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Amide containing NBTI antibacterials with reduced hERG inhibition, retained antimicrobial activity against gram-positive bacteria and in vivo efficacy
dc.creator | Kokot, Maja | |
dc.creator | Weiss, Matjaž | |
dc.creator | Zdovc, Irena | |
dc.creator | Šenerović, Lidija | |
dc.creator | Radakovic, Natasa | |
dc.creator | Anderluh, Marko | |
dc.creator | Minovski, Nikola | |
dc.creator | Hrast, Martina | |
dc.date.accessioned | 2023-03-01T11:03:36Z | |
dc.date.available | 2023-03-01T11:03:36Z | |
dc.date.issued | 2023 | |
dc.identifier.issn | 0223-5234 | |
dc.identifier.uri | https://www.sciencedirect.com/science/article/pii/S0223523423000752 | |
dc.identifier.uri | https://imagine.imgge.bg.ac.rs/handle/123456789/1779 | |
dc.description.abstract | 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. | |
dc.language | en | |
dc.relation | This work was supported by the Slovenian Research Agency (Grants P1-0017 and P1-0208, the young researcher’s program numbers 39010 and 50503) and by Proof of Concept project NICKI of the National Institute of Chemistry, and University of Ljubljana Innovation Fund. | |
dc.rights | openAccess | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | |
dc.source | European Journal of Medicinal Chemistry | |
dc.source | European Journal of Medicinal ChemistryEuropean Journal of Medicinal Chemistry | |
dc.subject | Antibacterials | |
dc.subject | DNA gyrase | |
dc.subject | hERG inhibition | |
dc.subject | In vivo efficacy | |
dc.subject | MRSA | |
dc.subject | NBTIs | |
dc.subject | Topoisomerase IV | |
dc.title | Amide containing NBTI antibacterials with reduced hERG inhibition, retained antimicrobial activity against gram-positive bacteria and in vivo efficacy | |
dc.type | article | en |
dc.rights.license | BY-NC-ND | |
dc.citation.rank | aM21~ | |
dc.citation.spage | 115160 | |
dc.citation.volume | 250 | |
dc.identifier.doi | 10.1016/j.ejmech.2023.115160 | |
dc.identifier.fulltext | https://imagine.imgge.bg.ac.rs/bitstream/id/98062/Amide_containing_NBTI_antibacterials_with_reduced_hERG_inhibition_retained_antimicrobial_activity_against_gram_positive_bacteria_and_in_vivo_efficacy_2023.pdf | |
dc.identifier.scopus | 2-s2.0-85147435975 | |
dc.type.version | publishedVersion |