20.500.12556/RUL-189711 Designing the DNA-intercalating moiety to improve the safety and efficacy of novel bacterial topoisomerase inhibitors Novel bacterial topoisomerase inhibitors (NBTIs) target bacterial topoisomerases through binding modes distinct from fluoroquinolones but are often limited by hERG channel inhibition. Our previous findings indicated that the introduction of a non-aminopiperidine linker and a halogenated phenyl enzyme-binding moiety can partially reduce cardiotoxicity. In this paper, we describe whether optimizing the DNA-intercalating 1,5-naphthyridine moiety could further improve safety while maintaining antibacterial potency. Several optimized compounds showed strong enzyme inhibition and potent antibacterial activity, particularly against Gram-positive pathogens. Compound 13 displayed broad-spectrum activity, with MICs as low as 0.008 μg/mL against Gram-positive and 0.125 μg/mL against Gram-negative bacteria. Safety profiling revealed reduced cytotoxicity and hERG binding compared to earlier series. Compounds 6, 20, 24, and 25 were nontoxic in zebrafish embryo assays. Compound 13 showed toxicity only at high doses and protected embryos in a lethal Staphylococcus aureus infection model, highlighting its potential as a preclinical lead. bacteria peptides and proteins extraction inhibition nuclear magnetic resonance spectroscopy bakterije peptidi in proteini ekstrakcija inhibicija spektroskopija jedrske magnetne resonance jedrska magnetna resonanca farmacevtska kemija true false true Angleški jezik Slovenski jezik Članek v reviji 2026-10-13 11:50:05 2026-10-13 11:50:10 2026-10-14 04:14:05 0000-00-00 00:00:00 2026 0 0 Str. 18117-18146 iss. 15 Vol. 69 2026 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 543.429.23:615 1520-4804 10.1021/acs.jmedchem.6c00415 286613763 acs.jmedchem.6c00415.pdf acs.jmedchem.6c00415.pdf 1 1498EFB621193115F3E71EF61727D372 f353e3da4585b937be61ef5ab47ef6adbdb46ec868c6cf7aaceb80275a8c49af 173c1619-c6ed-11f1-8bc5-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=250459 https://pubs.acs.org/jmcmar/article/doi/10.1021/acs.jmedchem.6c00415/5234419/Designing-the-DNA-Intercalating-Moiety-to-Improve 1 50c7d373-c6eb-11f1-8bc5-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=250458 Fakulteta za farmacijo Veterinarska fakulteta 0 0 0