27539-12-4Relevant articles and documents
Novel serotonin 5-HT2A receptor antagonists derived from 4-phenylcyclohexane-5-spiro-and 5-methyl-5-phenyl-hydantoin, for use as potential antiplatelet agents
Czopek, Anna,Kubacka, Monika,Bucki, Adam,Siwek, Agata,Filipek, Barbara,Paw?owski, Maciej,Ko?aczkowski, Marcin
, p. 1361 - 1372 (2021/06/15)
Background: Antiplatelet drugs have been used in the treatment of acute coronary syndromes and for the prevention of recurrent events. Unfortunately, many patients remain resistant to the available antiplatelet treatment. Therefore, there is a clinical need to synthesize novel antiplatelet agents, which would be associated with different pathways of platelet aggregation, to develop an alternative or additional treatment for resistant patients. Recent studies have revealed that 5-HT2A receptor antagonists could constitute alternative antiplatelet therapy. Methods: Based on the structures of the conventional 5-HT2A receptor ligands, two series of compounds with 4-phenylcyclohexane-5-spiro- or 5-methyl-5-phenyl-hydantoin core linked to various arylpiperazine moieties were synthesized and their affinity for 5-HT2A receptor was assessed. Further, we evaluated their antagonistic potency at 5-HT2A receptors using isolated rat aorta and cells expressing human 5-HT2A receptors. Finally, we studied their anti-aggregation effect and compared it with ketanserin and sarpogrelate, the reference 5-HT2A receptor antagonists. Moreover, the structure–activity relationships were studied following molecular docking to the 5-HT2A receptor model. Results: Functional bioassays revealed some of the synthesized compounds to be moderate antagonists of 5-HT2A receptors. Among them, 13, 8-phenyl-3-(3-(4-phenylpiperazin-1-yl)propyl)-1,3-diazaspiro[4.5]decane-2,4-dione, inhibited collagen stimulated aggregation (IC50 = 27.3?μM) being more active than sarpogrelate (IC50 = 66.8?μM) and comparable with ketanserin (IC50 = 32.1?μM). Moreover, compounds 2–5, 9–11, 13, 14 inhibited 5-HT amplified, ADP- or collagen-induced aggregation. Conclusions: Our study confirmed that the 5-HT2A antagonists effectively suppress platelet aggregation and remain an interesting option for the development of novel antiplatelet agents with an alternative mechanism of action.
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.
Continuous Synthesis of Hydantoins: Intensifying the Bucherer-Bergs Reaction
Monteiro, Julia L.,Pieber, Bartholom?us,Corrêa, Arlene G.,Kappe, C. Oliver
supporting information, p. 83 - 87 (2015/12/26)
A continuous Bucherer-Bergs hydantoin synthesis utilizing intensified conditions is reported. The methodology is characterized by a two-feed flow approach to independently feed the organic substrate and the aqueous reagent solution. The increased interfacial area of the biphasic reaction mixture and the lack of headspace enabled almost quantitative conversions within ca. 30 minutes at 120 °C and 20 bar even for unpolar starting materials. In addition, a selective N(3)-monoalkylation of the resulting heterocycles under batch microwave conditions is reported yielding potential acetylcholinesterase inhibitors.
