20.500.12556/RUL-158805 Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor a medicinal chemistry and QTAIM study N-(Benzothiazole-2-yl)pyrrolamide DNA gyrase inhibitors with benzyl or phenethyl substituents attached to position 3 of the benzothiazole ring or to the carboxamide nitrogen atom were prepared and studied for their inhibition of Escherichia coli DNA gyrase by supercoiling assay. Compared to inhibitors bearing the substituents at position 4 of the benzothiazole ring, the inhibition was attenuated by moving the substituent to position 3 and further to the carboxamide nitrogen atom. A co-crystal structure of (Z)-3-benzyl-2-((4,5-dibromo-1H-pyrrole-2-carbonyl)imino)-2,3-dihydrobenzo[d]-thiazole-6-carboxylic acid (I) in complex with E. coli GyrB24 (ATPase subdomain) was solved, revealing the binding mode of this type of inhibitor to the ATP-binding pocket of the E. coli GyrB subunit. The key binding interactions were identified and their contribution to binding was rationalised by quantum theory of atoms in molecules (QTAIM) analysis. Our study shows that the benzyl or phenethyl substituents bound to the benzothiazole core interact with the lipophilic floor of the active site, which consists mainly of residues Gly101, Gly102, Lys103 and Ser108. Compounds with substituents at position 3 of the benzothiazole core were up to two orders of magnitude more effective than compounds with substituents at the carboxamide nitrogen. In addition, the 6-oxalylamino compounds were more potent inhibitors of E. coli DNA gyrase than the corresponding 6-acetamido analogues. antibacterial agent DNA gyrase ATP-binding site N-(benzothiazol-2-yl)pyrrolamide inhibitor QTAIM analysis farmacevtska kemija true false true Angleški jezik Slovenski jezik Članek v reviji 2024-06-20 16:01:05 2024-06-20 16:01:11 2024-07-05 03:24:02 0000-00-00 00:00:00 2024 0 0 16 str. art. 117798 Vol. 109 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54 0968-0896 10.1016/j.bmc.2024.117798 199171075 1-s2.0-S0968089624002128-main.pdf 1-s2.0-S0968089624002128-main.pdf 1 80897DE88100B89079F6C36FF9888F3B db2a0f54eeef03ad087aba28f3eb5413a64e57c161ed0ae3c96d6542b23f1605 0586b5d3-2f0e-11ef-a73e-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=186530 https://www.sciencedirect.com/science/article/pii/S0968089624002128 1 8d24fe5b-2f0d-11ef-a73e-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=186529 Fakulteta za farmacijo 0 0 0