title: Discovery of anxiolytic 2-ferrocenyl-1,3-thiazolidin-4-ones exerting GABAA receptor interaction via the benzodiazepine-binding site.
abstract: Herein, we report on the synthesis, spectral, crystallographic and electrochemical properties of a small library of N-substituted 2-ferrocenyl-1,3-thiazolidin-4-ones, designed as novel GABAA benzodiazepine-binding site ligands. The anxiolytic properties of the title compounds were evaluated in several different in vivo models, whereas the involvement of the GABAA receptor complex in the activity of the most potent compound, 2-ferrocenyl-3-(4-methoxyphenylethyl)-1,3-thiazolidin-4-one, was inferred from experiments with known GABAA-targeting agents. Ligand docking experiments revealed that the high, dose-dependent, anxiolytic activity of the new compounds might be due to their favorable interactions with the benzodiazepine-binding site of the GABAA receptor complex. The incorporation of the ferrocene core and fine tuning of the distance between the thiazolidinone core and an additional aromatic ring were judged to be crucial structural requirements for the observed anxiolytic effect.
authors.affiliation: Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12, 34000 Kragujevac, Serbia.
authors.forename: Anka
authors.initials: A
authors.lastname: Pejović
authors.affiliation: Department of Chemistry, Faculty of Science and Mathematics, University of Niš, Višegradska 33, 18000 Niš, Serbia.
authors.forename: Marija S
authors.initials: MS
authors.lastname: Denić
authors.affiliation: Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12, 34000 Kragujevac, Serbia.
authors.forename: Dragana
authors.initials: D
authors.lastname: Stevanović
authors.affiliation: Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12, 34000 Kragujevac, Serbia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Damljanović
authors.affiliation: Department of Pharmacy, Faculty of Medicinal Sciences, University of Kragujevac, S. Markovića 69, 34000 Kragujevac, Serbia.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Vukićević
authors.affiliation: Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Bl. 9, Acad. G. Bonchev Str., Sofia 1113, Bulgaria.
authors.forename: Kalina
authors.initials: K
authors.lastname: Kostova
authors.affiliation: Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Bl. 9, Acad. G. Bonchev Str., Sofia 1113, Bulgaria.
authors.forename: Maya
authors.initials: M
authors.lastname: Tavlinova-Kirilova
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Niš, Bulevаr Zorana Đinđića 81, 18000 Niš, Serbia.
authors.forename: Pavle
authors.initials: P
authors.lastname: Randjelović
authors.affiliation: Faculty of Medicine, University of Niš, Bulevаr Zorana Đinđića 81, 18000 Niš, Serbia.
authors.forename: Nikola M
authors.initials: NM
authors.lastname: Stojanović
authors.affiliation: Vinča Institute of Nuclear Sciences, Laboratory of Theoretical Physics and Condensed Matter Physics, PO Box 522, 11001 Belgrade, Serbia.
authors.forename: Goran A
authors.initials: GA
authors.lastname: Bogdanović
authors.affiliation: Department of Chemistry, Faculty of Science and Mathematics, University of Niš, Višegradska 33, 18000 Niš, Serbia.
authors.forename: Polina
authors.initials: P
authors.lastname: Blagojević
authors.affiliation: SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Ghent University, Coupure Links 653, B-9000 Gent, Belgium.
authors.forename: Matthias
authors.initials: M
authors.lastname: D'hooghe
authors.affiliation: Department of Chemistry, Faculty of Science and Mathematics, University of Niš, Višegradska 33, 18000 Niš, Serbia. Electronic address: nikoradulovic@yahoo.com.
authors.forename: Niko S
authors.initials: NS
authors.lastname: Radulović
authors.affiliation: Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12, 34000 Kragujevac, Serbia. Electronic address: vuk@kg.ac.rs.
authors.forename: Rastko D
authors.initials: RD
authors.lastname: Vukićević
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001569:Benzodiazepines / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004563:Electrochemistry; D005296:Ferrous Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism*
chemical_list: C584087:2-ferrocenyl-2-thiazoline; D014151:Anti-Anxiety Agents; D005296:Ferrous Compounds; D011963:Receptors, GABA-A; D001569:Benzodiazepines
keywords: 2-Ferrocenyl-1,3-thiazolidin-4-ones; Anxiolytic agents; GABA(A) benzodiazepine-binding site; GABA(A) receptor complex; Ligand docking