23186-96-1Relevant articles and documents
Computer-aided studies for novel arylhydantoin 1,3,5-triazine derivatives as 5-HT6 serotonin receptor ligands with antidepressive-like, anxiolytic and antiobesity action in vivo
Kurczab, Rafal,Ali, Wesam,?azewska, Dorota,Kotánska, Magdalena,Jastrzebska-Wiesek, Magdalena,Sata?a, Grzegorz,Wiecek, Ma?gorzata,Lubelska, Annamaria,Latacz, Gniewomir,Partyka, Anna,Starek, Ma?gorzata,Dabrowska, Monika,Weso?owska, Anna,Jacob, Claus,Kiéc-Kononowicz, Katarzyna,Handzlik, Jadwiga
, (2018/10/20)
This study focuses on the design, synthesis, biological evaluation, and computer-aided structure-activity relationship (SAR) analysis for a novel group of aromatic triazine-methylpiperazines,with an hydantoin spacer between 1,3,5-traizine and the aromatic fragment. New compounds were synthesized and their affinities for serotonin 5-HT6, 5-HT1A, 5-HT2A, 5-HT7, and dopamineD2 receptorswere evaluated. The induced-fit docking (IFD) procedure was performed to explore the 5-HT6 receptor conformation space employing two lead structures. It resulted in a consistent binding mode with the activity data. For the most active compounds found in each modification line, anti-obesity and anti-depressive-like activity in vivo, as well as "druglikeness" in vitro, were examined. Two 2-naphthyl compounds (18 and 26) were identified as themost active 5-HT6R agents within each leadmodification line, respectively. The 5-(2-naphthyl)hydantoin derivative 26, themost active one in the series (5-HT6R: Ki = 87 nM), displayed also significant selectivity towards competitive G-protein coupled receptors (6-197-fold). Docking studies indicated that the hydantoin ring is stabilized by hydrogen bonding, but due to its different orientation, the hydrogen bonds formwith S5.44 and N6.55 or Q6.58 for 18 and 26, respectively. Compound 26 exerted anxiolytic-like and antidepressant-like activities. Importantly, it demonstrated anti-obesity properties in animals fed palatable feed, and did not show toxic effects in vitro.
Computer-aided insights into receptor-ligand interaction for novel 5-arylhydantoin derivatives as serotonin 5-HT7 receptor agents with antidepressant activity
Kucwaj-Brysz, Katarzyna,Kurczab, Rafa?,Jastrz?bska-Wi?sek, Magdalena,?es?awska, Ewa,Sata?a, Grzegorz,Nitek, Wojciech,Partyka, Anna,Siwek, Agata,Jankowska, Agnieszka,Weso?owska, Anna,Kie?-Kononowicz, Katarzyna,Handzlik, Jadwiga
, p. 102 - 114 (2018/02/10)
This paper presents a computer-aided insight into the receptor-ligand interaction for novel analogs of the lead structure 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione (1, MF-8), as part of the search for potent and selective serotonin 5-HT7 receptor (5-HT7R) agents. New hydantoin derivatives (4-19) were designed and synthesized. For 5-phenyl-3-(2-hydroxy-3-(4-(2-ethoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione (4), its crystal structure was determined experimentally. Molecular modeling studies were performed, including both pharmacophore and structure-based approaches. New compounds were investigated in radioligand binding assays (RBA) for their affinity toward 5-HT7R and selectivity over 5-HT1AR, dopamine D2R and α1-, α2-and β-adrenoceptors. Selected compounds (5-8) were assessed for their antidepressant and anxiolytic effects in vivo in mice. Most of the tested compounds displayed potent affinity and selectivity for 5-HT7R in RBA, in particular seven compounds (4, 5, 7, 8 and 10-12, Ki ≤ 10 nM). Antidepressant-like activity in vivo for all tested compounds (5-8) was confirmed. SAR analysis based on both crystallography-supported molecular modeling and RBA results indicated that mono-phenyl substituents at both hydantoin and piperazine are more favorable for 5-HT7R affinity than the di-phenyl ones.
Solvent effects on the absorption spectra of potentially pharmacologically active 5-alkyl-5-arylhydantoins: A structure-property relationship study
Hmuda, Sleem F.,Banjac, Nebojsa R.,Trisovic, Nemanja P.,Bozic, Bojan D.,Valentic, Natasa V.,Uscumlic, Gordana S.
, p. 627 - 637 (2013/07/26)
To obtain insight into the interactions of potential anticonvulsant drugs with their surrounding, two series of 5-methyl-5-aryl- and 5-ethyl-5- -arylhydantoins were synthesized and their absorption spectra were recorded in the region from 200 to 400 nm in a set of selected solvents. The effects of solvent dipolarity/polarizability and solvent-solute hydrogen bonding interactions on the absorption maxima shifts were analyzed by means of the linear solvation energy relationship (LSER) concept of Kamlet and Taft. The ratio of the contributions of specific and non-specific solvent-solute interactions were correlated with the corresponding absorption, distribution, metabolism, and excretion (ADME) properties of the studied compounds. The correlation equations were combined with different physicochemical parameters to generate new equations, which demonstrate the reasonable relationships between the solvent- solute interactions and the structure-activity parameters. Copyright (C)2013 SCS.
