A metallo-beta-lactamase inhibitor and its preparation method and application

A lactamase and inhibitor technology, applied in the field of new antibacterial drug development, can solve problems such as inability to effectively eliminate metallo-beta-lactamase drug resistance, and achieve the effects of easy industrial production, high inhibition efficiency and simple preparation

Active Publication Date: 2022-04-05
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Despite substantial research efforts in designing effective drugs to counteract hydrolysis in broad-spectrum drug-resistant bacteria, there are currently no clinical inhibitors effective in eliminating metallo-β-lactamase resistance

Method used

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  • A metallo-beta-lactamase inhibitor and its preparation method and application
  • A metallo-beta-lactamase inhibitor and its preparation method and application
  • A metallo-beta-lactamase inhibitor and its preparation method and application

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Experimental program
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Effect test

Embodiment 1

[0049] Synthetic route such as figure 1 As shown, it specifically includes the following steps:

[0050] (1) Dissolve lutinamine (200mg, 1.0mmol) in DMF (4mL), then add S-(2-bromoethyl) ester (220mg, 1.2mmol) and potassium carbonate (1.5mmol), 80 Stir at ℃, react for 12 hours, stop heating, cool to room temperature, pour the reaction product into a separatory funnel, add 15 mL of dichloromethane and water (3ⅹ10 mL) for extraction, collect the organic phase; add anhydrous sodium sulfate to the organic phase Dry and distill under reduced pressure to obtain the crude product. The crude product was purified with a silica gel column; wherein, methanol: dichloromethane = 5% to 15%, and the mercapto-protected product was obtained as a brown oily liquid (225mg), and the yield was 75%;

[0051] (2) Dissolve the thiol-protected product (225 mg, 0.75 mmol) in methanol (5 mL), add sodium methoxide (81 mg, 1.5 mmol), stir at room temperature, react for 1.5 hours, and pour the reaction pro...

Embodiment 2

[0054] Synthetic route such as figure 2 As shown, it specifically includes the following steps:

[0055] (1) Dissolve lutinamine (200mg, 1.0mmol) in acetonitrile (6mL), then add ethyl 2-bromoacetate (250mg, 1.5mmol) and potassium carbonate (2.5mmol), stir at 100°C, React for 11 hours, stop heating, cool to room temperature, pour the reaction product into a separatory funnel, add 15 mL of dichloromethane and water (3ⅹ10 mL) for extraction, collect the organic phase; add anhydrous sodium sulfate to the organic phase to dry and reduce pressure The crude product was obtained by distillation, and the crude product was purified with a silica gel column; wherein, methanol: dichloromethane = 5% to 15%, and the hydroxyl-protected product was obtained as a yellow oily liquid (194mg), and the yield was 68.3%;

[0056] (2) Dissolve the hydroxyl-protected product (194 mg, 0.68 mmol) in methanol (8 mL), add sodium hydroxide (1.2 mmol), stir at room temperature, react for 2.5 hours, and po...

Embodiment 3

[0059] Synthetic route such as image 3 As shown, it specifically includes the following steps:

[0060] (1) Dissolve lutinamine (200mg, 1.0mmol) in acetone (5mL), then add (2-bromoethyl) tert-butyl carbamate (269mg, 1.2mmol) and potassium carbonate (280mg, 2.0 mmol), stirred at 80°C, reacted for 13 hours, stopped heating, cooled to room temperature, poured the reaction product into a separatory funnel, added 15 mL of dichloromethane and water (3ⅹ10 mL) for extraction, collected the organic phase; added to the organic phase Drying over anhydrous sodium sulfate and distilling under reduced pressure to obtain the crude product. The crude product was purified with a silica gel column; wherein, methanol:dichloromethane=5% to 15%, the product protected by the amino group was obtained as a brown oily liquid (317mg), and the yield was 92.8%;

[0061] (2) Dissolve the amino-protected product (317mg, 0.92mmol) in dichloromethane (8mL), add trifluoroacetic acid (2mL), stir at room tem...

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Abstract

The invention discloses a metallo-beta-lactamase inhibitor, a preparation method and application thereof. The present invention is obtained by dissolving the pyridine amine compound in solvent 1, adding ester compound and carbonate, stirring at 80-100°C for 11-13 hours, cooling the reaction product to room temperature, extracting, vacuum-drying and purifying to obtain Product 1; Dissolve product 1 in solvent 2, add ester hydrolyzate, stir at room temperature for 1.5-2.5 hours, extract the reaction product, vacuum dry and purify to obtain Zn 2+ Chelating agent; dissolve the β-lactam compound in solvent 3, add Zn 2+ Chelating agent and alkali, stirring at room temperature for 11 to 13 hours, extracting, vacuum drying and purifying the reaction product to obtain a metallo-beta-lactamase inhibitor, which can be used as a combined agent for antibiotics to inhibit bacterial proliferation. The preparation of the inhibitor of the invention is simpler, the material cost is low, and the inhibitor reduces the biotoxicity of molecules and has higher antibacterial efficiency.

Description

technical field [0001] The invention belongs to the technical field of novel antibacterial drug development, and in particular relates to a metallo-beta-lactamase inhibitor and a preparation method and application thereof. Background technique [0002] Bacterial infections resistant to β-lactams are mainly due to the production of a large number of different β-lactamases, which are able to hydrolyze β-lactam antibiotics. According to Ambler's classification, β-lactamases are classified into classes A, B, C and D, where classes A, C and D are serine β-lactamases and class B are metallo-beta-lactamases (MBLs) . Among them, class B MBLs are the most worrisome because they catalyze the hydrolysis of almost all available β-lactam antibiotics. Despite substantial research efforts to design effective drugs to counteract hydrolysis by broad-spectrum drug-resistant bacteria, there are currently no therapies capable of reversing MBLs-mediated drug resistance. [0003] Metallo-β-lac...

Claims

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Application Information

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IPC IPC(8): C07D501/36C07D501/04C07D501/12A61K31/546A61K45/06A61P31/04
CPCC07D501/36C07D501/04C07D501/12A61P31/04
Inventor 王晓剑田宏妍李伟毛贤贤邹娟
Owner NANJING UNIV OF TECH
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