N-acylhydrazone-ciprofloxacin heterozygote and preparation method and application thereof

A technology of ciprofloxacin and acyl hydrazone, which is applied in the field of antibacterial and can solve the problems of increasing bacterial resistance and the like

Active Publication Date: 2021-02-12

GUANGDONG INST OF MICROBIOLOGY GUANGDONG DETECTION CENT OF MICROBIOLOGY

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Problems solved by technology

However, with the widespread use and even abuse of such drugs, bacterial drug ...

Abstract

The invention discloses an N-acylhydrazone-ciprofloxacin heterozygote and a preparation method and application thereof. The structural formula of the N-acylhydrazone-ciprofloxacin heterozygote is shown as a formula (II). A series of N-acylhydrazone-ciprofloxacin heterozygotes with brand-new structures are designed and synthesized by introducing an antibacterial pharmacophore N-acylhydrazone to thenitrogen atom of a ciprofloxacin C-7 piperazinyl, and the preparation method comprises the following steps: taking ethyl chloroacetate or ethyl bromoacetate and ciprofloxacin as raw materials, carrying out substitution reaction to obtain a precursor compound; reacting the precursor compound with hydrazine hydrate under a heating condition to obtain an N-hydrazide-ciprofloxacin intermediate (I), and reacting the intermediate (I) with aldehyde to obtain the N-acylhydrazone ciprofloxacin heterozygote (II). The heterozygote shows antibacterial activity, particularly has good antibacterial activity on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa, and can be used as an antibacterial candidate compound.

Application Domain

Antibacterial agentsOrganic chemistry +1

Technology Topic

PiperazinePharmacophore +19

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Examples

Experimental program(7)

Example Embodiment

[0022]Example 1

[0023](E)-1-Cyclopropyl-6-fluoro-7-(4-(2-(2,3-difluorobenzylidene)hydrazino-2-oxyethyl)piperazin-1-yl) Preparation steps of -4-oxy-1,4-dihydroquinoline-3-carboxylic acid (IIa):

[0024]

[0025]Add 5mmol of ciprofloxacin, 5mmol of ethyl chloroacetate, 50mL of N,N-dimethylformamide (DMF), and 0.1mol of triethylamine into a 100mL flask, stir and react at 100°C for 24 hours. After the reaction is complete, reduce pressure Most of the solvent was removed by rotary evaporation, cooled, filtered, and the filter residue was washed with methanol and filtered to obtain the precursor compound. 2.5mmol precursor compound, 12.5mmol hydrazine hydrate, and 10mL absolute ethanol were added to a 100mL flask, and the reaction was stirred at 75°C for 20 hours, cooled, filtered, washed with ethanol, and air-dried to obtain Intermediate I, namely 1-cyclopropyl- 6-Fluoro-7-(4-(2-hydrazino-2-oxyethyl)piperazin-1-yl)-4-oxy-1,4-dihydroquinoline-3-carboxylic acid.

[0026]Intermediate I (1-cyclopropyl-6-fluoro-7-(4-(2-hydrazino-2-oxyethyl)piperazin-1-yl)-4-oxy-1 ,4-Dihydroquinoline-3-carboxylic acid), 2.0mmol 2,3-difluorobenzaldehyde, 20mL of absolute ethanol were added to a 100mL flask, stirred at 60℃ for 24 hours, the reaction was completed, filtered, and finally the target Product (IIa), the yield is 80%.1H NMR(400MHz,DMSO)δ15.23(s,1H,-COOH), 11.56 and 11.52(s,1H,-NH-CO-is affected byketo-form and enol-form), 8.67(s,1H,quinoline ),8.60 and 8.17(s,1H,-CH=N-isaffected by keto-form and enol-form),7.92(d,J=13.3Hz,1H,quinoline),7.69(m,1H,phenyl),7.59 (d,J=7.5Hz,1H,quinoline),7.49(m,1H,phenyl),7.29(d,J=5.2Hz,1H,phenyl),3.84(s,1H,cyclopropyl),3.70and 3.24(s ,2H,methylene is affected by keto-form and enol-form),3.38(s,4H,piperazinyl),2.85(s,2H,piperazinyl),2.75(s,2H,piperazinyl),1.33(d,J=6.3Hz ,2H,cyclopropyl),1.19(s,2H,cyclopropyl).

