20.500.12556/RUL-144295 Amide containing NBTI antibacterials with reduced hERG inhibition, retained antimicrobial activity against gram-positive bacteria and in vivo efficacy 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. NBTIs DNA gyrase topoisomerase IV antibacterials MRSA hERG inhibition in vivo efficacy DNA giraza topoizomeraza IV antibakterijska zdravila inhibicija učinkovitost in vivo farmacevtska kemija bakterije true false true Angleški jezik Slovenski jezik Članek v reviji 2023-02-13 09:39:24 2023-02-13 09:39:29 2023-08-30 11:57:17 0000-00-00 00:00:00 2023 0 0 13 str. Vol. 250, art. 115160 2023 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.28 0223-5234 10.1016/j.ejmech.2023.115160 141418755 1-s2.0-S0223523423000752-main.pdf 1-s2.0-S0223523423000752-main.pdf 1 6FC6ED9BBB3E77C73C3AC851DC40CF97 93eea6e9772a564d7a0b88e67f1f697b91943cffdc78c57db2069bfb98e1b8f2 0092924a-ab7a-11ed-9c94-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=166522 https://www.sciencedirect.com/science/article/pii/S0223523423000752 1 9d201117-ab79-11ed-9c94-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=166521 Fakulteta za farmacijo Veterinarska fakulteta 0 0 0