Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 684
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Chem Rec ; 20(2): 120-141, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31250972

RESUMO

Fluorine-containing organic scaffolds are of significant interest in medicinal chemistry. The incorporation of fluorine into biomolecules can lead to remarkable changes in their physical, chemical, and biological properties. There are already many drugs on the market, which contain at least one fluorine atom. Saturated functionalized azaheterocycles as bioactive substances have gained increasing attention in pharmaceutical chemistry. Due to the high biorelevance of organofluorine molecules and the importance of N-heterocyclic compounds, selective stereocontrolled procedures to the access of new fluorine-containing saturated N-heterocycles are considered to be a hot research topic. This account summarizes the synthesis of functionalized and fluorine-containing saturated azaheterocycles starting from functionalized cycloalkenes and based on oxidative ring cleavage of diol intermediates followed by ring expansion with reductive amination.


Assuntos
Compostos Aza/química , Compostos Heterocíclicos/química , Aldeídos/química , Azepinas/síntese química , Azepinas/química , Ciclização , Flúor/química , Compostos Heterocíclicos/síntese química , Oxirredução , Estereoisomerismo
2.
Chem Commun (Camb) ; 55(82): 12348-12351, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31559401

RESUMO

A multimeric MRI contrast agent based on the closo-borane motif is reported. Twelve copies of a modified AAZTA chelate with an alkyne end group are appended on an azide-functionalized closo-borane motif using Cu(i) catalyzed click chemistry. The presence of two water molecules on the Gd-bound AAZTA chelate results in high relaxivity for the closomer in vitro/in vivo.


Assuntos
Acetatos/química , Azepinas/química , Boranos/química , Quelantes/química , Meios de Contraste/química , Complexos de Coordenação/química , Imagem por Ressonância Magnética , Acetatos/síntese química , Azepinas/síntese química , Boranos/síntese química , Quelantes/síntese química , Meios de Contraste/síntese química , Complexos de Coordenação/síntese química , Estrutura Molecular
3.
Eur J Med Chem ; 182: 111633, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31461688

RESUMO

Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1 at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases.


Assuntos
Azepinas/química , Descoberta de Drogas , Proteínas/antagonistas & inibidores , Pirazóis/química , Animais , Azepinas/síntese química , Azepinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Domínios Proteicos , Proteínas/metabolismo , Pirazóis/síntese química , Pirazóis/farmacologia , Relação Estrutura-Atividade
4.
Org Biomol Chem ; 17(24): 5951-5961, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31166343

RESUMO

The syntheses of conduramine B-2, ent-conduramine F-2, aminocyclopentitol and trihydroxyazepane were accomplished from a common precursor, through a divergent approach using ring closing metathesis (RCM) as the key step. Tri-O-benzyl-d-glucal was converted to 3,4,6-tri-O-benzyl-1,2-dideoxy-2-iodo-1-p-toluenesulfonamido-α-d-mannose. Exposure to NaBH4 in MeOH resulted in a facile 1,2-transposition of the -NHTs group with concomitant glycosylation to give methyl 3,4,6-tri-O-benzyl-2-deoxy-2-p-toluenesulfonamido-ß-d-glucoside, which was converted into methyl 6-deoxy-6-iodo-glucoside in three steps. Zinc-mediated Vasella's rearrangement proceeded smoothly to give the pluripotent formyl-olefin, possessing both electrophilic and nucleophilic sites, which was used as a common precursor in our diversity-oriented approach. Vinylation of the carbonyl group followed by RCM and subsequent deprotection resulted in the successful synthesis of conduramine B-2 and ent-conduramine F-2 for the first time. On the other hand, the Wittig reaction of the formyl-olefin affords the diene that undergoes Grubbs' I catalyzed RCM and deprotection/reduction to provide 3-amino-cyclopentan-1,2-diol. Utilizing the nucleophilic site at the nitrogen of the common precursor, base mediated N-allylation was carried out to obtain the corresponding diene that underwent a smooth RCM to afford trihydroxyazepane.


