(s, 1H), 8.66 (s, 1H), 8.11 (d, J = 6.1 Hz, 1H), 8.02 (d, J = 6.3 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 6.99 (t, J = 8.1 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 4.00 (d, J =5.6 Hz, 2H), 3.84 (s, 3H), 3.08 (q, J = 6.8 Hz, 2H), 1.94 (d, J = 7.6 Hz, 2H), 1.44 (m, 4H). 13 C NMR (101 MHz, DMSO) d169.41, 168.92, 165.42, 150.50, 141.93,132.12, 122.23, 113.72, 108.52, 56.02, 47.06, 38.78, 32.38, 29.16, 23.05.HRMS(ESI) of compoundJH4: calcd. for C 15 H 21 N4O4S [M + H] + =353.1279, found [M + H] + =353.1277.

[0056] Example 6: N -hydroxy-5-(2-((6-methylbenzo[ d Thiazol-2-yl)amino)acetamido)pentanamide (compound JH5)

[0057] Using 4e (0.175 g, 0.0005 mol) and hydroxylamine hydrochloride (1.389 g, 0.02 mol) as raw materials, the same method as compound JH1 was used to synthesize JH5 as a white solid of 0.122 g, with a yield of 69.71%. 1 H NMR (400 MHz, DMSO- d 6) d 10.33(s, 1H), 8.66 (s, 1H), 8.10 (d, J = 5.9 Hz, 1H), 7.99 (d, J = 6.1 Hz, 1H), 7.47(s, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 3.96 (d, J = 5.6 Hz, 2H), 3.07 (q, J = 6.6 Hz, 2H), 2.32 (s, 3H), 1.94 (t, J = 7.3 Hz, 2H), 1.48 (d, J =7.7 Hz, 2H), 1.39 (d, J = 7.6 Hz, 2H). 13 C NMR (101 MHz, DMSO) d169.42, 168.99,165.98, 150.53, 131.18, 130.61, 126.97, 121.34, 118.26, 47.05, 38.75, 32.39,29.14, 23.03, 21.23.HRMS (ESI) of compoundJH5: calcd. for C 15 H 21 N4O3S [M + H] + =337.1329, found [M + H] + =337.1324.

[0058] Example 7: N -hydroxy-4-(2-((6-methoxybenzo[ d Thiazol-2-yl)amino)acetamido)butyramide (compound JH6)

[0059] Using 4f (0.085 g, 0.00025 mol) and hydroxylamine hydrochloride (1.036 g, 0.015 mol) as raw materials, the same method as compound JH1 was used to synthesize JH6 as a white solid of 0.042 g, with a yield of 49.41%. 1 H NMR (400 MHz, DMSO- d 6) d 10.36(s, 1H), 8.72 (s, 1H), 8.20 – 7.89 (m, 2H), 7.44 – 7.18 (m, 2H), 6.82 (d, J =8.7 Hz, 1H), 3.95 (d, J = 5.2 Hz, 2H), 3.73 (s, 3H), 3.08 (q, J = 6.5 Hz, 2H), 1.97 (t, J = 7.3 Hz, 2H), 1.63 (p, J = 7.2 Hz, 2H). 13 CNMR (101 MHz, DMSO) d 169.27,169.19, 165.09, 154.87, 146.71, 132.13, 118.93, 113.40, 105.99,55.99, 47.08,38.67, 30.29, 25.83.HRMS (ESI) of compoundJH6: calcd. for C 14 H19 N4O4S [M + H] + =339.1122, found [M + H] + =339.1132.

[0060] Example 8: 5-(2-((5-fluorobenzo[ d ]Thiazol-2-yl)amino)acetamido)- N 1-Hydroxypentanamide (compound JH7)

[0061] Using 4 g (0.170 g, 0.0005 mol) and hydroxylamine hydrochloride (1.389 g, 0.02 mol) as raw materials, the same synthesis method as compound JH1 was used to obtain JH7 as a white solid of 0.144 g, with a yield of 84.72%. 1 H NMR (400 MHz, DMSO- d 6) d 10.34(s, 1H), 8.80 (s, 1H), 8.46 (d, J = 6.0 Hz, 1H), 8.04 (s, 1H), 7.69 (d, J = 2.6Hz, 1H), 7.39 (d, J = 3.2 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 4.00 (t, J = 3.8 Hz, 2H), 3.07 (d, J = 6.7 Hz, 2H), 1.95 (s, 2H), 1.49 (t, J = 7.6 Hz, 2H), 1.39 (d, J =7.6 Hz, 2H). 13 C NMR (101 MHz, DMSO) d 169.42, 168.89, 168.71, 161.70 (d, 1 J C-F =238.0 Hz), 153.89 (d, 3 J C-F = 12.5 Hz), 126.63, 122.21 (d, 3 J C-F = 10.1 Hz), 108.72(d, 2 JC-F = 24.2 Hz), 105.16 (d, 2 J C-F = 24.0 Hz), 46.99, 38.77, 32.36, 29.11,23.03.HRMS (ESI) of compoundJH7: calcd. for C 14 H 17 FN4O3SK[M + K] + =379.0637, found [M + K] + =379.0621.

