Novel multitarget 5-arylidenehydantoins with arylpiperazinealkyl fragment: Pharmacological evaluation and investigation of cytotoxicity and metabolic stability

Czopek, Anna; Bucki, Adam; Kołaczkowski, Marcin; Zagórska, Agnieszka; Drop, Marcin; Pawłowski, Maciej; Siwek, Agata; Głuch‐Lutwin, Monika; Pękala, Elżbieta; Chrzanowska, Alicja; Struga, Marta; Partyka, Anna; Wesołowska, Anna

doi:10.1016/j.bmc.2019.07.046

Cited by 9 publications

(7 citation statements)

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“…The threshold for the similarity coefficient Tanimoto (Tc) [28] applied was equal to 0.7. Excluding 2, 3 and 14 (compounds previously published [25,26]), no structures within datasets corresponding to considered targets were found to be similar by more than 0.7 (in terms of Tc); which confirmed the high structural novelty of the presented compounds.…”

Section: Evaluation Of Intrinsic Activity Towards α 1 -Ar Subtypessupporting

confidence: 58%

“…In the case of compounds with an epoxide group, no additional reagent was necessary, whereas for compounds with a chloroalkyl group, K 2 CO 3 was used. All of the newly synthesized and previously reported derivatives by Czopek et al (i.e., compound 14) [25] were tested in radioligand binding assays to measure the affinity at α-adrenergic receptors, and the serotoninergic 5-HT1AR, 5-HT6R and 5-HT7R. Additionally, for four compounds with the highest activity at α-ARs (10, 12, 14 and 16), functional affinities at α-AR subtypes (α1A-AR in rat tail artery, at α1B-AR in mouse spleen and at α1D-AR in rat aorta) were determined.…”

Section: Chemical Synthesismentioning

confidence: 99%

“…Interestingly, compounds 12 and 13 are strong dual 5-HT1AR/α-ARs ligands, whereas compound 5 indicates dual activity 5-HT7/α-AR (Table 1). [25,26]; 1 fentolamine, 2 buspirone, 3 olanzapine, 4 clozapine.…”

Section: Pharmacology 221 Radioligand Binding Assaysmentioning

confidence: 99%

“…Interestingly, another group of arylpiperazine hydantoins with 2-hydroxypropyl linker (Figure 3) shows lower α1-AR activity (Ki = 230 nM, for the best compound) but high and selective serotoninergic 5-HT7R activity (3 nM < Ki < 94 nM), suggesting that the modulation of hydantoin substitution in position 5 (balancing between sp2 and sp3 hybridization of carbon atom C5) may be one of the main determinants for the serotoninergic/adrenergic affinity profile. Hence, this study concerns the synthesis and in vitro pharmacological evaluation of novel 5-arylidenehydantoins (Figure 4) with very deep computer-aided insight into the structure-activity relationship in order to deal with the to-date unanswered questions, that is, (i) how the structural stiffening via double bond introduction influences the α1-AR and serotoninergic receptors' activity; Hence, this study concerns the synthesis and in vitro pharmacological evaluation of novel 5-arylidenehydantoins (Figure 4) with very deep computer-aided insight into the structure-activity relationship in order to deal with the to-date unanswered questions, that is, (i) how the structural stiffening via double bond introduction influences the All of the newly synthesized and previously reported derivatives by Czopek et al (i.e., compound 14) [25] were tested in radioligand binding assays to measure the affinity at α-adrenergic receptors, and the serotoninergic 5-HT1AR, 5-HT6R and 5-HT7R. Additionally, for four compounds with the highest activity at α-ARs (10, 12, 14 and 16), functional affinities at α-AR subtypes (α1A-AR in rat tail artery, at α1B-AR in mouse spleen and at α1D- All of the newly synthesized and previously reported derivatives by Czopek et al (i.e., compound 14) [25] were tested in radioligand binding assays to measure the affinity at α-adrenergic receptors, and the serotoninergic 5-HT 1A R, 5-HT 6 R and 5-HT 7 R. Additionally, for four compounds with the highest activity at α-ARs (10, 12, 14 and 16), functional affinities at α-AR subtypes (α 1A -AR in rat tail artery, at α 1B -AR in mouse spleen and at α 1D -AR in rat aorta) were determined.…”

Section: Introductionmentioning

confidence: 99%

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The Structural Determinants for α1-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives

et al. 2021

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Several studies confirmed the reciprocal interactions between adrenergic and serotoninergic systems and the influence of these phenomena on the pathogenesis of anxiety. Hence, searching for chemical agents with a multifunctional pharmacodynamic profile may bring highly effective therapy for CNS disorders. This study presents a deep structural insight into the hydantoin-arylpiperazine group and their serotonin/α-adrenergic activity. The newly synthesized compounds were tested in the radioligand binding assay and the intrinsic activity was evaluated for the selected derivatives. The computer-aided SAR analysis enabled us to answer questions about the influence of particular structural fragments on selective vs. multifunctional activity. As a result of the performed investigations, there were two leading structures: (a) compound 12 with multifunctional adrenergic-serotonin activity, which is a promising candidate to be an effective anxiolytic agent; (b) compound 14 with high α1A/α1D affinity and selectivity towards α1B, which is recommended due to the elimination of probable cardiotoxic effect. The structural conclusions of this work provide significant support for future lead optimization in order to achieve the desired pharmacodynamic profile in searching for new CNS-modulating agents.