Assuntos
Azepinas/síntese química , Cicloexanóis/síntese química , Cicloexilaminas/síntese química , Ciclopentanos/síntese química , Azepinas/química , Cicloexanóis/química , Cicloexilaminas/química , Ciclopentanos/química , Glicosilação , Estrutura Molecular
5.
Eur J Med Chem ; 177: 414-424, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158754

RESUMO

Due to the role of butyrylcholinesterase (BChE) in acetylcholine hydrolysis in the late stages of the Alzheimer's disease (AD), inhibitors of butyrylcholinesterase (BChE) have been recently envisaged, besides acetylcholinesterase (AChE) inhibitors, as candidates for treating mild-to-moderate AD. Herein, synthesis and AChE/BChE inhibition activity of some twenty derivatives of 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (HHAI) is reported. Most of the newly synthesized HHAI derivatives achieved the inhibition of both ChE isoforms with IC50s in the micromolar range, with a structure-dependent selectivity toward BChE. Apparently, molecular volume and lipophilicity do increase selectivity toward BChE, and indeed the N2-(4-phenylbutyl) HHAI derivative 15d, which behaves as a mixed-type inhibitor, resulted the most potent (IC50 0.17 µM) and selective (>100-fold) inhibitor toward either horse serum and human BChE. Moreover, 15d inhibited in vitro self-induced aggregation of neurotoxic amyloid-ß (Aß) peptide and displayed neuroprotective effects in neuroblastoma SH-SY5Y cell line, significantly recovering (P < 0.001) cell viability when impaired by Aß1-42 and hydrogen peroxide insults. Overall, this study highlighted HHAI as useful and versatile scaffold for developing new small molecules targeting some enzymes and biochemical pathways involved in the pathogenesis of AD.


Assuntos
Azepinas/farmacologia , Inibidores da Colinesterase/farmacologia , Indóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Peptídeos beta-Amiloides/metabolismo , Azepinas/síntese química , Azepinas/química , Azepinas/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Relação Dose-Resposta a Droga , Desenho de Drogas , Depuradores de Radicais Livres/síntese química , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/metabolismo , Depuradores de Radicais Livres/farmacologia , Humanos , Indóis/síntese química , Indóis/química , Indóis/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fragmentos de Peptídeos/metabolismo , Ligação Proteica/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
6.
Bull Exp Biol Med ; 166(6): 747-750, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31020589

RESUMO

Antithrombotic activity of a novel tricyclic derivative of diazepino[1,2-α]benzimidazole (DAB-15) was examined on the model of arterial thrombosis developed in rats without concomitant pathology and in rats with experimental myocardial infarction. DAB-15 demonstrated high antithrombotic efficacy in modeled thrombosis of carotid artery in rats without the concomitant pathology surpassing that of the reference drugs acetylsalicylic acid and clopidogrel by 5.1 and 4.8 times, respectively. In rats with experimental noncoronary myocardial infarction, DAB-15 increased the thrombus formation time by 86.2% in comparison with experimental control level in non-treated rats with similar myocardial infarction.


Assuntos
Azepinas/farmacologia , Benzimidazóis/farmacologia , Fibrinolíticos/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Trombose/prevenção & controle , Animais , Animais não Endogâmicos , Aspirina/farmacologia , Azepinas/síntese química , Benzimidazóis/síntese química , Testes de Coagulação Sanguínea , Cloretos/administração & dosagem , Clopidogrel/farmacologia , Modelos Animais de Doenças , Compostos Férricos/administração & dosagem , Fibrinolíticos/síntese química , Masculino , Infarto do Miocárdio/sangue , Infarto do Miocárdio/patologia , Agregação Plaquetária/efeitos dos fármacos , Ratos , Trombose/sangue , Trombose/induzido quimicamente , Trombose/patologia
7.
Molecules ; 24(3)2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30743991

RESUMO

A one-pot synthesis of triazolobenzodiazepine-containing polycyclic compounds is introduced. The reaction process involves a decarboxylative three-component [3 + 2] cycloaddition of nonstabilized azomethine ylides, N-propargylation, and intramolecular click reactions.


