Amide containing NBTI antibacterials with reduced hERG inhibition, retained antimicrobial activity against gram-positive bacteria and in vivo efficacy
Copyright © 2023 The Author(s). Published by Elsevier Masson SAS.. All rights reserved..
Novel bacterial topoisomerase inhibitors (NBTIs) are new promising antimicrobials for the treatment of multidrug-resistant bacterial infections. In recent years, many new NBTIs have been discovered, however most of them struggle with the same issue - the balance between antibacterial activity and hERG-related toxicity. We started a new campaign by optimizing the previous series of NBTIs, followed by the design and synthesis of a new, amide-containing focused NBTI library to reduce hERG inhibition and maintain antibacterial activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). This optimization strategy yielded the lead compound 12 that exhibits potent antibacterial activity against Gram-positive bacteria, reduced hERG inhibition, no cardiotoxicity in zebrafish model, and a favorable in vivo efficacy in a neutropenic murine thigh infection model of MRSA infection.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:250 |
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| Enthalten in: |
European journal of medicinal chemistry - 250(2023) vom: 15. März, Seite 115160 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kokot, Maja [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 15.03.2023 Date Revised 15.03.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejmech.2023.115160 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM352637366 |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Author(s). Published by Elsevier Masson SAS.. All rights reserved. | ||
| 520 | |a Novel bacterial topoisomerase inhibitors (NBTIs) are new promising antimicrobials for the treatment of multidrug-resistant bacterial infections. In recent years, many new NBTIs have been discovered, however most of them struggle with the same issue - the balance between antibacterial activity and hERG-related toxicity. We started a new campaign by optimizing the previous series of NBTIs, followed by the design and synthesis of a new, amide-containing focused NBTI library to reduce hERG inhibition and maintain antibacterial activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). This optimization strategy yielded the lead compound 12 that exhibits potent antibacterial activity against Gram-positive bacteria, reduced hERG inhibition, no cardiotoxicity in zebrafish model, and a favorable in vivo efficacy in a neutropenic murine thigh infection model of MRSA infection | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Antibacterials | |
| 650 | 4 | |a DNA gyrase | |
| 650 | 4 | |a In vivo efficacy | |
| 650 | 4 | |a MRSA | |
| 650 | 4 | |a NBTIs | |
| 650 | 4 | |a Topoisomerase IV | |
| 650 | 4 | |a hERG inhibition | |
| 650 | 7 | |a DNA Gyrase |2 NLM | |
| 650 | 7 | |a EC 5.99.1.3 |2 NLM | |
| 650 | 7 | |a Topoisomerase II Inhibitors |2 NLM | |
| 650 | 7 | |a 4-nitrobenzylthioinosine |2 NLM | |
| 650 | 7 | |a GV1L2DZM2Z |2 NLM | |
| 650 | 7 | |a Anti-Bacterial Agents |2 NLM | |
| 700 | 1 | |a Weiss, Matjaž |e verfasserin |4 aut | |
| 700 | 1 | |a Zdovc, Irena |e verfasserin |4 aut | |
| 700 | 1 | |a Senerovic, Lidija |e verfasserin |4 aut | |
| 700 | 1 | |a Radakovic, Natasa |e verfasserin |4 aut | |
| 700 | 1 | |a Anderluh, Marko |e verfasserin |4 aut | |
| 700 | 1 | |a Minovski, Nikola |e verfasserin |4 aut | |
| 700 | 1 | |a Hrast, Martina |e verfasserin |4 aut | |
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