20.500.12556/RUL-141912 Exploring the chemical space of benzothiazole-based DNA gyrase B inhibitors We designed and synthesized a series of inhibitors of the bacterial enzymes DNA gyrase and DNA topoisomerase IV, based on our recently published benzothiazole-based inhibitor bearing an oxalyl moiety. To improve the antibacterial activity and retain potent enzymatic activity, we systematically explored the chemical space. Several strategies of modification were followed: varying substituents on the pyrrole carboxamide moiety, alteration of the central scaffold, including variation of substitution position and, most importantly, modification of the oxalyl moiety. Compounds with acidic, basic, and neutral properties were synthesized. To understand the mechanism of action and binding mode, we have obtained a crystal structure of compound 16a, bearing a primary amino group, in complex with the N-terminal domain of E. coli gyrase B (24 kDa) (PDB: 6YD9). Compound 15a, with a low molecular weight of 383 Da, potent inhibitory activity on E. coli gyrase (IC50 = 9.5 nM), potent antibacterial activity on E. faecalis (MIC = 3.13 [micro]M), and efflux impaired E. coli strain (MIC = 0.78 [micro]M), is an important contribution for the development of novel gyrase and topoisomerase IV inhibitors in Gram-negative bacteria. DNA gyrase topoisomerase IV GyrB ParE antibacterial benzothiazole topoizomeraza IV giraza DNA antibakterijski benzotiazol inibitorji giraze B true false true Angleški jezik Slovenski jezik Članek v reviji 2022-10-11 12:48:41 2022-10-11 12:48:43 2022-10-12 03:52:41 0000-00-00 00:00:00 2020 0 0 Str. 2433-2440 iss. 12 Vol. 11 2020 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54 1948-5875 10.1021/acsmedchemlett.0c00416 32932099 acsmedchemlett.0c00416.pdf acsmedchemlett.0c00416.pdf 1 2F36CA91727B2E04DE1406F41A26D19F 0f859abc59a98fbb7b11b6e72321ef0c3288ec10722c813761c5b411f20f6304 d2cddf0f-4952-11ed-9c94-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=163095 https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.0c00416 1 3d76176f-4952-11ed-9c94-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=163093 https://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.0c00416# 1 3d5f94ee-4952-11ed-9c94-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=163092 Fakulteta za farmacijo 0 0 0