Assuntos
Azepinas/química , Compostos Azo/química , Química Click , Cobre/química , Reação de Cicloadição , Tiossemicarbazonas/química , Triazóis/química , Azepinas/síntese química , Estrutura Molecular , Estereoisomerismo
8.
Arch Pharm (Weinheim) ; 352(3): e1800298, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30648282

RESUMO

The synthesis of inhibitors of SphK2 with novel structural scaffolds is reported. These compounds were designed from a molecular modeling study, in which the molecular interactions stabilizing the different complexes were taken into account. Particularly interesting is that 7-bromo-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1,4-epoxynaphtho[1,2-b]azepine, which is a selective inhibitor of SphK2, does not exert any cytotoxic effects and has a potent anti-inflammatory effect. It was found to inhibit mononuclear cell adhesion to the dysfunctional endothelium with minimal impact on neutrophil-endothelial cell interactions. The information obtained from our theoretical and experimental study can be useful in the search for inhibitors of SphK2 that play a prominent role in different diseases, especially in inflammatory and cardiovascular disorders.


Assuntos
Anti-Inflamatórios/síntese química , Azepinas/síntese química , Inibidores Enzimáticos/síntese química , Compostos de Epóxi/síntese química , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/toxicidade , Azepinas/química , Azepinas/farmacologia , Adesão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desenho de Drogas , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/toxicidade , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Simulação de Acoplamento Molecular , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Ligação Proteica , Relação Estrutura-Atividade
9.
Mini Rev Med Chem ; 19(1): 79-86, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30039759

RESUMO

BACKGROUND: Several biologically active indole alkaloids have been isolated from marine organisms over the previous few years. Many scientsts interested in synthesis of the marine azepinoindole alkaloids due to their wide range of bioliogical activies. OBJECTIVE: We interested herein to synthesize a new series of some analogues of new naturally occurring azepinoindole alkaloids. METHOD: A novel series of [1,2,4,5]tetrazepino[6,7-b]indoles, Marine natural product Hyrtioreticuline C and D analogues, were synthesized via the reaction of 3-hydrazonoindolin-2-one with hydrzaonoyl chlorides in basic medium. RESULTS: The spectral data of the products proved their structure. All new derivatives were tested against two carcinoma cell lines ((A-549 & HepG2)) in comparison with the well-known anticancer standard drug (cisplatin) and two derivatives from the tested compounds showed activity more potent than the reference drug. CONCLUSION: We succeeded in synthesis of new antitumor active azepinoindole alkaloids.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Azepinas/química , Azepinas/farmacologia , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Células A549 , Animais , Antineoplásicos/síntese química , Organismos Aquáticos/química , Azepinas/síntese química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Fungos/química , Células Hep G2 , Humanos , Alcaloides Indólicos/síntese química , Neoplasias/tratamento farmacológico , Poríferos/química
10.
Mol Divers ; 23(3): 585-592, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30465252

RESUMO

This research describes a simple and efficient one-pot synthetic approach for the preparation of tetrahydrodiazepine and dihydropyrazine (or dihydroquinoxaline) derivatives in high yields in the presence of a substoichiometric amount of ammonium chloride as a green accelerator on water at 50 °C within 1-3 h.


Assuntos
Cloreto de Amônio/química , Azepinas/química , Azepinas/síntese química , Pirazinas/química , Pirazinas/síntese química , Catálise , Técnicas de Química Sintética , Química Verde , Água/química
11.
J Am Chem Soc ; 140(51): 17872-17877, 2018 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-30521324

RESUMO

Enantioenriched 2-aryl azepanes and 2-arylbenzazepines were generated biocatalytically by asymmetric reductive amination using imine reductases or by deracemization using monoamine oxidases. The amines were converted to the corresponding N'-aryl ureas, which rearranged on treatment with base with stereospecific transfer of the aryl substituent to the 2-position of the heterocycle via a configurationally stable benzyllithium intermediate. The products are previously inaccessible enantioenriched 2,2-disubstituted azepanes and benzazepines.