[0062] Example 9: 5-(2-(6-fluorobenzo[ d ]Thiazol-2-yl)amino)acetamido)- N 1-Hydroxypentanamide (compound JH8)

[0063] Using 4h (0.170 g, 0.0005 mol) and hydroxylamine hydrochloride (1.389 g, 0.02 mol) as raw materials, the same method as compound JH1 was used to synthesize JH8 as a white solid of 0.144 g, with a yield of 84.72%. 1 H NMR (400 MHz, DMSO- d 6) d 10.34(s, 1H), 8.67 (s, 1H), 8.23 ​​(t, J = 5.8 Hz, 1H), 8.07 – 7.97 (m, 1H), 7.61 (d, J = 2.7 Hz, 1H), 7.36 (q, J = 4.9 Hz, 1H), 7.05 (t, J = 9.1 Hz, 1H), 3.97 (d, J = 5.5Hz, 2H), 3.07 (q, J = 6.5 Hz, 2H), 1.94 (t, J = 7.2 Hz, 2H), 1.49 (p, J = 7.5 Hz, 2H), 1.38 (p, J = 7.2 Hz, 2H). 13 C NMR (101 MHz, DMSO) d 169.44, 168.85, 166.59,157.69 (d, 1J C-F = 236.6 Hz), 149.32, 132.15 (d, 3 J C-F = 11.1 Hz), 118.99 (d, 3 J C-F =8.9 Hz), 113.25 (d, 2 J C-F = 23.7 Hz), 108.31 (d, 2 J C-F = 26.7 Hz), 47.04, 38.77,32.39, 29.14, 23.03.HRMS (ESI) of compoundJH8: calcd. for C 14 H 18 FN4O3S [M + H] + =341.1079, found [M + H] + =341.1072..

[0064] Example 10: 5-(2-(6-(trifluoromethyl)benzo[] d ]Thiazol-2-yl)amino)acetamido)- N 1-Hydroxypentanamide (compound JH9)

[0065] Using 4i (0.078 g, 0.0002 mol) and hydroxylamine hydrochloride (0.552 g, 0.008 mol) as raw materials, the same method as compound JH1 was used to synthesize JH9 as a white solid of 0.051 g, with a yield of 65.38%. 1 H NMR (400 MHz, DMSO- d 6) d 10.34(s, 1H), 8.78 – 8.29 (m, 2H), 8.14 (s, 1H), 8.06 (q, J = 6.9 Hz, 1H), 7.50 (t, J = 6.6 Hz, 1H), 7.38 – 7.19 (m, 1H), 4.01 (dd, J = 20.3, 5.4 Hz, 2H), 3.08 (q, J =6.5 Hz, 2H), 1.95 (t, J= 7.3 Hz, 2H), 1.50 (p, J = 7.6 Hz, 2H), 1.39 (p, J = 6.9Hz, 2H). 13 C NMR (101 MHz, DMSO) d 169.34, 168.51, 167.26, 155.64, 140.94,131.79, 123.06 (q, 3 J C-F = 5.7 Hz), 119.08 (q, 3 J C-F = 5.9 Hz), 118.37 (q, 4 J C-F = 4.7Hz), 47.02, 38.78, 32.36, 29.11, 23.03.HRMS (ESI) of compoundJH9: calcd. forC 15 H 18 F3N4O3S [M + H] + =391.1047, found [M + H] + =391.1046.

[0066] Example 11: 5-(2-((6-chlorobenzo[ d ]Thiazol-2-yl)amino)acetamido)- N -Hydroxypentanamide (compound JH10)

[0067] Using 4j (0.107 g, 0.0003 mol) and hydroxylamine hydrochloride (0.691 g, 0.01 mol) as raw materials, the same method as compound JH1 was used to synthesize JH10, which was a white solid of 0.086 g with a yield of 80.37%. 1 H NMR (400 MHz, DMSO- d 6) d 10.31(s, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 7.8Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.02 (t, J= 7.0 Hz, 1H), 3.98 (s, 2H), 3.08(t, J = 7.1 Hz, 2H), 1.95 (q, J = 7.6 Hz, 2H), 1.44 (dq, J = 36.0, 7.3 Hz, 4H). 13 CNMR (101 MHz, DMSO) d 169.39, 168.93, 166.68, 152.65, 131.11, 125.94, 121.50,121.39, 118.57, 47.06, 38.76, 32.39, 29.13, 23.04.HRMS (ESI) of compoundJH10:calcd. for C 14 H 18 ClN4O3S [M + H] + = 357.0783, found [M + H] + =357.0775.

