RESUMO
The new dual 5HT1A/5HT7 receptor ligands were designed based on the purine-2,6-dione scaffold with the fluorine atom. Twenty-one new derivatives were synthesized, and their structure-activity relationship was summarized. Compound 11 (7-(2-(3-fluorophenyl)-2-oxoethyl)-8-((4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)amino)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione) showed the highest affinity to 5HT1AR and 5HT7R, and was the most potent antagonist of 5-HT1AR (Kb = 0.26 ± 0.1 nM) which activity can be to reference compound NAN-190 (Kb = 0.26 ± 0.1 nM). The experimentally established physicochemical parameters of compound 11 showed that compound, as slightly ionized in the blood, could penetrate the blood-brain barrier. A molecular docking study showed that the fluorine substitution introduces additional stabilization effects on binding to 5HT1A/5HT7Rs. In animal assays of depression and anxiety, compound 11 revealed activity in terms of dosage compared to marketed psychotropics such as fluoxetine, citalopram, and sertraline.
Assuntos
Antidepressivos , Flúor , Animais , Ligantes , Simulação de Acoplamento Molecular , Antidepressivos/farmacologia , Relação Estrutura-Atividade , Purinas/químicaRESUMO
Antiseizure drugs (ASDs) are commonly used to treat a wide range of nonepileptic conditions, including pain. In this context, the analgesic effect of four pyrrolidine-2,5-dione derivatives (compounds 3, 4, 6, and 9), with previously confirmed anticonvulsant and preliminary antinociceptive activity, was assessed in established pain models. Consequently, antinociceptive activity was examined in a mouse model of tonic pain (the formalin test). In turn, antiallodynic and antihyperalgesic activity were examined in the oxaliplatin-induced model of peripheral neuropathy as well as in the streptozotocin-induced model of painful diabetic neuropathy in mice. In order to assess potential sedative properties (drug safety evaluation), the influence on locomotor activity was also investigated. As a result, three compounds, namely 3, 6, and 9, demonstrated a significant antinociceptive effect in the formalin-induced model of tonic pain. Furthermore, these substances also revealed antiallodynic properties in the model of oxaliplatin-induced peripheral neuropathy, while compound 3 attenuated tactile allodynia in the model of diabetic streptozotocin-induced peripheral neuropathy. Apart from favorable analgesic properties, the most active compound 3 did not induce any sedative effects at the active dose of 30 mg/kg after intraperitoneal (i.p.) injection.
Assuntos
Neuropatias Diabéticas , Neuralgia , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Neuropatias Diabéticas/tratamento farmacológico , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Camundongos , Neuralgia/tratamento farmacológico , Oxaliplatina/uso terapêutico , Pirrolidinas , EstreptozocinaRESUMO
A series of 17 arylpiperazine derivatives of the 5-spiroimidazolidine-2,4-diones (6-22) has been explored, including variations in (i) the number of aromatic rings at position 5, (ii) the length of the linker, as well as (iii) the kind and position of the linked arylpiperazine terminal fragment. Synthesis (6-16) and X-ray crystallographic studies for representative compounds (8, 10, 14 and 18) have been performed. The ability to inhibit the tumor multidrug resistance (MDR) efflux pump P-glycoprotein (P-gp, ABCB1) overexpressed in mouse T-lymphoma cells was investigated. The cytotoxic and antiproliferative actions of the compounds on both the reference and the ABCB1-overproducing cells were also examined. The pharmacophore-based molecular modeling studies have been performed. ADMET properties in vitro of selected most active derivatives (6, 11 and 12) have been determined. All compounds, excluding 18, inhibited the cancer P-gp efflux pump with higher potency than that of reference verapamil. The spirofluorene derivatives with amine alkyl substituents at position 1, and the methyl group at position 3 (6-16), occurred the most potent P-gp inhibitors in the MDR T-lymphoma cell line. In particular, compounds 7 and 12 were 100-fold more potent than verapamil. Crystallography-supported pharmacophore-based SAR analysis has postulated specific structural properties that could explain this excellent cancer MDR-inhibitory action.