Assuntos
Azepinas/síntese química , Biocatálise , Iminas/química , Lítio/química , Monoaminoxidase/química , Compostos Organometálicos/química , Oxirredução , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/química , Estereoisomerismo
12.
Molecules ; 23(10)2018 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-30274224

RESUMO

In order to provide a more detailed view on the structure⁻antimycobacterial activity relationship (SAR) of phenylcarbamic acid derivatives containing two centers of protonation, 1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(dipropylammonio)propyl]pyrrolidinium oxalates (1a⁻d)/dichlorides (1e⁻h) as well as 1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(di-propylammonio)propyl]azepanium oxalates (1i⁻l)/dichlorides (1m⁻p; alkoxy = butoxy to heptyloxy) were physicochemically characterized by estimation of their surface tension (γ; Traube's stalagmometric method), electronic features (log ε; UV/Vis spectrophotometry) and lipophilic properties (log kw; isocratic RP-HPLC) as well. The experimental log kw dataset was studied together with computational logarithms of partition coefficients (log P) generated by various methods based mainly on atomic or combined atomic and fragmental principles. Similarities and differences between the experimental and in silico lipophilicity descriptors were analyzed by unscaled principal component analysis (PCA). The in vitro activity of compounds 1a⁻p was inspected against Mycobacterium tuberculosis CNCTC My 331/88 (identical with H37Rv and ATCC 2794, respectively), M. tuberculosis H37Ra ATCC 25177, M. kansasii CNCTC My 235/80 (identical with ATCC 12478), the M. kansasii 6509/96 clinical isolate, M. kansasii DSM 44162, M. avium CNCTC My 330/80 (identical with ATCC 25291), M. smegmatis ATCC 700084 and M. marinum CAMP 5644, respectively. In vitro susceptibility of the mycobacteria to reference drugs isoniazid, ethambutol, ofloxacin or ciprofloxacin was tested as well. A very unique aspect of the research was that many compounds from the set 1a⁻p were highly efficient almost against all tested mycobacteria. The most promising derivatives showed MIC values varied from 1.9 µM to 8 µM, which were lower compared to those of used standards, especially if concerning ability to fight M. tuberculosis H37Ra ATCC 25177, M. kansasii DSM 44162 or M. avium CNCTC My 330/80. Current in vitro biological assays and systematic SAR studies based on PCA approach as well as fitting procedures, which were supported by relevant statistical descriptors, proved that the compounds 1a⁻p represented a very promising molecular framework for development of 'non-traditional' but effective antimycobacterial agents.


Assuntos
Antituberculosos/síntese química , Azepinas/síntese química , Mycobacterium/efeitos dos fármacos , Oxalatos/química , Fenilcarbamatos/síntese química , Pirrolidinas/síntese química , Antituberculosos/farmacologia , Azepinas/farmacologia , Ciprofloxacino/química , Ciprofloxacino/uso terapêutico , Simulação por Computador , Desenho de Drogas , Etambutol/química , Etambutol/uso terapêutico , Isoniazida/química , Isoniazida/uso terapêutico , Testes de Sensibilidade Microbiana , Mycobacterium avium/efeitos dos fármacos , Mycobacterium kansasii/efeitos dos fármacos , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Ofloxacino/química , Ofloxacino/uso terapêutico , Oxalatos/farmacologia , Fenilcarbamatos/farmacologia , Pirrolidinas/farmacologia , Solubilidade , Relação Estrutura-Atividade
13.
Future Med Chem ; 10(14): 1649-1664, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29957068

