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1.
Phytochemistry ; 169: 112177, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31707275

RESUMO

Two undescribed prenylated quinolinone alkaloids, aspoquinolones E and F, and three undescribed prenylated isoindolinone alkaloids aspernidines F-H, were isolated from the fungus Aspergillus nidulans. Their structures and configurations were elucidated based on spectroscopic analyses and ECD spectra. Aspoquinolones E and F possess a C10 moiety with an unusual 2,2,4-trimethyl-3oxa-bicyclo[3.1.0]hexane unit, and aspernidines F-H own a C15 side chain. These compounds were evaluated for cytotoxic activities against five human cancer cell lines, compounds 1 and 5 exhibited strong inhibitory activities against A-549 and SW-480 cells with IC50 values of 3.50 and 4.77 µM, respectively.


Assuntos
Alcaloides/farmacologia , Antineoplásicos/farmacologia , Aspergillus nidulans/química , Ftalimidas/farmacologia , Quinolonas/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Ftalimidas/química , Ftalimidas/isolamento & purificação , Prenilação , Quinolonas/química , Quinolonas/isolamento & purificação , Relação Estrutura-Atividade
2.
Chem Commun (Camb) ; 55(86): 12916-12919, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31603445

RESUMO

An enantioselective aerobic decarboxylative Povarov reaction of N-aryl α-amino acids with methylenephthalimidines through cooperative photoredox and chiral Brønsted acid catalysis is reported. With a transition metal-free dual catalytic system including a chiral phosphoric acid and DPZ as a photosensitizer mediated by visible light, the transformations provided a series of valuable chiral isoindolin-1-ones containing a 3,3-spiro-tetrahydroquinoline-based stereocenter in high yields (up to 83%) with good to excellent enantioselectivities (up to 98% ee) and excellent diastereoselectivity (>20 : 1 dr).


Assuntos
Aminoácidos/química , Luz , Ácidos Fosfóricos/química , Ftalimidas/química , Catálise , Oxirredução , Compostos de Espiro/química , Estereoisomerismo
3.
Chem Biodivers ; 16(11): e1900370, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31523926

RESUMO

A novel series of phthalimide-dithiocarbamate hybrids was synthesized and evaluated for in vitro inhibitory potentials against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The anti-cholinesterase results indicated that among the synthesized compounds, the compounds 7g and 7h showed the most potent anti-AChE and anti-BuChE activities, respectively. Molecular docking and dynamic studies of the compounds 7g and 7h, respectively, in the active site of AChE and BuChE revealed that these compounds as well interacted with studied cholinesterases. These compounds also possessed drug-like properties and were able to cross the BBB.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Ftalimidas/farmacologia , Tiocarbamatos/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Butirilcolinesterase/metabolismo , Electrophorus , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Cavalos , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular , Ftalimidas/química , Tiocarbamatos/química
4.
Dalton Trans ; 48(33): 12615-12621, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31378802

RESUMO

Here, we demonstrated the synthesis, characterization and application of a phthalimide-functionalized UiO-66 metal-organic framework, which showed an intrinsic detection capability for hydrazine. The MOF material (1) was solvothermally prepared by the reaction between ZrCl4 and 2-(1,3-dioxoisoindolin-2-yl)benzene-1,4-dioic acid (H2L) ligand in DMF solvent in the presence of benzoic acid for 48 h at 120 °C. The guest molecule free material (1') was used as a turn-on fluorescent sensor for the selective detection of hydrazine under biological conditions. The phthalimide group anchored in the structure of 1' is converted to the amine group by reaction with hydrazine and this free amine is accountable for the turn-on fluorescence behavior. The probe exhibited an extraordinary detection limit towards hydrazine (0.87 µM). The cellular imaging ability of the MOF probe for hydrazine was also demonstrated with MDAMB-231 breast cancer cells. The probe-loaded cells didn't show considerable cellular cytotoxicity and morphological deformities. They responded towards hydrazine solution by giving an intense blue fluorescent signal. Hence, 1' is capable of monitoring hydrazine in both the aqueous phase and living cells.


Assuntos
Corantes Fluorescentes/análise , Hidrazinas/análise , Estruturas Metalorgânicas/química , Imagem Óptica , Ftalimidas/química , Linhagem Celular Tumoral , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Estruturas Metalorgânicas/síntese química , Conformação Molecular , Espectrometria de Fluorescência
5.
J Enzyme Inhib Med Chem ; 34(1): 1259-1270, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31287341

RESUMO

Pyrazolylphthalimide derivative 4 was synthesized and reacted with different reagents to afford the target compounds imidazopyrazoles 5-7, pyrazolopyrimidines 9, 12, 14 and pyrazolotriazines 16, 17 containing phthalimide moiety. The prepared compounds were established by different spectral data and elemental analyses. Additionally, all synthesized derivatives were screened for their antibacterial activity against four types of Gram + ve and Gram-ve strains, and for antifungal activity against two fungi micro-organisms by well diffusion method. Moreover, the antiproliferative activity was tested for all compounds against human liver (HepG-2) cell line in comparison with the reference vinblastine. Moreover, drug-likeness and toxicity risk parameters of the newly synthesized compounds were calculated using in silico studies. The data from structure-actvity relationship (SAR) analysis suggested that phthalimide derivative bearing 3-aminopyrazolone moiety, 4 illustrated the best antimicrobial and antitumor activities and might be considered as a lead for further optimization. To investigate the mechanism of the antimicrobial and anticancer activities, enzymatic assay and molecular docking studies were carried out on E. coli topoisomerase II DNA gyrase B and VEGFR-2 enzymes.


Assuntos
Ftalimidas/química , Ftalimidas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Ftalimidas/síntese química , Análise Espectral/métodos , Relação Estrutura-Atividade
6.
Chem Pharm Bull (Tokyo) ; 67(4): 345-350, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30930439

RESUMO

Based on the "cluster effect" and the structure characters of acetylcholinesterase (AChE; EC 3.1.1.7), a new series of 1,2,4-triazolin-3-one and phthalimide heterodimers were designed, synthesized, and evaluated as potent dual acetylcholinesterase inhibitors (AChEIs). Most of the synthesized compounds showed good in vitro inhibitory activities towards both Drosophila melanogaster acetylcholinesterase (DmAChE) and Musca domestica acetylcholinesterase (MdAChE). Among them, 5g was found to be the most potent anti-AChE derivate (5g, IC50 = 8.07 µM to DmAChE, IC50 = 32.24 µM to MdAChE). It was 2.31- and 1.35-fold more active than the positive control ethion (CP, IC50 = 18.62 µM to DmAChE, IC50 = 43.56 µM to MdAChE). The docking model study revealed that 5g possessed the fitted spatial structure and bound to the central pocket and peripheral site of DmAChE. Moreover, most compounds demonstrated high insecticidal activity to Lipaphis erysimi and Tetranychus cinnabarinus at the concentration of 300 mg/L.


Assuntos
Inibidores da Colinesterase/síntese química , Desenho de Drogas , Inseticidas/síntese química , Ftalimidas/química , Triazóis/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Sítios de Ligação , Inibidores da Colinesterase/farmacologia , Dimerização , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/enzimologia , Moscas Domésticas/efeitos dos fármacos , Moscas Domésticas/enzimologia , Concentração Inibidora 50 , Inseticidas/farmacologia , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína
7.
Nat Commun ; 10(1): 801, 2019 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-30778067

RESUMO

The ubiquitous biomacromolecule DNA has an axial rigidity persistence length of ~50 nm, driven by its elegant double helical structure. While double and multiple helix structures appear widely in nature, only rarely are these found in synthetic non-chiral macromolecules. Here we report a double helical conformation in the densely charged aromatic polyamide poly(2,2'-disulfonyl-4,4'-benzidine terephthalamide) or PBDT. This double helix macromolecule represents one of the most rigid simple molecular structures known, exhibiting an extremely high axial persistence length (~1 micrometer). We present X-ray diffraction, NMR spectroscopy, and molecular dynamics (MD) simulations that reveal and confirm the double helical conformation. The discovery of this extreme rigidity in combination with high charge density gives insight into the self-assembly of molecular ionic composites with high mechanical modulus (~ 1 GPa) yet with liquid-like ion motions inside, and provides fodder for formation of other 1D-reinforced composites.


