20.500.12556/RUL-144326 Discovery and hit-to-lead optimization of benzothiazole scaffold-based DNA gyrase inhibitors with potent activity against Acinetobacter baumannii and Pseudomonas aeruginosa We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aeruginosa, which are both on the WHO priority list of antibiotic-resistant bacteria. Starting from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of human topoisomerase IIα, and no cross-resistance to novobiocin. Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of 27 were improved by fine-tuning of lipophilicity. In particular, analogs of 27 with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities. antibacterial activity bacteria genetics inhibitors solubility antibakterijsko delovanje zaviralci topnost genetika bakterije bakterijska rezistenca true false true Angleški jezik Slovenski jezik Članek v reviji 2023-02-14 14:58:18 2023-02-14 14:58:21 2023-03-17 03:33:50 0000-00-00 00:00:00 2023 0 0 Str. 1380–1425 iss. 2 Vol. 66 2023 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.015.8 1520-4804 10.1021/acs.jmedchem.2c01597 138544899 acs.jmedchem.2c01597.pdf acs.jmedchem.2c01597.pdf 1 2EF0E995627D74F4171CA528F2DAD8EF de682d27236990ef4bd21f923407770b125bc0058f3bfe1658de5a41741e784d e8be9862-c400-11ed-a314-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=167389 https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c01597 0 7224a6c3-ac6f-11ed-9c94-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=166579 Fakulteta za farmacijo 0 0 0