RESUMO

AIM: Using cytotoxic agents with apoptosis induction may represent one of new strategies for cancer treatment to overcome the increased resistance of the disease. METHODOLOGY: Two series of benzo[f][1,4]oxazepine-3,5(2H,4H)-diones (compounds 5, 6a-f) and 3-phenylbenzo[f][1,4]oxazepin-5(4H)-ones (compounds 10, 11a-f) were synthesized and screened for their cytotoxicity against leukemia K-562 and breast T-47D cancer cell lines as well as normal fibroblasts WI-38. RESULTS: The tested compounds revealed good cytotoxicity and selectivity toward cancer cell lines relative to the normal cells, especially compounds 6f, 10 and 11e, f. These compounds were screened for cell cycle disturbance and apoptosis induction. They were found to cause PreG1 apoptosis and complete cell growth arrest at G2/M. They induce apoptosis via caspase-3 and Bax activation and downregulation of Bcl2. CONCLUSION: benzo[f][1,4]oxazepine represents a scaffold for further optimization to obtain promising anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Azepinas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Azepinas/síntese química , Azepinas/farmacologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Relação Estrutura-Atividade , Proteína X Associada a bcl-2/metabolismo
14.
Bioorg Med Chem ; 26(12): 3559-3572, 2018 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-29805075

RESUMO

The chemokine CC receptor subtype 2 (CCR2) has attracted intensive interest for drug development in diverse therapeutic areas, including chronic inflammatory diseases, diabetes, neuropathic pain, atherogenesis and cancer. By employing a cut-and-sew scaffold hopping strategy, we identified an active scaffold of 3,4-dihydro-2,6-naphthyridin-1(2H)-one as the central pharmacophore to derive novel CCR2 antagonists. Systematic structure-activity relationship study with respect to the ring size and the substitution on the naphthyridinone ring gave birth to 1-arylamino-6-alkylheterocycle-6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-ones as a brand new chemotype of CCR2 antagonists with nanomolar inhibitory activity. The best antagonism activity in this series was exemplified by compound 13a, which combined the optimal substitutions of 3,4-dichlorophenylamino at C-1 and 3-(4-(N-methylmethylsulfonamido)piperidin-1-yl)propyl at N-6 position, leading to an IC50 value of 61 nM and 10-fold selectivity for CCR2 over CCR5. Efficient and general synthesis was established to construct the innovative core structure and derive the compound collections. This is the first report on our designed 6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-one as novel CCR2 antagonist scaffold and its synthesis.


Assuntos
Azepinas/química , Receptores CCR2/antagonistas & inibidores , Animais , Azepinas/síntese química , Células CHO , Cálcio/metabolismo , Cricetinae , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Receptores CCR2/metabolismo , Relação Estrutura-Atividade
15.
Bioorg Med Chem ; 26(9): 2573-2585, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29681486

RESUMO

A series of 1- and 2-naphthyloxy derivatives were synthesized and evaluated for histamine H3 receptor affinity. Most compounds showed high affinities with Ki values below 100 nM. The most potent ligand, 1-(5-(naphthalen-1-yloxy)pentyl)azepane (11) displayed high affinity for the histamine H3 receptor with a Ki value of 21.9 nM. The antagonist behaviour of 11 was confirmed both in vitro in the cAMP assay (IC50 = 312 nM) and in vivo in the rat dipsogenia model (ED50 = 3.68 nM). Moreover, compound 11 showed positive effects on scopolamine induced-memory deficits in mice (at doses of 10 and 15 mg/kg) and an analgesic effect in the formalin test in mice with ED50 = 30.6 mg/kg (early phase) and ED50 = 20.8 mg/kg (late phase). Another interesting compound, 1-(5-(Naphthalen-1-yloxy)pentyl)piperidine (13; H3R Ki = 53.9 nM), was accepted for Anticonvulsant Screening Program at the National Institute of Neurological Disorders and Stroke/National Institute of Health (Rockville, USA). The screening was performed in the maximal electroshock seizure (MES), the subcutaneous pentylenetetrazole (scPTZ) and the 6-Hz psychomotor animal models of epilepsy. Neurologic deficit was evaluated by the rotarod test. Compound 13 inhibited convulsions induced by the MES with ED50 of 19.2 mg/kg (mice, i.p.), 17.8 (rats, i.p.), and 78.1 (rats, p.o.). Moreover, 13 displayed protection against the 6-Hz psychomotor seizures (32 mA) in mice (i.p.) with ED50 of 33.1 mg/kg and (44 mA) ED50 of 57.2 mg/kg. Furthermore, compounds 11 and 13 showed in vitro weak influence on viability of tested cell lines (normal HEK293, neuroblastoma IMR-32, hepatoma HEPG2), weak inhibition of CYP3A4 activity, and no mutagenicity. Thus, these compounds may be used as leads in a further search for histamine H3 receptor ligands with promising in vitro and in vivo activity.


