20.500.12556/RUL-106640 Discovery of substituted oxadiazoles as a novel scaffold for DNA gyrase inhibitors DNA gyrase and topoisomerase IV are type IIa topoisomerases that are essential bacterial enzymes required to oversee the topological state of DNA during transcription and replication processes. Their ATPase domains, GyrB and ParE, respectively, are recognized as viable targets for small molecule inhibitors, however, no synthetic or natural product GyrB/ParE inhibitors have so far reached the clinic for use as novel antibacterial agents, except for novobiocin which was withdrawn from the market. In the present study, a series of substituted oxadiazoles have been designed and synthesized as potential DNA gyrase inhibitors. Structure-based optimization resulted in the identification of compound 35, displaying an IC50 of 1.2 mM for Escherichia coli DNA gyrase, while also exhibiting a balanced low micromolar inhibition of E. coli topoisomerase IV and of the respective Staphylococcus aureus homologues. The most promising inhibitors identified from each series were ultimately evaluated against selected Grampositive and Gram-negative bacterial strains, of which compound 35 inhibited Enterococcus faecalis with a MIC90 of 75 mM. OuDNA gyrase and topoisomerase IV are type IIa topoisomerases that are essential bacterial enzymes required to oversee the topological state of DNA during transcription and replication processes. Their ATPase domains, GyrB and ParE, respectively, are recognized as viable targets for small molecule inhibitors, however, no synthetic or natural product GyrB/ParE inhibitors have so far reached the clinic for use as novel antibacterial agents, except for novobiocin which was withdrawn from the market. In the present study, a series of substituted oxadiazoles have been designed and synthesized as potential DNA gyrase inhibitors. Structure-based optimization resulted in the identification of compound 35, displaying an IC50 of 1.2 mM for Escherichia coli DNA gyrase, while also exhibiting a balanced low micromolar inhibition of E. coli topoisomerase IV and of the respective Staphylococcus aureus homologues. The most promising inhibitors identified from each series were ultimately evaluated against selected Grampositive and Gram-negative bacterial strains, of which compound 35 inhibited Enterococcus faecalis with a MIC90 of 75 mM. Our study thus provides further insight into the structural requirements of substituted oxadiazoles for dual inhibition of DNA gyrase and topoisomerase IVr study thus provides further insight into the structural requirements of substituted oxadiazoles for dual inhibition of DNA gyrase and topoisomerase IV. 1 2 4-oxadiazoles DNA gyrase inhibition topoisomerase IV inhibition antibacterial screening computer-aided drug design true false false Angleški jezik Slovenski jezik Znanstveno delo 2019-03-09 19:28:01 2019-03-09 19:28:05 2022-08-19 03:46:36 0000-00-00 00:00:00 2017 0 0 Str. 171-184 Vol. 130 Apr. 2017 0000-00-00 PostprintKoncna Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 2019-04-21 615.4:54 0223-5234 10.1016/j.ejmech.2017.02.046 4292465 25429760 RAZ_Jakopin_Ziga_i2017.pdf RAZ_Jakopin_Ziga_i2017.pdf 1 71A99EA364434907B14700799B0BD7D3 8587f9e19c99393d72e20477f21388bb49ce0edc881411f10a70a689150a3e15 5cdfdac2-a1b6-11eb-a523-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=117454 https://www.sciencedirect.com/science/article/pii/S0223523417301198 1 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=140389 Fakulteta za farmacijo 0 0 0