Amide containing NBTI antibacterials with reduced hERG inhibition, retained antimicrobial activity against gram-positive bacteria and in vivo efficacy

Kokot, Maja (avtor), Weiss, Matjaž (avtor), Zdovc, Irena (avtor), Senerovic, Lidija (avtor), Radakovic, Natasa (avtor), Anderluh, Marko (avtor), Minovski, Nikola (avtor), Hrast, Martina (avtor)

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.

• Jezik: Angleški jezik
• Ključne besede: NBTIs, DNA gyrase, topoisomerase IV, antibacterials, MRSA, hERG inhibition, in vivo efficacy
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo ; VF - Veterinarska fakulteta
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2023
• Št. strani: 13 str.
• Številčenje: Vol. 250, art. 115160
• PID: 20.500.12556/RUL-144295
• UDK: 615.28
• ISSN pri članku: 0223-5234
• DOI: 10.1016/j.ejmech.2023.115160
• COBISS.SI-ID: 141418755
• Datum objave v RUL: 13.02.2023

Gradivo je del revije

• Naslov: European journal of medicinal chemistry
• Skrajšan naslov: Eur. j. med. chem.
• Založnik: Elsevier
• ISSN: 0223-5234
• COBISS.SI-ID: 25429760

Licence

• Licenca: CC BY-NC-ND 4.0, Creative Commons Priznanje avtorstva-Nekomercialno-Brez predelav 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by-nc-nd/4.0/deed.sl
• Opis: Najbolj omejujoča licenca Creative Commons. Uporabniki lahko prenesejo in delijo delo v nekomercialne namene in ga ne smejo uporabiti za nobene druge namene.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: DNA giraza, topoizomeraza IV, antibakterijska zdravila, inhibicija, učinkovitost in vivo, farmacevtska kemija, bakterije