Assuntos
Anticonvulsivantes/farmacologia , Azepinas/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Naftalenos/farmacologia , Piperidinas/farmacologia , Analgésicos/administração & dosagem , Analgésicos/síntese química , Analgésicos/farmacologia , Analgésicos/toxicidade , Animais , Antazolina/farmacologia , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/síntese química , Anticonvulsivantes/toxicidade , Atropina/farmacologia , Azepinas/administração & dosagem , Azepinas/síntese química , Azepinas/toxicidade , Relação Dose-Resposta a Droga , Cobaias , Células HEK293 , Antagonistas dos Receptores Histamínicos H3/administração & dosagem , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/toxicidade , Humanos , Ligantes , Masculino , Camundongos , Naftalenos/administração & dosagem , Naftalenos/síntese química , Naftalenos/toxicidade , Piperidinas/administração & dosagem , Piperidinas/síntese química , Piperidinas/toxicidade , Ratos Wistar , Receptor Muscarínico M3/metabolismo , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H3/metabolismo
16.
J Med Chem ; 61(8): 3685-3696, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29627981

RESUMO

C-X-C chemokine receptor type 7 (CXCR7) is involved in cardiac and immune pathophysiology. We report the discovery of a novel 1,4-diazepine CXCR7 modulator, demonstrating for the first time the role of pharmacological CXCR7 intervention in cardiac repair. Structure-activity-relationship (SAR) studies demonstrated that a net reduction in lipophilicity (log D) and an incorporation of saturated ring systems yielded compounds with good CXCR7 potencies and improvements in oxidative metabolic stability in human-liver microsomes (HLM). Tethering an ethylene amide further improved the selectivity profile (e.g., for compound 18, CXCR7 Ki = 13 nM, adrenergic α 1a Kb > 10 000 nM, and adrenergic ß 2 Kb > 10 000 nM). The subcutaneous administration of 18 in mice led to a statistically significant increase in circulating concentrations of plasma stromal-cell-derived factor 1α (SDF-1α) of approximately 2-fold. Chronic dosing of compound 18 in a mouse model of isoproterenol-induced cardiac injury further resulted in a statistically significant reduction of cardiac fibrosis.


Assuntos
Acetamidas/uso terapêutico , Azepinas/uso terapêutico , Cardiotônicos/uso terapêutico , Fibrose/tratamento farmacológico , Cardiopatias/tratamento farmacológico , Receptores CXCR/metabolismo , Acetamidas/síntese química , Acetamidas/química , Acetamidas/farmacologia , Animais , Azepinas/síntese química , Azepinas/química , Azepinas/farmacologia , Cardiotônicos/síntese química , Cardiotônicos/química , Cardiotônicos/farmacologia , Cães , Fibrose/induzido quimicamente , Cardiopatias/induzido quimicamente , Humanos , Interações Hidrofóbicas e Hidrofílicas , Isoproterenol , Células Madin Darby de Rim Canino , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade
17.
J Org Chem ; 83(9): 5323-5330, 2018 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-29641205

RESUMO

A formal total synthesis of pyrrolo[1,4]benzodiazepine anticancer antibiotic family member limazepine E is described. The synthesis features a stereoselective introduction of a trisubstituted double bond using novel sterically demanding Julia-Kocienski reagents, allowing the number of linear steps to be significantly reduced. The potential of the newly developed reagents has also been demonstrated by the formal total synthesis of barmumycin.


