Discovery of anxiolytic 2-ferrocenyl-1,3-thiazolidin-4-ones exerting GABAA receptor interaction via the benzodiazepine-binding site

Anka Pejović; Marija S Denić; Dragana Stevanović; Ivan Damljanović; Mirjana Vukićević; Kalina Kostova; Maya Tavlinova-Kirilova; Pavle Randjelović; Nikola M Stojanović; Goran A Bogdanović; Polina Blagojević; Matthias D'hooghe; Niko S Radulović; Rastko D Vukićević

doi:10.1016/j.ejmech.2014.05.062

Discovery of anxiolytic 2-ferrocenyl-1,3-thiazolidin-4-ones exerting GABAA receptor interaction via the benzodiazepine-binding site

Eur J Med Chem. 2014 Aug 18:83:57-73. doi: 10.1016/j.ejmech.2014.05.062. Epub 2014 May 28.

Authors

Affiliations

¹ Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12, 34000 Kragujevac, Serbia.
² Department of Chemistry, Faculty of Science and Mathematics, University of Niš, Višegradska 33, 18000 Niš, Serbia.
³ Department of Pharmacy, Faculty of Medicinal Sciences, University of Kragujevac, S. Markovića 69, 34000 Kragujevac, Serbia.
⁴ Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Bl. 9, Acad. G. Bonchev Str., Sofia 1113, Bulgaria.
⁵ Department of Physiology, Faculty of Medicine, University of Niš, Bulevаr Zorana Đinđića 81, 18000 Niš, Serbia.
⁶ Faculty of Medicine, University of Niš, Bulevаr Zorana Đinđića 81, 18000 Niš, Serbia.
⁷ Vinča Institute of Nuclear Sciences, Laboratory of Theoretical Physics and Condensed Matter Physics, PO Box 522, 11001 Belgrade, Serbia.
⁸ SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Ghent University, Coupure Links 653, B-9000 Gent, Belgium.
⁹ Department of Chemistry, Faculty of Science and Mathematics, University of Niš, Višegradska 33, 18000 Niš, Serbia. Electronic address: nikoradulovic@yahoo.com.
¹⁰ Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12, 34000 Kragujevac, Serbia. Electronic address: vuk@kg.ac.rs.

PMID: 24950490
DOI: 10.1016/j.ejmech.2014.05.062

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.

Keywords: 2-Ferrocenyl-1,3-thiazolidin-4-ones; Anxiolytic agents; GABA(A) benzodiazepine-binding site; GABA(A) receptor complex; Ligand docking.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Anxiety Agents / chemistry
Anti-Anxiety Agents / metabolism*
Anti-Anxiety Agents / pharmacology*
Benzodiazepines / metabolism*
Binding Sites
Crystallography, X-Ray
Drug Design*
Electrochemistry
Ferrous Compounds / chemistry
Ferrous Compounds / metabolism*
Ferrous Compounds / pharmacology*
Male
Mice
Molecular Docking Simulation
Protein Binding
Protein Conformation
Receptors, GABA-A / chemistry
Receptors, GABA-A / metabolism*

Substances

2-ferrocenyl-2-thiazoline
Anti-Anxiety Agents
Ferrous Compounds
Receptors, GABA-A
Benzodiazepines