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Section: Evaluation Of Intrinsic Activity Towards α 1 -Ar Subtypessupporting

confidence: 58%

Section: Chemical Synthesismentioning

confidence: 99%

Section: Pharmacology 221 Radioligand Binding Assaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Structural Determinants for α1-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives

et al. 2021

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“…Czopek et al. synthesized a series of novel piperazine bearing 5‐arylidenehydantoin derivatives as multitargeting agents with anticancer and antidepressant activities [110] . The in vitro studies against serotonin receptors revealed that 5‐(3,4‐dimethoxybenzylidene‐3‐(4‐(4‐(2,3‐dichlorophenyl)piperazine‐1‐yl)butyl)‐imidazolidine‐2,4‐dione ( 69 ) and 5‐(3‐cyclopentyloxy‐4‐methoxybenzylidene‐3‐(4‐(4‐(2‐methoxyphenyl)piperazine‐1‐yl)butyl)‐imidazolidine‐2,4‐dione ( 70 ) possess the highest affinity for serotonin receptors with K i values of 0.2±0.1 and 1.0±0.2 nM for 5‐HT 1A receptors, respectively, while 0.8±0.2 and 1.0±0.2 nM for 5‐HT 7 receptors, respectively.…”

Section: Recent Advancements In Piperazine Derivatives As Antidepressantsmentioning

confidence: 99%

Piperazine, a Key Substructure for Antidepressants: Its Role in Developments and Structure‐Activity Relationships

et al. 2021

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Depression is the single largest contributor to global disability with a huge economic and social burden on the world. There are a number of antidepressant drugs on the market, but treatment‐resistant depression and relapse of depression in a large number of patients have increased problems for clinicians. One peculiarity observed in most of the marketed antidepressants is the presence of a piperazine substructure. Although piperazine is also used in the optimization of other pharmacological agents, it is almost extensively used for the development of novel antidepressants. One common understanding is that this is due to its favorable CNS pharmacokinetic profile; however, in the case of antidepressants, piperazine plays a much bigger role and is involved in specific binding conformations of these agents. Therefore, in this review, a critical analysis of the significance of the piperazine moiety in the development of antidepressants has been performed. An overview of current developments in the designing and synthesis of piperazine‐based antidepressants (2015 onwards) along with SAR studies is also provided. The various piperazine‐based therapeutic agents in early‐ or late‐phase human testing for depression are also discussed. The preclinical compounds discussed in this review will help researchers understand how piperazine actually influences the design and development of novel antidepressant compounds. The SAR studies discussed will provide crucial clues about the structural features and optimizations required to enhance the efficacy and potency of piperazine‐based antidepressants.

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Advances in drug design and therapeutic potential of selective or multitarget 5‐HT1A receptor ligands

Giorgioni,

Bonifazi,

Botticelli

et al. 2024

Medicinal Research Reviews

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Abstract5‐HT1A receptor (5‐HT1A‐R) is a serotoninergic G‐protein coupled receptor subtype which contributes to several physiological processes in both central nervous system and periphery. Despite being the first 5‐HT‐R identified, cloned and studied, it still represents a very attractive target in drug discovery and continues to be the focus of a myriad of drug discovery campaigns due to its involvement in numerous neuropsychiatric disorders. The structure‐activity relationship studies (SAR) performed over the last years have been devoted to three main goals: (i) design and synthesis of 5‐HT1A‐R selective/preferential ligands; (ii) identification of 5‐HT1A‐R biased agonists, differentiating pre‐ versus post‐synaptic agonism and signaling cellular mechanisms; (iii) development of multitarget compounds endowed with well‐defined poly‐pharmacological profiles targeting 5‐HT1A‐R along with other serotonin receptors, serotonin transporter (SERT), D2‐like receptors and/or enzymes, such as acetylcholinesterase and phosphodiesterase, as a promising strategy for the management of complex psychiatric and neurodegenerative disorders. In this review, medicinal chemistry aspects of ligands acting as selective/preferential or multitarget 5‐HT1A‐R agonists and antagonists belonging to different chemotypes and developed in the last 7 years (2017–2023) have been discussed. The development of chemical and pharmacological 5‐HT1A‐R tools for molecular imaging have also been described. Finally, the pharmacological interest of 5‐HT1A‐R and the therapeutic potential of ligands targeting this receptor have been considered.

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Novel multitarget 5-arylidenehydantoins with arylpiperazinealkyl fragment: Pharmacological evaluation and investigation of cytotoxicity and metabolic stability

Cited by 9 publications

References 49 publications

The Structural Determinants for α1-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives

The Structural Determinants for α1-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives

Piperazine, a Key Substructure for Antidepressants: Its Role in Developments and Structure‐Activity Relationships

Advances in drug design and therapeutic potential of selective or multitarget 5‐HT1A receptor ligands

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