Example Embodiment

[0027]Example 2

[0028](E)-1-Cyclopropyl-6-fluoro-7-(4-(2-(2,5-difluorobenzylidene)hydrazino-2-oxyethyl)piperazin-1-yl) Preparation steps of -4-oxy-1,4-dihydroquinoline-3-carboxylic acid (IIb):

[0029]

[0030]Add 5mmol of ciprofloxacin, 5mmol of ethyl bromoacetate, 50mL of N,N-dimethylformamide (DMF), and 0.1mol of triethylamine into a 100mL flask, stir and react at 100°C for 24 hours. After the reaction is complete, reduce pressure Most of the solvent was removed by rotary evaporation, cooled, filtered, and the filter residue was washed with methanol and filtered to obtain the precursor compound. 2.5mmol precursor compound, 12.5mmol hydrazine hydrate, and 10mL absolute ethanol were added to a 100mL flask, and the reaction was stirred at 75°C for 20 hours, cooled, filtered, washed with ethanol, and air-dried to obtain Intermediate I, namely 1-cyclopropyl- 6-Fluoro-7-(4-(2-hydrazino-2-oxyethyl)piperazin-1-yl)-4-oxy-1,4-dihydroquinoline-3-carboxylic acid.

[0031]Intermediate I (1-cyclopropyl-6-fluoro-7-(4-(2-hydrazino-2-oxyethyl)piperazin-1-yl)-4-oxy-1 , 4-dihydroquinoline-3-carboxylic acid), 2.0mmol 2,5-difluorobenzaldehyde, 20mL of absolute ethanol were added to a 100mL flask, stirred at 60°C for 24 hours, after the reaction was completed, filtered, washed with ethanol, Air-dried to obtain the target product (IIb) with a yield of 83%.1H NMR(400MHz,DMSO)δ15.22(s,1H,-COOH), 11.54and 11.53(s,1H,-NH-CO-isaffected by keto-form and enol-form), 8.67(s,1H,quinoline ),8.67(s,1H,quinoline),8.57 and 8.13(s,1H,-CH=N-is affected by keto-form and enol-form),7.91(dd,J=13.3,2.7Hz,1H,quinoline ), 7.64(m,1H,phenyl),7.58(d,J=7.4Hz,1H,quinoline),7.35(m,2H,phenyl),3.84(s,1H,cyclopropyl),3.71and 3.24(s,2H ,methylene is affected by keto-form and enol-form),3.38(s,4H,piperazinyl),2.84(s,2H,piperazinyl),2.75(s,2H,piperazinyl),1.33(d,J=6.2Hz, 2H,cyclopropyl),1.19(s,2H,cyclopropyl).

Example Embodiment

[0032]Example 3

[0033](E)-1-Cyclopropyl-6-fluoro-7-(4-(2-((1E,2E)-3-(furan-2-yl)allyl)hydrazino-2-oxy (Ethyl)piperazin-1-yl)-4-oxy-1,4-dihydroquinoline-3-carboxylic acid (IIc) preparation steps:

[0034]

[0035]Intermediate I (1-cyclopropyl-6-fluoro-7-(4-(2-hydrazino-2-oxyethyl)piperazin-1-yl)-4-oxy-1 ,4-dihydroquinoline-3-carboxylic acid), 2.0mmol(E)-3-(furan-2-yl)acrolein, and 20mL of absolute ethanol were added to a 100mL flask, and the reaction was stirred at 60°C for 24 hours. After finishing, filter, wash with ethanol, and air-dry to obtain the target product (IIc) with a yield of 80%.1H NMR(400MHz,DMSO)δ15.15(s,1H,-COOH), 11.21 and 11.15(s,1H,-NH-CO-is affected by keto-form and enol-form), 8.61(s,1H, quinoline),8.06,8.03and 7.75(s,1H,-CH=N-is affected by keto-form and enol-form),7.82 and7.79(d,1H,quinoline),7.75,7.73 and 7.71(m, 1H,furyl),7.54 and 7.52(d,1H,quinoline),6.86(t,1H,furyl),6.69-6.57(m,3H,furyl and allylidene),3.80(s,1H,cyclopropyl),3.57 and 3.18 (s,2H,methylene is affected by keto-form and enol-form),3.38(s,4H,piperazinyl),2.81(s,2H,piperazinyl),2.73(s,2H,piperazinyl),1.34 and 1.33(d ,2H,cyclopropyl),1.18(s,2H,cyclopropyl).

PUM

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