[0068] Example 12: 5-(2-((5-chlorobenzo[ d ]Thiazol-2-yl)amino)acetamido)- N -Hydroxypentanamide (compound JH11)

[0069] Using 4kJ (0.071 g, 0.0002 mol) and hydroxylamine hydrochloride (0.691 g, 0.01 mol) as raw materials, the same method as compound JH1 was used to synthesize JH11, which was a white solid of 0.046 g with a yield of 64.79%. 1 H NMR (400 MHz, DMSO- d 6) d 10.34(s, 1H), 8.69 (s, 1H), 8.41 (d, J = 5.9 Hz, 1H), 8.04 (d, J = 6.2 Hz, 1H), 7.67(q, J = 3.2 Hz, 1H), 7.18 (d, J = 10.5 Hz, 1H), 6.87 (t, J = 9.2 Hz, 1H), 4.07 –3.92 (m, 2H), 3.08 (t, J = 6.8 Hz, 2H), 1.94 (t, J= 7.4 Hz, 2H), 1.48 (q, J = 7.8Hz, 2H), 1.39 (q, J = 7.4 Hz, 2H). 13 C NMR (101 MHz, DMSO) d 169.43, 168.70,168.40, 153.92, 130.62, 129.92, 122.66, 121.17, 117.93, 47.04, 38.76, 32.37,29.08, 23.04.HRMS (ESI) of compoundJH11: calcd. for C 14 H 18 ClN4O3S [M + H] + =357.0783, found [M + H] + =357.0765.

[0070] Example 13: 5-(2-((6-bromobenzo[ d ]Thiazol-2-yl)amino)acetamido)- N 1-Hydroxypentanamide (compound JH12)

[0071] Using 4 L (0.201 g, 0.0005 mol) and hydroxylamine hydrochloride (1.389 g, 0.02 mol) as raw materials, the same method as compound JH1 was used to synthesize JH12 as a white solid of 0.144 g, with a yield of 71.64%. 1 H NMR (400 MHz, DMSO- d 6) d 10.36(s, 1H), 8.69 (s, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 7.92 (s, 1H), 7.44 – 7.24(m, 2H), 3.99 (s, 2H), 3.07 (d, J = 6.7 Hz, 2H), 1.94 (d, J = 7.3 Hz, 2H), 1.49(t, J = 7.5 Hz, 2H), 1.39 (q, J = 7.3 Hz, 2H). 13 C NMR (101 MHz, DMSO) d169.38,168.70, 167.29, 151.90, 133.35, 128.81, 123.82, 119.95, 112.83, 47.02, 38.77,32.37, 29.12, 23.04.HRMS (ESI) of compoundJH12: calcd. for C 14 H 18 BrN4O3S [M +H] + =401.0278, found [M + H] + =401.0273.

[0072] Example 14: N -hydroxy-6-(2-((6-methoxybenzo[ d [Thiazol-2-yl)amino)acetamido)hexamylamide (compound JH13)

[0073] Using 4m (0.088 g, 0.00025 mol) and hydroxylamine hydrochloride (0.691 g, 0.01 mol) as raw materials, the same method as compound JH1 was used to synthesize JH13, which was a white solid of 0.055 g with a yield of 62.50%. 1 H NMR (400 MHz, DMSO- d 6) d 10.40(s, 1H), 8.68 (s, 1H), 8.04 (dt, J = 14.7, 5.7 Hz, 2H), 7.32 (d, J = 2.6 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 6.82 (dd, J = 8.7, 2.6 Hz, 1H), 3.94 (d, J = 5.5 Hz, 2H), 3.74 (s, 3H), 3.06 (q, J = 6.6 Hz, 2H), 1.93 (t, J = 7.4 Hz, 2H), 1.46 (q, J = 7.4Hz, 2H), 1.39 (q, J = 7.4 Hz, 2H), 1.24 (d, J = 2.7 Hz, 2H). 13 C NMR (101 MHz, DMSO) d169.57, 169.07, 165.11, 154.84, 146.70, 132.13, 118.90, 113.38, 105.98,56.00, 47.11, 38.90, 32.64, 29.27, 26.42, 25.32.HRMS (ESI) of compoundJH13:calcd. for C 16 H 23 N4O4S [M + H] + =367.1435, found [M + H] + =367.1435.

[0074] Example 15: 6-(2-(benzo[ d ]Thiazol-2-ylamino)acetamido)- N -Hydroxyhexanoamide (compound JH14)

[0075] Using 4n (0.084 g, 0.00025 mol) and hydroxylamine hydrochloride (0.691 g, 0.01 mol) as raw materials, the same method as compound JH1 was used to synthesize JH14, which was a white solid of 0.060 g with a yield of 71.43%. 1 H NMR (400 MHz, DMSO- d 6) d 10.35(s, 1H), 8.69 (s, 1H), 8.24 (s, 1H), 8.01 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.22 (s, 1H), 7.02 (s, 1H), 3.98 (d, J = 5.0 Hz, 2H), 3.07 (d, J = 6.8 Hz, 2H), 1.92 (s, 2H), 1.44 (d, J = 29.4 Hz, 4H), 1.24 (d, J = 7.5Hz, 2H). 13 C NMR (101 MHz, DMSO) d169.50, 168.88, 166.68, 152.65, 131.11,125.94, 121.51, 121.40, 118.56, 47.06, 38.93, 32.65, 29.29, 26.43, 25.33.HRMS(ESI) of compoundJH14: calcd. for C 15 H 21 N4O3S [M + H] + =337.1329, found [M + H] + =337.1322.

