title: Design, synthesis and biological evaluation of 4,5-dibromo-N-(thiazol-2-yl)-1H-pyrrole-2-carboxamide derivatives as novel DNA gyrase inhibitors.
abstract: Development of novel DNA gyrase B inhibitors is an important field of antibacterial drug discovery whose aim is to introduce a more effective representative of this mechanistic class into the clinic. In the present study, two new series of Escherichia coli DNA gyrase inhibitors bearing the 4,5-dibromopyrrolamide moiety have been designed and synthesized. 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazole-2,6-diamine derivatives inhibited E. coli DNA gyrase in the submicromolar to low micromolar range (IC50values between 0.891 and 10.4μM). Their "ring-opened" analogues, based on the 2-(2-aminothiazol-4-yl)acetic acid scaffold, displayed weaker DNA gyrase inhibition with IC50values between 15.9 and 169μM. Molecular docking experiments were conducted to study the binding modes of inhibitors.
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia. Electronic address: tihomir.tomasic@ffa.uni-lj.si.
authors.forename: Tihomir
authors.initials: T
authors.lastname: Tomašič
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
authors.forename: Matic
authors.initials: M
authors.lastname: Mirt
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
authors.forename: Michaela
authors.initials: M
authors.lastname: Barančoková
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
authors.forename: Janez
authors.initials: J
authors.lastname: Ilaš
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
authors.forename: Nace
authors.initials: N
authors.lastname: Zidar
authors.affiliation: University of Helsinki, Faculty of Pharmacy, Division of Pharmaceutical Biosciences, P.O. Box 56, FI-00014 Helsinki, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Tammela
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
authors.forename: Danijel
authors.initials: D
authors.lastname: Kikelj
mesh_terms: D000083:Acetanilides / Q000138:chemical synthesis / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D013293:Enterococcus faecalis / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000083:Acetanilides; D000900:Anti-Bacterial Agents; D052160:Benzothiazoles; D008024:Ligands; D011758:Pyrroles; D059005:Topoisomerase II Inhibitors
keywords: Antibacterial; DNA gyrase; Docking; Inhibitor; Thiazole