title: Discovery of 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazoles as Novel DNA Gyrase Inhibitors Targeting the ATP-Binding Site.
abstract: Bacterial DNA gyrase and topoisomerase IV are essential enzymes that control the topological state of DNA during replication and validated antibacterial drug targets. Starting from a library of marine alkaloid oroidin analogues, we identified low micromolar inhibitors of Escherichia coli DNA gyrase based on the 5,6,7,8-tetrahydroquinazoline and 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole scaffolds. Structure-based optimization of the initial hits resulted in low nanomolar E. coli DNA gyrase inhibitors, some of which exhibited micromolar inhibition of E. coli topoisomerase IV and of Staphylococcus aureus homologues. Some of the compounds possessed modest antibacterial activity against Gram positive bacterial strains, while their evaluation against wild-type, impA and ΔtolC E. coli strains suggests that they are efflux pump substrates and/or do not possess the physicochemical properties necessary for cell wall penetration. Our study provides a rationale for optimization of this class of compounds toward balanced dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.
authors.affiliation: †Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Tihomir
authors.initials: T
authors.lastname: Tomašič
authors.affiliation: †Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.|‡Faculty of Health Sciences, School of Pharmacy, Department of Pharmaceutical Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
authors.forename: Sotirios
authors.initials: S
authors.lastname: Katsamakas
authors.affiliation: †Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Žiga
authors.initials: Ž
authors.lastname: Hodnik
authors.affiliation: †Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Janez
authors.initials: J
authors.lastname: Ilaš
authors.affiliation: §Laboratory for Biocomputing and Bioinformatics, National Institute of Chemistry, Hajdrihova ulica 19, 1001 Ljubljana, Slovenia.
authors.forename: Matjaž
authors.initials: M
authors.lastname: Brvar
authors.affiliation: §Laboratory for Biocomputing and Bioinformatics, National Institute of Chemistry, Hajdrihova ulica 19, 1001 Ljubljana, Slovenia.
authors.forename: Tom
authors.initials: T
authors.lastname: Solmajer
authors.affiliation: ∥Faculty of Pharmacy, Centre for Drug Research, University of Helsinki, P.O. Box 56, FI-00014 Helsinki, Finland.
authors.forename: Sofia
authors.initials: S
authors.lastname: Montalvão
authors.affiliation: ∥Faculty of Pharmacy, Centre for Drug Research, University of Helsinki, P.O. Box 56, FI-00014 Helsinki, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Tammela
authors.affiliation: ⊥Galapagos Istraživački Ctr D.o.o, Prilaz Baruna Filipovića 29, HR-10000 Zagreb, Croatia.
authors.forename: Mihailo
authors.initials: M
authors.lastname: Banjanac
authors.affiliation: ⊥Galapagos Istraživački Ctr D.o.o, Prilaz Baruna Filipovića 29, HR-10000 Zagreb, Croatia.
authors.forename: Gabrijela
authors.initials: G
authors.lastname: Ergović
authors.affiliation: †Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Marko
authors.initials: M
authors.lastname: Anderluh
authors.affiliation: †Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Lucija
authors.initials: L
authors.lastname: Peterlin Mašič
authors.affiliation: †Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Danijel
authors.initials: D
authors.lastname: Kikelj
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D027081:DNA Gyrase / Q000737:chemistry / Q000378:metabolism*; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors; D015195:Drug Design; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011487:Protein Conformation; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D013844:Thiazoles; D059005:Topoisomerase II Inhibitors; D000255:Adenosine Triphosphate; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase