In the search for a lead structure among series of potent and selective hydantoin 5‐HT₇R agents: The drug‐likeness in vitro study

Abstract

Since the year 1993, when 5-HT receptor (5-HT R) was discovered, there is no selective 5-HT R ligand introduced to the pharmaceutical market. One out of the main reasons disqualifying the 5-HT R ligands is weak drugability properties, including metabolic instability or low permeability. This study is focused on the search of a lead compound by "drug-likeness" estimation of the first series of selective and potent 5-HT R ligands among 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-aryl-piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione derivatives (11-16). The most important drugability parameters, i.e., permeability, metabolic stability, and safety, have been evaluated. The main metabolic pathways were determined. The forced swim test (FST) in mice was performed as a primary in vivo assay for compound 13 and the reference 2. The experiments showed promising drug-like properties for all ligands, with special attention to the benzhydryl (diphenylmethyl) derivative 13. The studies have also indicated in vivo activity of the compound 13 that was observed as a significant and specific antidepressant-like activity in the FST. Taking into account the beneficial properties of 13, i.e., good drug-like parameters, the significant antagonistic action, high selectivity to 5-HT R, and its in vivo antidepressant-like activity, the compound should be considered as a new lead in the search for drugs acting on CNS via 5-HT receptor.

Pronounced activity of aromatic selenocyanates against multidrug resistant ESKAPE bacteria

“…The concentrations of the compounds tested in the donor and acceptor compartments were estimated by capillary electrophoresis (CE) as described previously. [60][61][62] The data on permeability obtained was compared to the one for selected reference drugs, i.e., highly permeable caffeine and lowly permeable norfloxacin (see ESI for details).…”

“…Compounds 1, 2, 4, and 13 and reference substances were dissolved in PBS buffer (pH = 7.4) from 10 mM DMSO stocks, according to a protocol described previously. 60 The concentrations of compounds and references drugs -in this case caffeine, and norfloxacin -were estimated in the donor and acceptor compartments employing capillary electrophoresis (CE), and calibration curves were determined accordingly. Finally, the permeability coefficients (Kp, (cm s -1 )) of the compounds tested were calculated employing the formula provided by the PAMPA Plate System manufacturer.…”

Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro

“…The affinity to P-glycoprotein test was performed as described previously [22,[35][36][37] by using commercial the Pgp-Glo TM Assay System (Promega, Madison, WI, USA), accordingly to the manufacturer's protocol. The reactions were prepared in triplicate in white polystyrene, flat-bottom Nunc TM MicroWell TM 96-well microplates (Thermo Scientific, Waltham, MA USA).…”

“…The metabolic stability assays were performed as described in our previous articles [22,[35][36][37]. The pharmacokinetic parameters of compounds were estimated by using human liver microsomes (HLMs) (Sigma-Aldrich, St. Louis, MO, USA).…”

Synthesis of imidazolidine‐2,4‐dione and 2‐thioxoimidazolidin‐4‐one derivatives as inhibitors of virulence factors production in Pseudomonas aeruginosa

“…In view of the aforementioned approaches, the current study attempted to design and synthesize new virulence factor inhibitors containing imidazolidine‐2,4‐dione (hydantoin) and 2‐thioxoimidazolidin‐4‐one (2‐thiohydantoin) scaffolds. The versatile structures of hydantoin and 2‐thiohydantoin provide metabolic stability, [ 28 ] in addition to unique reactivity that allows introducing different substituents in positions 3 and 5 needed for the structure–activity relationship study. [ 29 ] Furthermore, the two carbonyl groups in the imidazolidine‐2,4‐dione ring could increase capacity to form hydrogen bonds with LuxR receptors.…”