Assuntos
Azepinas/química , Azepinas/síntese química , Pirrolidinas/química , Pirrolidinas/síntese química , Técnicas de Química Sintética , Indicadores e Reagentes/química , Estereoisomerismo
18.
Eur J Med Chem ; 150: 64-73, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29524729

RESUMO

5,7-Diaryl-substituted symmetrical diazepinoporphyrazine and tribenzodiazepinoporphyrazine were synthesized and characterized using UV-Vis, MS MALDI, and various NMR techniques. The expected photosensitizing potentials of these porphyrazines were evaluated by measuring their abilities to generate singlet oxygen in organic solvents and by comparing them with that of the recently obtained dendrimeric G1-type diazepinoporhyrazine. Absorbance and fluorescence measurements were performed to study the aggregation properties of the novel macrocycles. The photocytotoxicity of tribenzodiazepinoporphyrazine towards LNCaP cells in its free form and after its incorporation into liposomes was examined using MTT assay under normoxic and hypoxic conditions. It is interesting that all tested liposome formulations maintained their phototoxic activity in hypoxia. Also, tribenzodiazepinoporphyrazine incorporated into liposomes revealed better photocytotoxic effect (IC50 values of 0.600 ±â€¯0.357 µM and 0.378 ±â€¯0.002 µM) than its free form (IC50 values of 3.135 ±â€¯0.156 µM). Following the in vitro experiments, the most promising liposomal formulation containing l-α-phosphatidyl-DL-glycerol for tribenzodiazepinoporphyrazine was found. Moreover, tribenzodiazepinoporphyrazine incorporated into liposomes containing 1,2-dioleoyl-3-trimethylammonium-propane (chloride salt) revealed moderate phototoxicity at 5 × 10-5 µM for antibacterial photodynamic therapy. It was established that an irradiation of planktonic bacterial strains significantly reduced CFUs of Staphylococcus aureus ATCC 25923 in comparison to tribenzodiazepinoporphyrazine containing l-α-phosphatidyl-DL-glycerol liposomes.


Assuntos
Azepinas/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Azepinas/síntese química , Azepinas/química , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Lipossomos/química , Estrutura Molecular , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Relação Estrutura-Atividade
19.
Bioorg Med Chem Lett ; 28(8): 1371-1375, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29550094

RESUMO

A novel series of 1,3,6-trisubstituted 1,4-diazepan-7-ones were investigated as human kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Based on the X-ray co-crystal structure of compound 1 bound to human KLK7, the derivatives of this scaffold were designed, synthesized, and evaluated. Through structure-activity relationship studies focused on the side chain located in the prime site region of the enzyme, representative compounds 15, 33a, and 35a were identified as highly potent and selective inhibitors of human KLK7.


Assuntos
Azepinas/farmacologia , Calicreínas/antagonistas & inibidores , Azepinas/síntese química , Azepinas/química , Sítios de Ligação , Cristalografia por Raios X , Desenho de Drogas , Humanos , Calicreínas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade
20.
J Org Chem ; 83(7): 4119-4130, 2018 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-29546756

RESUMO

A convenient synthesis of 3,4-dihydro-2 H-naphtho[2,3- b][1,4]oxazine-5,10-diones and 2,3,4,5-tetrahydro-1 H-naphtho[2,3- b]azepine-6,11-diones via the copper-catalyzed intramolecular C-O/C-C coupling reaction is described. This method showed a good tolerance for functional groups and was applied to the synthesis of natural product core structures. Some coupling products exhibited moderate activities against lung cancer A549 cells.


Assuntos
Azepinas/síntese química , Cobre/química , Oxazinas/síntese química , Células A549 , Azepinas/química , Azepinas/farmacologia , Catálise , Humanos , Estrutura Molecular , Oxazinas/química , Oxazinas/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA