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New antibacterial compounds

a technology of antibacterial compounds and compounds, applied in the field of new antibacterial compounds, can solve the problems of increasing the risk of infection spreading to others, ineffective standard treatment, and inability to meet the needs of patients, and achieve the effect of facilitating preparation and detection

Active Publication Date: 2020-03-26
AZIENDE CHIMHE RIUNITE ANGELINI FRANCESCO A C R A F
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The compounds provide broad-spectrum antibacterial activity, potentially slowing the emergence of resistance by simultaneously targeting DNA gyrase and topoisomerase IV, effectively treating various bacterial infections, including those resistant to other antibiotics.

Problems solved by technology

Resistant bacteria are able to withstand attack by antibiotics and antibacterial drugs, so that standard treatments become ineffective and infections persist increasing risk of spread to others.

Method used

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  • New antibacterial compounds
  • New antibacterial compounds
  • New antibacterial compounds

Examples

Experimental program
Comparison scheme
Effect test

example 1

Inhibition of DNA Gyrase and Topo IV in E. coli and S. aureus

[0557]The above compounds were tested for the inhibition of the enzyme DNA gyrase in a gyrase supercoiling assay and for the inhibition of the enzyme topoisomerase IV in a decatenation assay, in both Gram positive and Gram negative bacteria, according to the following methods.

[0558]Both the assays were carried out according to a set-up method modified from the article to Blanche F, et al. “Differential Behaviors of Staphylococcus aureus and Escherichia coli Type II DNA Topoisomerases”, Antimicrob. Agents Chemother., 1996, Vol. 40, No. 12 p. 2714-2720.

[0559]The compounds were screened at single concentration (200, 100 or 50 μM), in duplicate.

[0560]Ciprofloxacin and novobiocin were used as reference compounds, at single concentration of 200 and 50 μM, respectively.

[0561]DNA Gyrase Supercoiling Assay.

[0562]Reagents from S. aureus and E. coli Gyrase Supercoiling Assay kits (Inspiralis, UK) were used. A master mix with a total...

example 2

Determination of IC50

[0586]The compounds that in the above example 1 showed an inhibitory activity were further assayed in concentration-response curve (eight half-log concentrations ranging from 0.1 to 300 μM) in order to determine the IC50.

[0587]The supercoiled or decatenated DNA bands obtained as described in Example 1 were analysed as follows.

[0588]Bands were analyzed by gel documentation equipment (Syngene, Cambridge, UK) and quantitated using Syngene Gene Tools software. Raw gel data (fluorescent band volumes) collected from Syngene, GeneTools gel analysis software were converted to a percentage of the 100% control (the fully supercoiled or decatenated DNA band). These data were analyzed using SigmaPlot Version 12.3 (2013). The IC50 data were calculated by using the global curve fit non-linear regression tool by selecting the Single, 2 Parameter fit function from the Exponential Decay equation category.

[0589]The results are reported in the following table 3.

TABLE 3CompoundIC5...

example 3

Determination of IC50

[0590]Compounds 301-303, 314, 343 and 354 were assayed in concentration-response curve (eight half-log concentrations ranging from 0.1 to 300 μM) in order to determine the IC50, following the procedure described in example 2.

[0591]The results are reported in the following table 4.

TABLE 4CompoundIC50IC50IC50IC50No.DNA gyraseTopo IVDNA gyraseTopo IV3010.460.430.7270.33020.590.120.583.263032.670.629.92>1003140.851.147.1>1003430.911.271.988.733540.470.180.350.92

[0592]The data of Table 3 are comparable to the data of Table 2, and confirmed the activity of Compounds 301-303, 314, 343 and 354 to effectively inhibit both DNA gyrase and Topo IV of E. coli and / or S. aureus.

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Abstract

The present invention relates to novel antibacterial compounds, pharmaceutical compositions containing them and their use as antimicrobials.

Description

FIELD OF THE INVENTION[0001]The present invention relates to novel antibacterial compounds, pharmaceutical compositions containing them and their use as antimicrobials.BACKGROUND OF THE INVENTION[0002]DNA topoisomerases are enzymes involved in the modification of the DNA-supercoiling during replication or transcription. These enzymes bind to single-stranded or double-stranded DNA and they cut the phosphate backbone of the DNA such that the DNA strand is untangled or unwound. At the end of the replication or transcription processes, the enzymes themselves reseal the DNA backbone.[0003]DNA topoisomerases are classified as type I when they cut a single strand of a DNA double helix and as type II when they cut both strands of a DNA double helix.[0004]Bacterial type II topoisomerases comprise DNA gyrase and topoisomerase IV (TopoIV), which are heterotetrameric enzymes concurrently present in almost all the prokaryotic cells. Both the enzymes are necessary for DNA replication and, hence, ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D401/14A61P31/04C07D471/04C07D491/052C07D519/00C07D498/04C07D471/16
CPCC07D401/14A61P31/04C07D471/04C07D471/16C07D519/00C07D498/04C07D491/052C07D491/04C07D493/04C07D513/04A61K31/436A61K31/4985
Inventor OMBRATO, ROSELLAMAGARO, GABRIELEGAROFALO, BARBARAFURLOTTI, GUIDOMANGANO, GIORGINACAPEZZONE DE JOANNON, ALESSANDRA
Owner AZIENDE CHIMHE RIUNITE ANGELINI FRANCESCO A C R A F