Assuntos
Antineoplásicos/farmacologia , Imidazolidinas/farmacologia , Linfoma de Células T/tratamento farmacológico , Compostos de Espiro/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazolidinas/síntese química , Imidazolidinas/química , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
The new series of 3-(2-chlorophenyl)- and 3-(3-chlorophenyl)-pyrrolidine-2,5-dione-acetamide derivatives as potential anticonvulsant and analgesic agents was synthesized. The compounds obtained were evaluated in the following acute models of epilepsy: maximal electroshock (MES), psychomotor (6 Hz, 32 mA), and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The most active substance-3-(2-chlorophenyl)-1-{2-[4-(4-fluorophenyl)piperazin-1-yl]-2-oxoethyl}-pyrrolidine-2,5-dione (6) showed more beneficial ED50 and protective index values than the reference drug-valproic acid (68.30 mg/kg vs. 252.74 mg/kg in the MES test and 28.20 mg/kg vs. 130.64 mg/kg in the 6 Hz (32 mA) test, respectively). Since anticonvulsant drugs are often effective in neuropathic pain management, the antinociceptive activity for two the promising compounds-namely, 6 and 19-was also investigated in the formalin model of tonic pain. Additionally, for the aforementioned compounds, the affinity for the voltage-gated sodium and calcium channels, as well as GABAA and TRPV1 receptors, was determined. As a result, the most probable molecular mechanism of action for the most active compound 6 relies on interaction with neuronal voltage-sensitive sodium (site 2) and L-type calcium channels. Compounds 6 and 19 were also tested for their neurotoxic and hepatotoxic properties and showed no significant cytotoxic effect.
Assuntos
Analgésicos/síntese química , Analgésicos/farmacologia , Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Analgésicos/química , Animais , Anticonvulsivantes/química , Linhagem Celular , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Células Hep G2 , Humanos , Técnicas In Vitro , Masculino , Camundongos , Estrutura Molecular , Neuralgia/tratamento farmacológico , Pirrolidinas/química , Convulsões/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
The present study aimed to design and synthesize a new series of hybrid compounds with pyrrolidine-2,5-dione and thiophene rings in the structure as potential anticonvulsant and antinociceptive agents. For this purpose, we obtained a series of new compounds and evaluated their anticonvulsant activity in animal models of epilepsy (maximal electroshock (MES), psychomotor (6 Hz), and subcutaneous pentylenetetrazole (scPTZ) seizure tests). To determine the mechanism of action of the most active anticonvulsant compounds (3, 4, 6, 9), their influence on the voltage-gated sodium and calcium channels as well as GABA transporter (GAT) was assessed. The most promising compound 3-(3-methylthiophen-2-yl)-1-(3-morpholinopropyl)pyrrolidine-2,5-dione hydrochloride (4) showed higher ED50 value than those of the reference drugs: valproic acid (VPA) and ethosuximide (ETX) (62.14 mg/kg vs. 252.7 mg/kg (VPA) in the MES test, and 75.59 mg/kg vs. 130.6 mg/kg (VPA) and 221.7 mg/kg (ETX) in the 6 Hz test, respectively). Moreover, in vitro studies of compound 4 showed moderate but balanced inhibition of the neuronal voltage-sensitive sodium (site 2) and L-type calcium channels. Additionally, the antinociceptive activity of the most active compounds (3, 4, 6, 9) was also evaluated in the hot plate test and writhing tests, and their hepatotoxic properties in HepG2 cells were also investigated. To determine the possible mechanism of the analgesic effect of compounds 3, 6, and 9, the affinity for the TRPV1 receptor was investigated.
Assuntos
Analgésicos/síntese química , Analgésicos/farmacologia , Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Analgésicos/química , Animais , Anticonvulsivantes/química , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Masculino , Camundongos , Pirrolidinas/químicaRESUMO
In this study, a series of compounds derived from 4-methoxy-1H-isoindole-1,3(2H)-dione, potential ligands of phosphodiesterase 10A and serotonin receptors, were investigated as potential antipsychotics. A library of 4-methoxy-1H-isoindole-1,3(2H)-dione derivatives with various amine moieties was synthesized and examined for their phosphodiesterase 10A (PDE10A)-inhibiting properties and their 5-HT1A and 5-HT7 receptor affinities. Based on in vitro studies, the most potent compound, 18 (2-[4-(1H-benzimidazol-2-yl)butyl]-4-methoxy-1H-isoindole-1,3(2H)-dione), was selected and its safety in vitro was evaluated. In order to explain the binding mode of compound 18 in the active site of the PDE10A enzyme and describe the molecular interactions responsible for its inhibition, computer-aided docking studies were performed. The potential antipsychotic properties of compound 18 in a behavioral model of schizophrenia were also investigated.
Assuntos
Antipsicóticos , Simulação de Acoplamento Molecular , Diester Fosfórico Hidrolases/química , Receptor 5-HT1A de Serotonina/química , Receptores de Serotonina/química , Animais , Antipsicóticos/síntese química , Antipsicóticos/química , Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Células Hep G2 , Humanos , Camundongos , Diester Fosfórico Hidrolases/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Esquizofrenia/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
The aim of this study was to design and synthesize two series of N-Mannich bases with imidazolidine-2,4-dione core as a potential anticonvulsant with reduced toxicity and broad antiseizure activity. Preliminary screening revealed that the majority of synthesized compounds were effective in the maximal electroshock seizure (MES) and/or subcutaneous pentylenetetrazole (scPTZ) test. The most active in vivo compound, 18 (3-((4-methylpiperazin-1-yl)methyl)-5,5-diphenylimidazolidine-2,4-dione), exhibited an ED50 value comparable to that of phenytoin in the MES test (38.5â¯mg/kg vs 28.1â¯mg/kg), and more importantly, it showed four times higher potency than phenytoin in the 6â¯Hz test (12.2â¯mg/kg vsâ¯>â¯60â¯mg/kg). Additionally, 18 exhibited antiallodynic properties in the von Frey test in neuropathic (oxaliplatin-treated) mice. Compound 18 also demonstrated a broader spectrum of anticonvulsant activity than phenytoin and showed statistically significant antinociceptive properties in selected models of chronic pain.
Assuntos
Anticonvulsivantes/uso terapêutico , Imidazolidinas/uso terapêutico , Bases de Mannich/uso terapêutico , Dor/tratamento farmacológico , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/síntese química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Imidazolidinas/administração & dosagem , Imidazolidinas/síntese química , Bases de Mannich/administração & dosagem , Bases de Mannich/síntese química , Camundongos , Estrutura Molecular , Oxaliplatina , Dor/induzido quimicamente , Ratos , Convulsões/induzido quimicamente , Relação Estrutura-AtividadeRESUMO
On the basis of the structures of serotonin modulators or drugs (NAN-190, buspirone, aripiprazole) and phosphodiesterase 4 (PDE4) inhibitors (rolipram, RO-20-1724), a series of novel multitarget 5-arylidenehydantoin derivatives with arylpiperazine fragment was synthesized. Among these compounds, 5-(3,4-dimethoxybenzylidene-3-(4-(4-(2,3-dichlorophenyl)piperazine-1-yl)butyl)-imidazolidine-2,4-dione (13) and 5-(3-cyclopentyloxy-4-methoxybenzylidene-3-(4-(4-(2-methoxyphenyl)piperazine-1-yl)butyl)-imidazolidine-2,4-dione (18) were found to be the most promising showing very high affinity toward 5-HT1A and 5-HT7 receptors (Kiâ¯=â¯0.2-1.0â¯nM) but a negligible inhibitory effect on PDE4. The high affinity of the compounds for 5-HT1A and 5-HT7 receptors was further investigated by computer-aided studies. Moreover, compounds 13 and 18 showed no significant cytotoxicity in the MTT assay, but high clearance in the in vitro assay. In addition, these compounds behaved like 5-HT1A and 5-HT7 receptor antagonists and exhibited antidepressant-like activity, similar to the reference drug citalopram, in an animal model of depression.
Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Receptores de Serotonina/metabolismo , Animais , Antidepressivos/farmacologia , Modelos Animais de Doenças , Humanos , Relação Estrutura-AtividadeRESUMO
Discovering hit compounds and optimization processes in medicinal chemistry nowadays could be improved by predictive tools, based on the relationship between structure of molecules and lipophilic properties. Lipophilicity of drug candidate can affect both the pharmacokinetic and pharmacodynamics properties, in particular, the ability of a molecule to cross the cell membrane. Among the new methods for determination of the lipophilicity of compounds, micellar electrokinetic chromatography (MEKC) is considered to be an appropriate one for bioactive molecules, as it closely mimics the physiological conditions. In this paper MEKC was used for the estimation of the lipophilicity of 24 derivatives of 8-alkoxy-7H-purine-2,6-dione, designed and synthesized as potential antidepressant/anxiolytic and antipsychotic agents. The results of experimental method were compared with calculated in silico parameters (AlogPs and milogP by Virtual Computational Laboratory website, log PPallas by Pallas 3.1, Mlog P by Marvin, log PChemS by ChemSketch, log PChemDraw by ChemBioUltra) using Principal Component Analysis (PCA) method. Finally, using estimated log P values for selected compounds ligand - lipophilicity efficiency (LLE), per cent efficiency index (PEI), and binding efficiency index (BEI) parameters were calculated. Applied MEKC procedure could be used for selection of potential lead structure in a group of 7H-purine-2,6-dione derivatives.
Assuntos
Cromatografia Capilar Eletrocinética Micelar/métodos , Psicotrópicos/química , Xantinas/química , Descoberta de Drogas , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Modelos Lineares , Psicotrópicos/análise , Psicotrópicos/farmacocinética , Xantinas/análise , Xantinas/farmacocinéticaRESUMO
A series of new arylpiperazinylpropyl derivatives of 8/6-phenyl-1,3-diazaspiro[4.5]decan-2,4-dione and spiro[imidazolidine-4,1'-indene/naphthalene]-2,5-dione was synthesized and their affinity was evaluated toward serotonin 5-HTIA, 5-HT2A, 5-HT7 receptors, dopaminergic D2, D3 receptors, adrenergic ox, receptors, and serotonin transporter (SERT). The highest affinity for serotonin 5-HT1A/2A/7 receptors was found for compounds containing a tetralin or indane moiety in the imide part. Among these, two compounds (19, 20) were selected for further pharmacological in vivo studies. A binding mode of representative molecule 19, which behaved as a 5-HT1A agonist and weak 5-HT7 antagonist in the site of 5-HT 1A/7, was also analyzed in computational stud- ies. Moreover, two highly selective (9 and HI) 5-HT2A receptor antagonists were obtained.
Assuntos
Hidantoínas/farmacologia , Modelos Moleculares , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Hidantoínas/síntese química , Hidantoínas/química , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Agonistas do Receptor de Serotonina/síntese química , Agonistas do Receptor de Serotonina/química , Relação Estrutura-AtividadeRESUMO
A series of novel spirohydantoin derivatives with arylpiperazinylbutyl moiety were synthesized and evaluated for serotonin 5-HT1A, 5-HT2A, 5-HT7 and dopamine D2 receptors. Based on these data, four compounds were selected for further binding affinity assays on dopamine D1, D3, D4, and 5-HT2C, 5-HT6 as well as adrenergic α1 and α2C receptors, which are involved in various CNS diseases such as schizophrenia, anxiety and/or depression. The compound 14, 1-{4-[4-(2-metoxyphe-nyl)piperazin-1-yl]butyl}-3',4'-dihydro-2H,2'H,5H-spiro[imidazolidine-4,1'-naphthalene]-2,5-dione, with the most promising functional profile, mixed 5-HT2A/D2 antagonist and 5-HT1A partial agonist, was selected. In the mouse d-amphetamine-induced locomotor hyperactivity model, compound 14 produced antipsychotic-like activity, which is devoid of cataleptogenic effects and in the forced swim test in mice, it showed a significant antidepressant-like effect unlike the reference drug aripiprazole.
Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Antipsicóticos/farmacologia , Hidantoínas/farmacologia , Imidazolidinas/farmacologia , Piperazinas/farmacologia , Animais , Ansiolíticos/síntese química , Antidepressivos/síntese química , Antipsicóticos/síntese química , Ansiedade/tratamento farmacológico , Ansiedade/fisiopatologia , Aripiprazol/farmacologia , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Dextroanfetamina , Hidantoínas/síntese química , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Hipercinese/fisiopatologia , Imidazolidinas/síntese química , Masculino , Camundongos , Piperazinas/síntese química , Receptor 5-HT1A de Serotonina/química , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/química , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D2/química , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Relação Estrutura-Atividade , NataçãoRESUMO
The present study is a part of our physicochemical and pharmacological studies in a group of tricyclic theophylline derivatives. The investigated compounds exhibit different pharmacological profiles in comparison to theophylline and have been tested as potential antidepressant and/or antipsychotic agents. The differences in pharmacological action between theophylline and their tricyclic derivatives can be explained by their various physicochemical properties, especially lipophilicity. The chromatographic behavior of twenty three derivatives of imidazo[2,1-ƒ]theophylline was investigated, using reversed-phase high performance liquid chromatography (RP-HPLC) method. Moreover, partition coefficients and selected pharmacokinetic parameters were calculated computationally. Principal component analysis (PCA) method was used to establish the relationship between obtained experimental and computational parameters.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cromatografia de Fase Reversa/métodos , Imidazóis/química , Teofilina/análogos & derivados , Análise de Componente Principal , Solubilidade , Teofilina/químicaRESUMO
The chromatographic parameters of arylpiperazinylpropyl derivatives of imidazolidine-2,4-dione and imidazo[2,1-f]purine-2,4-dione were investigated using reversed-phase thin layer chromatography method. The results revealed that R(M0) of investigated compounds depended on substituent in arylpiperazinyl fragment as well as on a nature of (cycloalkyl)aromatic ring at 5 position of imidazolidine-2,4-dione and at 7 position of imidazo[2,1-f]theophylline. The R(M0) parameters were compared with computationally calculated partition coefficients values by principal component analysis (PCA). To verify the influence of lipophilic parameter of investigated compounds on their biological activity the statistical analysis of Mann-Whitney was performed.
Assuntos
Cromatografia de Fase Reversa/métodos , Cromatografia em Camada Fina/métodos , Hidantoínas/análise , Piperazinas/análise , Purinas/análise , Simulação por Computador , Estrutura Molecular , Análise de Componente PrincipalRESUMO
The main protease (Mpro) of SARS-CoV-2 is an essential enzyme that plays a critical part in the virus's life cycle, making it a significant target for developing antiviral drugs. The inhibition of SARS-CoV-2 Mpro has emerged as a promising approach for developing therapeutic agents to treat COVID-19. This review explores the structure of the Mpro protein and analyzes the progress made in understanding protein-ligand interactions of Mpro inhibitors. It focuses on binding kinetics, origin, and the chemical structure of these inhibitors. The review provides an in-depth analysis of recent clinical trials involving covalent and non-covalent inhibitors and emerging dual inhibitors targeting SARS-CoV-2 Mpro. By integrating findings from the literature and ongoing clinical trials, this review captures the current state of research into Mpro inhibitors, offering a comprehensive understanding of challenges and directions in their future development as anti-coronavirus agents. This information provides new insights and inspiration for medicinal chemists, paving the way for developing more effective Mpro inhibitors as novel COVID-19 therapies.
Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , Proteases 3C de Coronavírus , Inibidores de Proteases , SARS-CoV-2 , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Humanos , Antivirais/farmacologia , Antivirais/química , Antivirais/uso terapêutico , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Proteases 3C de Coronavírus/química , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/uso terapêutico , COVID-19/virologiaRESUMO
A computer aided ligand design study of imidazolidine-2,4-dione derivatives was conducted in order to obtain compounds with dual 5-HT(1A) receptor and serotonin transporter (SERT) affinity. According to molecular modeling results, series of Mannich bases were chosen and synthesized. Investigated compounds were tested for 5-HT(1A) , 5-HT(2A) , α(1) and SERT affinity. Two selected compounds (5, 9) were characterized in functional experiments and possessed a pharmacological profile which may enhance SERT blocking efficacy - 5-HT(1A) partial agonism and 5-HT(2A) antagonism in one molecule. Furthermore these compounds displayed satisfactory selectivity over adrenergic α(1) receptors. The most promising compounds, 5-arylimidazolidine-2,4-dione derivatives with 4-(3-chlorophenyl)piperazinylmethyl moiety were tested for antidepressant and anxiolytic activity. In particular, compound 5 (5-(2-methoxyphenyl)-3-{1-[4-(3-chlorophenyl)piperazin-1-yl]methyl}-imidazolidine-2,4-dione), tested in the forced swim test in mice, exhibited a favorable antidepressant-like profile without affecting spontaneous locomotor activity.