Assuntos
Ftalimidas/química , Polieletrólitos/química , Polímeros/química , Espectroscopia de Ressonância Magnética , Conformação Molecular , Simulação de Dinâmica Molecular , Difração de Raios X
8.
Eur J Med Chem ; 168: 110-122, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30802729

RESUMO

Histone deacetylases (HDACs) as appealing targets for the treatment of many diseases has been studied extensively and its use in cancer care is the most important. Here, we developed a series of novel derivatives containing isoindolinone skeleton. Twelve compounds demonstrated nanomolar IC50 values against HDAC1, and the best compounds were 5a (65.6 nM), 5b (65.1 nM) and 13a (57.9 nM). In vitro, 5a and 5b also showed potent antiproliferative activities against several cancer cell lines, in particular 5b, which behaved better than approved drug chidamide. Morever, enzyme inhibition and western blot assay established 5b to be a selective inhibitor for HDAC1-3. Molecular docking was performed to rationalize the high potency of isoindolinones. Additionally, 5b had more appropriate drug metabolism in human liver microsome (HLM) compared with chidamide and moderate pharmacokinetics properties. These results indicated that 5b was worthy of further biological studies.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Ftalimidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Ftalimidas/síntese química , Ftalimidas/química , Relação Estrutura-Atividade
9.
Cell Chem Biol ; 26(2): 300-306.e9, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30595531

RESUMO

The design of selective small molecules is often stymied by similar ligand binding pockets. Here, we report BSJ-03-123, a phthalimide-based degrader that exploits protein-interface determinants to achieve proteome-wide selectivity for the degradation of cyclin-dependent kinase 6 (CDK6). Pharmacologic CDK6 degradation targets a selective dependency of acute myeloid leukemia cells, and transcriptomics and phosphoproteomics profiling of acute degradation of CDK6 enabled dynamic mapping of its immediate role in coordinating signaling and transcription.


Assuntos
Quinase 6 Dependente de Ciclina/metabolismo , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/química , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/química , Quinase 6 Dependente de Ciclina/genética , Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Ftalimidas/química , Ftalimidas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química
10.
Mini Rev Med Chem ; 19(8): 679-687, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29692241

RESUMO

BACKGROUND AND OBJECTIVE: N-aryl derivatives of phthalimide and 4-nitro phthalimide have demonstrated cyclooxygenase inhibitory activity. Also, they possess excellent analgesic and antiinflammatory activity. In this work, a new series of N-arylmethylideneamino derivatives of phthalimide and 4-nitro phthalimide were designed and synthesized. METHODS: The designed compounds were synthesized by condensation of the appropriate aldehyde and N-aminophthalimide in ethanol at room temperature at PH around 3. Their analgesic and antiinflammatory activity were evaluated by acetic acid-induced pain test and carrageenan-induced paw edema test in mice and rats, respectively. RESULTS AND CONCLUSION: The details of the synthesis and chemical characterization of the analogs are described. In vivo screening showed compounds 3a, 3b, 3f and 3h were the most potent analgesic compounds. In addition, compounds 3a, 3c, 3d, 3e and 3j indicated comparable anti-inflammatory activity to indomethacin as a reference drug.


Assuntos
Analgésicos/síntese química , Analgésicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Drogas , Ftalimidas/química , Ftalimidas/farmacologia , Animais , Avaliação Pré-Clínica de Medicamentos , Masculino , Camundongos , Ftalimidas/síntese química , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Ratos Sprague-Dawley , Espectrofotometria Infravermelho
11.
Med Chem ; 15(1): 102-118, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29793411

RESUMO

BACKGROUND: Thalidomide, the first synthesized phthalimide, has demonstrated sedative- hypnotic and antiepileptic effects on the central nervous system. N-substituted phthalimides have an interesting chemical structure that confers important biological properties. OBJECTIVE: Non-chiral (ortho and para bis-isoindoline-1,3-dione, phthaloylglycine) and chiral phthalimides (N-substituted with aspartate or glutamate) were synthesized and the sedative, anxiolytic and anticonvulsant effects were tested. METHOD: Homology modeling and molecular docking were employed to predict recognition of the analogues by hNMDA and mGlu receptors. The neuropharmacological activity was tested with the open field test and elevated plus maze (EPM). The compounds were tested in mouse models of acute convulsions induced either by pentylenetetrazol (PTZ; 90 mg/kg) or 4-aminopyridine (4-AP; 10 mg/kg). RESULTS: The ortho and para non-chiral compounds at 562.3 and 316 mg/kg, respectively, decreased locomotor activity. Contrarily, the chiral compounds produced excitatory effects. Increased locomotor activity was found with S-TGLU and R-TGLU at 100, 316 and 562.3 mg/kg, and S-TASP at 316 and 562.3 mg/kg. These molecules showed no activity in the EPM test or PTZ model. In the 4-AP model, however, S-TGLU (237.1, 316 and 421.7 mg/kg) as well as S-TASP and R-TASP (316 mg/kg) lowered the convulsive and death rate. CONCLUSION: The chiral compounds exhibited a non-competitive NMDAR antagonist profile and the non-chiral molecules possessed selective sedative properties. The NMDAR exhibited stereoselectivity for S-TGLU while it is not a preference for the aspartic derivatives. The results appear to be supported by the in silico studies, which evidenced a high affinity of phthalimides for the hNMDAR and mGluR type 1.


Assuntos
Ansiolíticos/farmacologia , Anticonvulsivantes/farmacologia , Hipnóticos e Sedativos/farmacologia , Ftalimidas/farmacologia , Animais , Ansiolíticos/síntese química , Ansiolíticos/química , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Humanos , Hipnóticos e Sedativos/síntese química , Hipnóticos e Sedativos/química , Ligantes , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Ftalimidas/síntese química , Ftalimidas/química , Receptores de Glutamato Metabotrópico/química , Receptores de N-Metil-D-Aspartato/química , Convulsões/tratamento farmacológico , Estereoisomerismo
12.
J Med Chem ; 62(2): 688-698, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30516998

RESUMO

Phosphodiesterase 10A (PDE10A) is a newly identified therapeutic target for central-nervous-system disorders. 2-(2-(3-(4-([18F]Fluoroethoxy)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([18F]MNI-659, [18F]5) is a useful positron-emission-tomography (PET) ligand for imaging of PDE10A in the human brain. However, the radiolabeled metabolite of [18F]5 can accumulate in the brain. In this study, using [18F]5 as a lead compound, we designed four new 18F-labeled ligands ([18F]6-9) to find one more suitable than [18F]5. Of these, 2-(2-(3-(4-([18F]fluoromethoxy- d2)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([18F]9) exhibited high in vitro binding affinity ( Ki = 2.9 nM) to PDE10A and suitable lipophilicity (log D = 2.2). In PET studies, the binding potential (BPND) of [18F]9 (5.8) to PDE10A in the striatum of rat brains was significantly higher than that of [18F]5 (4.6). Furthermore, metabolite analysis showed much lower levels of contamination with radiolabeled metabolites in the brains of rats given [18F]9 than in those given [18F]5. In conclusion, [18F]9 is a useful PET ligand for PDE10A imaging in brain.


Assuntos
Diester Fosfórico Hidrolases/metabolismo , Ftalimidas/química , Quinazolinonas/química , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Avaliação Pré-Clínica de Medicamentos , Radioisótopos de Flúor/química , Marcação por Isótopo , Ligantes , Masculino , Camundongos , Diester Fosfórico Hidrolases/química , Ftalimidas/sangue , Ftalimidas/metabolismo , Tomografia por Emissão de Pósitrons , Ligação Proteica , Quinazolinonas/sangue , Quinazolinonas/metabolismo , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
13.
Int J Mol Sci ; 20(1)2018 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-30577600

RESUMO

Metastatic castration-resistant prostate cancer is commonly treated with chemotherapy, whose effect is less than satisfactory. This raised the need for novel agents for the treatment of prostate cancer. In the present study, five phthalimide-based curcumin derivatives were synthesized and completely characterized to assess improved stability, pharmacodynamics, and radical scavenging ability. To investigate the potential application in anti-cancer therapy, the anti-proliferative activity of the synthesized molecules was determined on aggressive prostate tumor cells. We demonstrated that the K3F21 derivative has increased potency compared to curcumin, in terms of GI50, anti-proliferative and anti-migrating activities. K3F21 inhibits anchorage-dependent and -independent growth of prostate cancer cells by altering the expression of key genes controlling cell proliferation, such as Cylins D1, B1 and B2, and apoptosis, among which Puma, Noxa, and Bcl-2 family members. Finally, the anti-cancer activity of K3F21 was demonstrated by the analysis of cancer-associated PI3K/AKT, ERK, and p38 signaling pathways.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Curcumina/química , Curcumina/farmacologia , Ftalimidas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Estrutura Molecular , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
J Org Chem ; 83(24): 14905-14922, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30460849

RESUMO

A series of tetrapeptides and pentapeptides was synthesized bearing a phthalimide chromophore at the N-terminus. The C-terminus of the peptides was strategically substituted with an amino acid, Phe, Phe(OMe), or Phe(OMe)2 characterized by different oxidation potentials. The photochemical reactivity of the peptides was investigated by preparative irradiation and isolation of photoproducts, as well as with laser flash photolysis. Upon photoexcitation, the peptides undergo photoinduced electron transfer (PET) and decarboxylation, followed by diastereoselective cyclization with the retention of configuration for tetrapeptides or inversion of configuration for pentapeptides. Molecular dynamics (MD) simulations and NOE experiments enabled assignment of the stereochemistry of the cyclic peptides. MD simulations of the linear peptides disclosed conformational reasons for the observed diastereoselectivity, being due to the peptide backbone spatial orientation imposed by the Phe amino acids. The photochemical efficiency for the decarboxylation and cyclization is not dependent on the peptide length, but it depends on the oxidation potential of the amino acid at the C-terminus. The results described herein are particularly important for the rational design of efficient photochemical reactions for the preparation of cyclic peptides with the desired selectivity.


Assuntos
Oligopeptídeos/química , Fenilalanina/química , Fotólise , Ftalimidas/química , Ciclização , Conformação Molecular , Simulação de Dinâmica Molecular , Estereoisomerismo
15.
Bioorg Med Chem ; 26(23-24): 6115-6127, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30470598

RESUMO

A series of 2,5-dihydroxyterephthalamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives exhibited good multifunctional activities. Among them, compound 9d showed the best inhibitory activity against both RatAChE and EeAChE (IC50 = 0.56 µM and 5.12 µM, respectively). Moreover, 9d exhibited excellent inhibitory effects on self-induced Aß1-42 aggregation (IC50 = 3.05 µM) and Cu2+-induced Aß1-42 aggregation (71.7% at 25.0 µM), and displayed significant disaggregation ability to self- and Cu2+-induced Aß1-42 aggregation fibrils (75.2% and 77.2% at 25.0 µM, respectively). Furthermore, 9d also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activities and appropriate BBB permeability. These multifunctional properties highlight 9d as promising candidate for further studies directed to the development of novel drugs against AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Quelantes/farmacologia , Inibidores da Colinesterase/farmacologia , Ftalimidas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antioxidantes/síntese química , Antioxidantes/química , Butirilcolinesterase/metabolismo , Quelantes/síntese química , Quelantes/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Modelos Moleculares , Estrutura Molecular , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Ftalimidas/síntese química , Ftalimidas/química , Agregados Proteicos/efeitos dos fármacos , Relação Estrutura-Atividade
16.
J Org Chem ; 83(19): 12192-12206, 2018 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-30153021

RESUMO

A Smiles-type radical rearrangement induced by visible-light-mediated decarboxylation of ω-aryl- N-(acyloxy)phthalimides was developed, giving rise to pharmacologically important substance classes: phenylethylamine derivatives, dihydroisoquinolinones, and benzoazepinones were synthesized on the basis of readily available benzoic acids or benzaldehydes and ß- or γ-amino acids. This methodology facilitates the synthesis of enantiopure D-amphetamine and of precursors of capsazepinoid bronchodilators.


Assuntos
Luz , Processos Fotoquímicos , Ftalimidas/química , Descarboxilação , Estereoisomerismo
17.
Bioorg Chem ; 80: 693-705, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30064080

RESUMO

A series of six novel and six known thieno[2,3-d]pyrimidin-4-amines 2-13 were synthesized, and further were used as a starting material for preparation of a small series of eight novel thieno[2,3-d]pyrimidin-4-phthalimides 14-21. Eight compounds, five amine and three phthalimide derivatives, inhibited bovine pancreatic DNase I with an IC50 below 200 µM, being more effective than referent inhibitor crystal violet. Phthalimide derivatives 16, 18 and 19 exhibited higher DNase I inhibitory activity compared to their amine precursors 7, 10 and 11. Compound 19, as the most potent (IC50 = 106 ±â€¯16 µM), offers a good starting point for a design of new DNase I inhibitors. The Pharma RQSAR model showed a significant enhancement of thieno[2,3-d]pyrimidines activity using aryl substituents at R1 position. The E-State RQSAR model clarified the most important structural fragments relevant for DNase I inhibition. Molecular docking and Site Finder module defined the thieno[2,3-d]pyrimidines interactions with the most important catalytic residues of DNase I, including Glu 39, His 134, Asp 168 and His 252. We also found that steric effects and increase of molecular volume play a vital role in DNase I inhibition.