[0076] Example 16: 6-(2-((6-chlorobenzo[ d ]Thiazol-2-yl)amino)acetamido)- N -Hydroxyhexanoamide (compound JH15)

[0077] Using 4O (0.074 g, 0.0002 mol) and hydroxylamine hydrochloride (0.691 g, 0.01 mol) as raw materials, the same synthesis method as compound JH1 was used to obtain JH15 as a white solid of 0.066 g, with a yield of 89.19%. 1 H NMR (400 MHz, DMSO- d 6) d 10.34(s, 1H), 8.67 (s, 1H), 8.37 (t, J = 5.8 Hz, 1H), 8.01 (t, J = 5.6 Hz, 1H), 7.80(d, J = 2.3 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1H), 3.99 (d, J =5.4 Hz, 2H), 3.07 (q, J = 6.5 Hz, 2H), 1.92 (t, J = 7.4 Hz, 2H), 1.48 (q, J = 7.5Hz, 2H), 1.39 (q, J = 7.9 Hz, 2H), 1.24 (d, J = 5.8 Hz, 2H). 13 C NMR (101 MHz, DMSO) d169.54, 168.71, 167.31, 151.57, 132.83, 126.07, 125.23, 121.09, 119.41,47.03,38.94, 32.65, 29.26, 26.42, 25.32. (ESI) of compoundJH15: calcd.for C 15 H 20 ClN4O3S [M + H] + =371.0940, found [M + H] + =371.0937.

[0078] Example 17: 7-(2-(benzo[ d ]Thiazol-2-ylamino)acetamido)- N -Hydroxyheptanamide (compound JH16)

[0079] Using 4p (0.063 g, 0.00018 mol) and hydroxylamine hydrochloride (0.518 g, 0.0075 mol) as raw materials, the same method as compound JH1 was used to synthesize JH16, which was a pale yellow solid of 0.048 g, with a yield of 77.16%. 1 H NMR (400 MHz, DMSO- d 6) d 10.32 (s, 1H), 8.66 (s, 1H), 8.23 ​​(s, 1H), 7.98 (t, J = 5.7 Hz, 1H), 7.71 –7.64 (m, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.27 – 7.18 (m, 1H), 7.03 (t, J = 7.5 Hz, 1H), 3.98 (d, J = 5.6 Hz, 2H), 3.07 (d, J = 6.4 Hz, 2H), 1.92 (t, J = 7.3 Hz, 2H), 1.43 (dt, J = 24.7, 7.0 Hz, 4H), 1.24 (m, 4H). 13 C NMR (101 MHz, DMSO) d169.57,168.90, 166.68, 152.64, 131.10, 125.94, 121.52, 121.40, 118.55, 47.07, 38.97,32.68, 29.43, 28.77, 26.52, 25.53.HRMS (ESI) of compoundJH16: calcd. forC 16 H 23 N4O3S [M + H] + =351.1486, found [M + H] + =351.1482.

[0080] Example 18: 7-(2-((6-chlorobenzo[ d ]Thiazol-2-yl)amino)acetamido)- N -Hydroxyheptanamide (compound JH17)

[0081] Using 4q (0.115 g, 0.0003 mol) and hydroxylamine hydrochloride (0.828 g, 0.012 mol) as raw materials, the same method as compound JH1 was used to synthesize JH17, which was a white solid of 0.098 g with a yield of 85.22%. 1 H NMR (400 MHz, DMSO- d 6) d 10.34(s, 1H), 8.68 (s, 1H), 8.37 (t, J = 5.6 Hz, 1H), 8.00 (t, J = 5.6 Hz, 1H), 7.80(s, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 3.99 (d, J = 5.0 Hz, 2H), 3.07 (q, J = 6.5 Hz, 2H), 1.92 (t, J = 7.3 Hz, 2H), 1.42 (dp, J = 20.3, 7.0Hz, 4H), 1.27 – 1.17 (m, 4H). 13 C NMR (101 MHz, DMSO) d169.56, 168.69, 167.29,151.59, 132.84, 126.07, 125.22, 121.09, 119.40, 47.04, 38.98, 32.68, 29.42,28.76, 26.52, 25.53.HRMS (ESI) of compoundJH17: calcd. for C 16 H 22 ClN4O3S [M +H] + =385.1096, found [M + H] + =385.1096.

[0082] Example 19: N -hydroxy-2-(4-((2-((4-methoxybenzo[ d Thiazol-2-yl)amino)acetamido)methyl)phenyl)acetamide (compound JH18)

[0083] Using 4r (0.120 g, 0.0003 mol) and hydroxylamine hydrochloride (0.828 g, 0.012 mol) as raw materials, the same method as compound JH1 was used to synthesize JH18 as a pale yellow solid of 0.107 g, with a yield of 83.33%. 1 H NMR (400 MHz, DMSO- d 6) d 10.63 (s, 1H), 8.80 (s, 1H), 8.54 (d, J = 6.5 Hz, 1H), 8.22 (d, J = 6.0 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.19 (q, J = 7.6 Hz, 4H), 7.00 (s, 1H), 6.86 (d, J = 8.0Hz, 1H), 4.29 (t, J = 3.9 Hz, 2H), 4.15 – 4.01 (m, 2H), 3.86 (s, 3H), 3.24 (s, 2H). 13 C NMR (101 MHz, DMSO) d169.29, 167.51, 165.40, 150.58, 141.92, 137.91,134.91, 132.16, 129.22 (2C), 127.52 (2C), 122.31, 113.70, 108.47, 56.04,47.12, 42.28, 39.63.HRMS (ESI) of compoundJH118: calcd. for C 19 H 21 N4O4S [M + H] + = 401.1279, found [M + H] + = 401.1275.

[0084] Example 20: N -hydroxy-2-(4-((2-((6-methoxybenzo[ d Thiazol-2-yl)amino)acetamido)methyl)phenyl)acetamide (compound JH19)

[0085] Using 4S (0.081 g, 0.0002 mol) and hydroxylamine hydrochloride (0.552 g, 0.008 mol) as raw materials, the same method as compound JH1 was used to synthesize JH19, which was a white solid of 0.064 g with a yield of 79.01%. 1 H NMR (400 MHz, DMSO- d 6) d 10.62(s, 1H), 8.79 (s, 1H), 8.48 (d, J = 7.4 Hz, 1H), 8.09 (q, J = 4.9 Hz, 1H), 7.31(d, J = 12.2 Hz, 2H), 7.26 – 7.08 (m, 4H), 6.85 (d, J = 8.7 Hz, 1H), 4.28 (d, J =5.7 Hz, 2H), 4.01 (t, J = 4.3 Hz, 2H), 3.75 (d, J = 3.3 Hz, 3H), 3.24 (d, J = 3.3Hz, 2H). 13C NMR (101 MHz, DMSO) δ 168.97, 167.08, 164.64, 154.45, 146.28,137.56, 134.47, 131.74, 128.78 (2C), 127.06(2C), 118.49, 113.00, 105.57,55.55, 46.71, 41.80, 39.07.HRMS (ESI) of compoundJH19: calcd. for C 19 H 21 N4O4S[M + H] + =401.1279, found [M + H] + =401.1273.

[0086] Example 21: 2-((6-ethoxybenzo[ d ]thiazol-2-yl)amino)- N -(4-(2-(hydroxyamino)-2-oxoethyl)benzyl)acetamide (compound JH20)

[0087] Using 4t (0.124 g, 0.0003 mol) and hydroxylamine hydrochloride (0.828 g, 0.012 mol) as raw materials, the same synthesis method as compound JH1 was used to obtain JH20 as a white solid of 0.071 g, with a yield of 57.26%. 1 H NMR (400 MHz, DMSO- d 6) d 10.64(s, 1H), 8.81 (s, 1H), 8.50 (d, J = 7.3 Hz, 1H), 8.08 (d, J = 6.4 Hz, 1H), 7.30(q, J = 3.3 Hz, 2H), 7.27 – 7.09 (m, 4H), 6.84 (d, J = 8.6 Hz, 1H), 4.28 (t, J =4.3 Hz, 2H), 4.12 – 3.89 (m, 4H), 3.24 (d, J = 2.9 Hz, 2H), 1.31 (q, J = 6.1 Hz, 3H). 13 C NMR (101 MHz, DMSO) d169.46, 167.58, 165.10, 154.13, 146.65, 138.00,134.90, 132.15, 129.23 (2C), 127.51 (2C), 118.96, 113.99, 106.69, 64.01,47.16, 42.25, 15.22, 39.47.HRMS (ESI) of compoundJH20: calcd. for C 20 H 23 N4O4S[M + H] + =415.1435, found [M + H] + =415.1436.

[0088] Example 22: 2-((5-fluorobenzo[ d ]thiazol-2-yl)amino)- N -(4-(2-(hydroxyamino)-2-oxoethyl)benzyl)acetamide (compound JH21)

[0089] Using 4u (0.117 g, 0.0003 mol) and hydroxylamine hydrochloride (0.828 g, 0.012 mol) as raw materials, the same method as compound JH1 was used to synthesize JH21 as a white solid of 0.082 g, with a yield of 70.09%. 1 H NMR (400 MHz, DMSO- d 6) d 10.62(s, 1H), 8.79 (s, 1H), 8.50 (dt, J = 23.3, 5.7 Hz, 2H), 7.68 (q, J = 5.5 Hz, 1H), 7.19 (q, J = 7.1 Hz, 5H), 6.98 – 6.84 (m, 1H), 4.28 (d, J = 5.8 Hz, 2H), 4.06 (d, J = 5.6 Hz, 2H), 3.25 (s, 2H). 13 C NMR (101 MHz, DMSO) d 169.02, 168.91, 167.50,161.72 (d, 1 J C-F = 238.1 Hz), 153.90 (d, 3 JC-F = 12.3 Hz), 137.93, 134.98, 129.26(2C), 127.56 (2C), 126.67 (d, 4 J C-F = 1.6 Hz), 122.27 (d, 3 J C-F = 10.2 Hz), 108.80(d, 2 J C-F = 23.8 Hz), 105.16 (d, 2 J C-F = 24.1 Hz), 47.07, 42.30, 40.56.HRMS (ESI) ofcompoundJH21: calcd. for C 18 H 18 FN4O3S [M + H] + =389.1079, found [M + H] + =389.1073.

[0090] Example 23: N -hydroxy-2-(4-((2-((6-methylbenzo[ d Thiazol-2-yl)amino)acetamido)methyl)phenyl)acetamide (compound JH22)

[0091] Using 4V (0.096 g, 0.00025 mol) and hydroxylamine hydrochloride (0.691 g, 0.01 mol) as raw materials, the same synthesis method as compound JH1 was used to obtain JH22 as a yellow solid of 0.077 g, with a yield of 80.21%. 1 H NMR (400 MHz, DMSO- d 6) d 10.62(s, 1H), 8.79 (s, 1H), 8.51 (d, J = 6.6 Hz, 1H), 8.20 (d, J = 6.7 Hz, 1H), 7.48(s, 1H), 7.33 – 7.26 (m, 1H), 7.19 (q, J = 8.1 Hz, 4H), 7.06 (d, J = 8.2 Hz, 1H), 4.28 (t, J= 4.1 Hz, 2H), 4.03 (t, J = 3.8 Hz, 2H), 3.24 (s, 2H), 2.33 (s, 3H). 13 CNMR (101 MHz, DMSO) d 169.33, 167.51, 165.95, 150.53, 137.98, 134.91, 131.22,130.67, 129.22(2C), 127.50 (2C), 127.00, 121.36, 118.25, 47.13, 42.25, 40.57,21.23.HRMS (ESI) of compoundJH22: calcd. for C 19 H 21 N4O3S [M + H] + =385.1329, found [M + H] + =385.1329.

[0092] Example 24: 2-((5-bromobenzo[ d ]thiazol-2-yl)amino)- N -(4-(2-(hydroxyamino)-2-oxoethyl)benzyl)acetamide (compound JH23)

[0093] Using 4w (0.090 g, 0.0002 mol) and hydroxylamine hydrochloride (0.691 g, 0.01 mol) as raw materials, the same synthesis method as compound JH1 was used to obtain JH23 as a white solid of 0.067 g, with a yield of 74.44%. 1 H NMR (400 MHz, DMSO- d 6) d 10.63(s, 1H), 8.80 (s, 1H), 8.54 (dt, J = 11.0, 5.8 Hz, 2H), 7.66 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.25 – 7.14 (m, 5H), 4.28 (d, J = 5.9 Hz, 2H), 4.07 (d, J = 5.7 Hz, 2H), 3.25 (s, 2H). 13 C NMR (101 MHz, DMSO) d168.97, 168.20, 167.52,154.21, 137.91, 134.96, 130.43, 129.26(2C), 127.58(2C), 123.99, 123.14,120.85, 118.74, 47.08, 42.30, 39.98.HRMS (ESI) of compoundJH23: calcd. forC 18 H 18 BrN4O3S [M + H] + =449.0278, found [M + H] + =449.0269.

[0094] Example 25: 2-((6-bromobenzo[ d ]thiazol-2-yl)amino)- N -(4-(2-(hydroxyamino)-2-oxoethyl)benzyl)acetamide (compound JH24)

[0095] Using 4x (0.135 g, 0.0003 mol) and hydroxylamine hydrochloride (0.828 g, 0.012 mol) as raw materials, the same synthesis method as compound JH1 was used to obtain JH24 as a white solid of 0.067 g, with a yield of 74.44%. 1 H NMR (400 MHz, DMSO- d 6) d 10.64(s, 1H), 8.81 (s, 1H), 8.50 (d, J = 39.0 Hz, 2H), 7.81 (s, 1H), 7.37 (s, 1H), 7.23 (d, J = 27.0 Hz, 5H), 4.28 (s, 2H), 4.06 (s, 2H), 3.25 (s, 2H). 13 C NMR (101MHz, DMSO) d 169.07, 167.54, 167.31, 151.60, 137.95, 134.96, 132.90, 129.25(2C), 127.54(2C), 126.12, 125.29, 121.13, 119.44, 55.37, 47.12, 42.29.HRMS(ESI) of compoundJH24: calcd. for C 18 H 18 BrN4O3S [M + H]+ =449.0278, found [M +H] + =449.0267..

[0096] Example 26: N -hydroxy-2-(4-(2-((6-methoxybenzo[ d Thiazol-2-yl)amino)acetamido)phenyl)acetamide (compound JH25)

[0097] Using 4y (0.077 g, 0.0002 mol) and hydroxylamine hydrochloride (0.552 g, 0.008 mol) as raw materials, the same synthesis method as compound JH1 was used to obtain JH25 as a white solid of 0.061 g, with a yield of 79.22%. 1 H NMR (400 MHz, DMSO- d 6) d 10.62(s, 1H), 10.08 (s, 1H), 8.81 (s, 1H), 8.13 (t, J = 5.8 Hz, 1H), 7.52 (d, J = 8.1Hz, 2H), 7.32 (d, J = 2.6 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 6.81 (dd, J = 8.8, 2.6 Hz, 1H), 4.18 (d, J = 5.8 Hz, 2H), 3.73 (s, 3H), 3.22(s, 2H). 13 C NMR (101 MHz, DMSO) d 168.16, 167.59, 165.17, 154.91, 146.65,137.79, 132.15, 131.34, 129.69 (2C), 119.46 (2C), 118.97, 113.43, 106.03,56.00, 47.50, 39.23.HRMS (ESI) of compoundJH25: calcd. for C 18 H 19 N4O4S [M + H] + =387.1122, found [M + H] + =387.1129.