Assuntos
Ansiolíticos , Antidepressivos , Hidantoínas , Bases de Mannich , Receptor 5-HT1A de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Animais , Ansiolíticos/síntese química , Ansiolíticos/química , Ansiolíticos/farmacologia , Antidepressivos/síntese química , Antidepressivos/química , Antidepressivos/farmacologia , Sítios de Ligação , Desenho Assistido por Computador , Cricetinae , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Hidantoínas/síntese química , Hidantoínas/química , Hidantoínas/farmacologia , Ligantes , Masculino , Bases de Mannich/síntese química , Bases de Mannich/química , Bases de Mannich/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Ligação Proteica , Ratos , Receptor 5-HT2A de Serotonina/metabolismo , NataçãoRESUMO
Dementia, most often associated with neurodegenerative diseases, affects millions of people worldwide, predominantly the elderly. Unfortunately, no treatment is still available. Therefore, there is an urgent need to address this situation. This review presents the state of the art of drug discovery and developments in targeting dementia. Several approaches are discussed, such as drug repurposing, the use of small molecules, and phosphodiesterase inhibitors. Furthermore, the review also provides insights into clinical trials of these molecules. Emphasis has been placed on small molecules and multi-target-directed ligands, as well as disease-modifying therapies. Finally, attention is drawn to the possibilities of applications of nanotechnology in managing dementia.
RESUMO
Affinities of arylpiperazinylalkyl derivatives of imidazo[2,1-f]purine-2,4-dione and imidazolidine-2,4-dione for serotonin transporter and their acid-base properties were evaluated. The dissociation constant (pK(a)) of compounds 1-22 were determinated by potentiometric titration and calculated using pKalc 3.1 module of the Pallas system. The data from experimental methods and computational calculations were compared and suitable conclusions were reached.
RESUMO
Synthesis, physicochemical and anticonvulsant properties of new N-Mannich bases derived from 5-cyclopropyl-5-phenyl- and 5-cyclopropyl-5-(4-chlorophenyl)-imidazolidine-2,4-diones have been described. Initial anticonvulsant screening was performed using intraperitoneal (ip.) maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The neurotoxicity was determined applying the rotarod test. The in vivo results in mice showed that all compounds were effective especially in the MES screen. The quantitative evaluation after oral administration in rats showed that the most active was 5-cyclopropyl-5-phenyl-imidazolidine-2,4-dione (1) with ED(50) values of 5.76 mg/kg (MES) and 57.31 mg/kg (scPTZ). This molecule was more potent than phenytoin and ethosuximide which were used as reference antiepileptic drugs. Additionally compound 1 with ED(50) of 26.06 mg/kg in psychomotor seizure test (6-Hz) in mice showed comparable activity to new generation anticonvulsant - levetiracetam.
Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Imidazolidinas/síntese química , Imidazolidinas/farmacologia , Bases de Mannich/síntese química , Bases de Mannich/farmacologia , Animais , Imidazolidinas/química , Masculino , Bases de Mannich/química , Camundongos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Synthesis, physicochemical and anticonvulsant properties of new N-Mannich bases 3-24 derived from 5-cyclopropyl-5-phenyl- and 5-cyclopropyl-5-(4-chlorophenyl)-hydantoins were described here. Initial anticonvulsant screening was performed using intraperitoneal (i.p.) maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. Selected derivatives were also screened in the 6-Hz test. The neurotoxicity was determined applying the rotorod test. The pharmacological results revealed that the majority of compounds were effective in MES and/or scPTZ tests. The quantitative studies after oral administration into rats showed that several molecules were more potent than phenytoin and ethosuximide which were used as reference antiepileptic drugs. From the whole series the most active was 3-[(4-phenylpiperazin-1-yl)-methyl]-5-cyclopropyl-5-phenyl-imidazolidine-2,4-dione (3) with the ED(50) value of 5.29 mg/kg in the MES test.
Assuntos
Anticonvulsivantes/síntese química , Hidantoínas/química , Bases de Mannich/síntese química , Administração Oral , Animais , Anticonvulsivantes/química , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/toxicidade , Modelos Animais de Doenças , Masculino , Bases de Mannich/química , Bases de Mannich/uso terapêutico , Bases de Mannich/toxicidade , Camundongos , Estrutura Molecular , Síndromes Neurotóxicas/etiologia , Ratos , Ratos Sprague-Dawley , Convulsões/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
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.