[0098] Example 27: N -hydroxy-2-(4-(2-((6-methylbenzo[ d Thiazol-2-yl)amino)acetamido)phenyl)acetamide (compound JH26)

[0099] Using 4z (0.111 g, 0.0003 mol) and hydroxylamine hydrochloride (0.828 g, 0.012 mol) as raw materials, the same synthesis method as compound JH1 was used to obtain JH26 as a white solid of 0.0547 g, with a yield of 49.28%. 1 H NMR (400 MHz, DMSO- d 6) d 10.64(s, 1H), 10.10 (s, 1H), 8.83 (s, 1H), 8.25 (t, J = 5.8 Hz, 1H), 7.54 (d, J = 8.1Hz, 2H), 7.48 (d, J = 1.7 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 8.1 Hz, 2H), 7.03 (dd, J = 8.2, 1.8 Hz, 1H), 4.21 (d, J = 5.6 Hz, 2H), 3.24 (s, 2H), 2.32(s, 3H). 13 C NMR (101 MHz, DMSO) d 168.09, 167.58, 166.05, 150.46, 137.79,131.35, 131.20, 130.72, 129.70(2C), 126.99, 121.39, 119.46 (2C), 118.29,47.49, 39.24, 21.23.HRMS (ESI) of compoundJH26: calcd. for C 18 H 19 N4O3S [M + H] + =371.1173, found [M + H] + =371.1174.

[0100] Example 28: N -hydroxy-2-(4-(2-((4-methoxybenzo[d Thiazol-2-yl)amino)acetamido)phenyl)acetamide (compound JH27)

[0101] Using 5a (0.112 g, 0.0003 mol) and hydroxylamine hydrochloride (0.828 g, 0.012 mol) as raw materials, the same synthesis method as compound JH1 was used to obtain JH27 as a white solid of 0.0479 g, with a yield of 43.15%. 1 H NMR (400 MHz, DMSO- d 6) d 10.63(s, 1H), 10.15 (s, 1H), 8.82 (s, 1H), 8.27 (t, J = 5.8 Hz, 1H), 7.53 (d, J = 8.3Hz, 2H), 7.27 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 8.2 Hz, 2H), 7.00 (t, J = 8.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 4.24 (d, J = 5.7 Hz, 2H), 3.82 (s, 3H), 3.23 (s, 2H). 13 C NMR (101 MHz, DMSO) d 168.04, 167.61, 165.50, 150.50, 141.83, 137.78,132.12, 131.35, 129.71 (2C), 122.35, 119.45 (2C), 113.75, 108.51, 55.99,47.54, 39.24.HRMS (ESI) of compoundJH27: calcd. for C 18 H 19 N4O4S [M + H] + =387.1122, found [M + H] + =387.1123.

[0102] Example 29: Inhibitory activity of the compound against Pseudomonas aeruginosa biofilm

[0103] Experimental Methods: This experiment used crystal violet staining to quantitatively determine biofilm content. The maximum screening concentration of the compound was 10 μM. A blank control group and a negative control group were set up, with azithromycin as the positive control. The compound was diluted to a series of concentration gradients using a two-fold dilution method. 75 μL of drug-containing culture medium was added to each well of a 96-well plate, followed by inoculation with 75 μL of *Pseudomonas aeruginosa* PAO1 bacterial suspension. After incubation at 37 ℃ for 24 h, airborne bacteria were washed away with PBS buffer, and the plates were fixed with 160 μL of methanol at room temperature for 20 min. Then, 150 μL of 0.1% crystal violet was added for staining, and the plates were incubated at room temperature for 15 min. Excess dye was washed away with distilled water, and 150 μL of 33% glacial acetic acid was added. After shaking and homogenization, the absorbance was measured at 570 nm using a microplate reader. The experiment was repeated three times to screen for compounds with biofilm inhibitory activity. The results of the biofilm inhibitory activity experiment are shown in Table 1.

[0104] Table 1. Inhibition rate of benzothiazole-coupled isohydroxamic acid derivatives on Pseudomonas aeruginosa PAO1 biofilm.

[0105]

[0106] a, For all compounds, their IC 50 All results were obtained when the biofilm inhibition rate of the positive control drug azithromycin was >50%.

[0107] Experimental Results: Table 1 shows that the inhibitory activity of compounds on PAO1 biofilms decreases with increasing aliphatic carbon chain length, with compounds with a carbon chain length of 4 exhibiting the best biofilm inhibitory activity. This phenomenon may be related to the solubility of the compounds due to carbon chain length. Furthermore, the biofilm inhibitory activity of compounds did not significantly change when the aliphatic chain was replaced by an aromatic ring. Overall, compounds substituted with electron-donating groups showed better biofilm inhibitory activity than those substituted with electron-withdrawing groups; methoxy > methyl > electron-withdrawing group. Among methoxy substitutions at different positions, compounds substituted at position 4 exhibited the strongest biofilm inhibitory activity, followed by those at positions 6 and 5. This trend may be related to the position of the substituent on the benzene ring, affecting the electron distribution and spatial configuration of the molecule. Among these, compound JH2, substituted with a methoxy group at position 6, showed the best biofilm inhibitory activity, with an IC50 value of [missing value]. 50 = 0.40±0.09 μM.

[0108] Example 30: Synergistic effect of compound JH2 on ciprofloxacin (CIP) in a mouse wound infection model

[0109] Experimental Methods: This animal experiment was conducted in accordance with relevant national regulations for animal experiments. *Pseudomonas aeruginosa* strain PAO1 was used in this experiment. Female 5-week-old Babl / c mice were purchased from SPF (Beijing) Biotechnology.co. Ltd. Throughout the experiment, the mice were kept in a constant temperature environment of 25℃ with a 12-hour light / night cycle, and were provided with ample food and water. Twenty mice were randomly divided into four groups of five. After anesthetizing with 4% chloral hydrate, the fur on the backs of the mice was shaved, and a 4-5 mm circular wound was created on the back of each mouse. 5 × 10⁻⁶ cells were then inoculated into the wound. 8 CFU PAO1 was used to establish a wound infection model for 24 hours. Then, different groups of mice were treated with different drugs (physiological saline, 1 mg / ml CIP, 0.002 mg / ml CIP + 2.5 μMJH2, 0.001 mg / ml CIP + 2.5 μMJH2). After 3 consecutive days of treatment, skin samples were taken from the wound site for CFU counting, and the wound area was calculated by photographing the wounds daily.

[0110] Experimental results: such as Figure 1 As shown, after 3 consecutive days of administration, the number of bacteria at the wound site in the combined treatment group was significantly lower than that in the saline group (Control). Calculations of bacterial survival rate at the wound site showed that the saline group had a 100% survival rate, while after 3 days of treatment with 1 mg / ml CIP, the bacteria were almost completely eliminated, with a survival rate of 0%. After combined treatment with 0.001 mg / ml CIP and 2.5 μM JH2, very few bacteria survived, with a survival rate approaching 0%, indicating that JH2's synergistic effect on CIP reached 500-1000 times. Subsequent monitoring of the mouse wound area yielded consistent results. After 3 days of combined administration of JH2 and diluted CIP, the wound area was essentially the same as that of the CIP-only group, and significantly smaller than that of the Control group. By day 9, the wound healing rate reached approximately 75%. All these results indicate that JH2, as a biofilm inhibitor, has a good synergistic effect on CIP, with a synergistic effect of 500-1000 times.

[0111] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make various improvements and modifications to the present invention without departing from the principles of the invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A benzothiazole of formula (I) coupled with an isohydroxamic acid or a pharmaceutically acceptable salt thereof: Equation (I) Where R1 is a substituent group. L is one of the following structures: 。 2. The benzothiazole-coupled isohydroxamic acid compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that... The compound is selected from:

3. A method for preparing the benzothiazole-coupled isohydroxamic acid compound as described in claim 1, characterized in that... Includes the following steps: (1.1) 2-aminobenzothiazoles with different substitutions, di-tert-butyl dicarbonate and triethylamine were reacted in a solvent. After the reaction was completed, the reaction solution was purified to obtain compound 1a-1m. (1.2) Compound 1a-1m, ethyl bromoacetate and sodium hydride were placed in a solvent and reacted at 0°C. The resulting reaction solution was purified to obtain compound 2a-2m. (1.3) Compound 2a-2m and sodium hydroxide aqueous solution were placed in a solvent and reacted at 50°C. The resulting reaction solution was purified to obtain compound 3a-3m. (1.4) Compounds 3a-3m, fatty amines or aromatic amine methyl esters, react with HATU and triethylamine in a solvent. The resulting reaction solution is purified to obtain an intermediate. The intermediate is then reacted in a dichloromethane solution of trifluoroacetic acid. The resulting reaction solution is purified to obtain compounds 4a-5a. (1.5) Compounds 4a-5a were placed in methanol with hydroxylamine hydrochloride and potassium hydroxide. The resulting reaction solution was purified to obtain compounds JH1-JH27. Its synthesis circuit is as follows: 。 4. The use of the benzothiazole-coupled hydroxamic acid compound or a pharmaceutically acceptable salt thereof as described in claim 1 or 2 in the preparation of an antibiofilm drug and an antibiotic potentiator; wherein the antibiofilm drug is an antibiofilm drug against Pseudomonas aeruginosa; and the antibiotic potentiator is a ciprofloxacin potentiator.

5. A pharmaceutical composition comprising the benzothiazole-coupled hydroxamic acid compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition according to claim 5, characterized in that, The pharmaceutical composition also contains ciprofloxacin.

7. The pharmaceutical composition according to claim 6, characterized in that, The weight ratio of benzothiazole coupled with hydroxamic acid compounds or their pharmaceutically acceptable salts to ciprofloxacin is 0.2-10.0:

1.

8. The pharmaceutical composition according to claim 7, characterized in that, The weight ratio of benzothiazole coupled with hydroxamic acid compounds or their pharmaceutically acceptable salts to ciprofloxacin is 0.8-2.0:1.

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