Assuntos
Desoxirribonuclease I/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Animais , Bovinos , Desoxirribonuclease I/química , Desoxirribonuclease I/metabolismo , Inibidores Enzimáticos/síntese química , Simulação de Acoplamento Molecular , Ftalimidas/síntese química , Ftalimidas/química , Ftalimidas/farmacologia , Pirimidinas/síntese química , Relação Estrutura-Atividade
18.
ChemMedChem ; 13(19): 2080-2089, 2018 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-30134015

RESUMO

The introduction of fluorine into bioactive molecules is a matter of importance in medicinal chemistry. In this study, representatives of various chemical entities of fluoroaromatic compounds were synthesized. Depending on the reaction conditions, either tetrafluorophthalimides or ammonium tetrafluorophthalamates are accessible from tetrafluorophthalic anhydride and primary amines. Tetrafluorophthalamic acids undergo thermal decarboxylation to yield tetrafluorobenzamides. These could be successfully converted upon treatment with primary amines, in the course of an aromatic nucleophilic substitution, to 2,3,5-trifluorobenzamides with respective amino substituents at the 4-position. The five structure types were characterized by means of spectroscopic and crystallographic methods. The synthesized compounds were evaluated as inhibitors of angiogenesis by measuring microvessel outgrowth in a rat aortic ring assay. The biological activity was maintained throughout these different polyfluorinated chemotypes.


Assuntos
Inibidores da Angiogênese/farmacologia , Benzamidas/farmacologia , Fluorcarbonetos/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/toxicidade , Animais , Aorta/efeitos dos fármacos , Benzamidas/síntese química , Benzamidas/química , Benzamidas/toxicidade , Fluorcarbonetos/síntese química , Fluorcarbonetos/química , Fluorcarbonetos/toxicidade , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Microvasos/efeitos dos fármacos , Estrutura Molecular , Ftalimidas/síntese química , Ftalimidas/química , Ftalimidas/farmacologia , Ftalimidas/toxicidade , Ratos Sprague-Dawley , para-Aminobenzoatos/síntese química , para-Aminobenzoatos/química , para-Aminobenzoatos/farmacologia , para-Aminobenzoatos/toxicidade
19.
Anal Bioanal Chem ; 410(26): 6861-6871, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30105623

RESUMO

Thermally labile pesticides (captafol, captan, dicofol, and folpet) are highly prone to suffer thermal degradation during sample introduction into a gas chromatograph (GC) to tetrahydrophthalimide (THPI), 4,4'-dichlorobenzophenone (DCBP), and phthalimide (PI), respectively, mainly produced in the glass liner of the injector. This undesired behavior leads to inaccurate qualitative and quantitative results. Direct on-column injection (OCI) technique is evaluated as an alternative to avoid or minimize compound alteration during the analysis. This configuration was studied and evaluated for the determination of this group of thermally troublesome pesticides. The OCI inlet was operated in "track oven" temperature and connected to a wide-bore deactivated guard column that is itself connected to a capillary GC analytical column. This technique has demonstrated to be useful for avoiding degradation generated in the hot inlet. Limitations observed for OCI in routine analysis were injection volume, guard column length, and maintenance issues. Analytical standards spiked in vegetable solutions were injected in OCI, not observing any thermal degradation rate. On the contrary, classical splitless injection (SLI) produced high degradation rates in all cases. This OCI approach was validated in citrate QuEChERS extracts of tomato, apple, and orange matrices for these four compounds and their corresponding transformation products (THPI, DCBP, and PI), evaluating recoveries, repeatability, linearity, and matrix effect. This set-up enabled the correct identification and quantitation for most compounds at LOQs of 0.010 mg/kg in fruit and vegetable samples. The OCI grants evident differentiation between metabolites naturally occurring in food and thermal degradation products created during the analysis. Graphical abstract ᅟ.


Assuntos
Cromatografia Gasosa/métodos , Frutas/química , Praguicidas/análise , Verduras/química , Benzofenonas/química , Captana/química , Limite de Detecção , Ftalimidas/química , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Temperatura Ambiente
20.
Artigo em Inglês | MEDLINE | ID: mdl-30007901

RESUMO

A novel lysosome-targetable phthalimide fluorescent probe was designed for detecting palladium based on ESIPT for signal transduction. The fluorescent probe conjugating with allylcarbamate displayed weak fluorescent due to the ESIPT process hinder by allylcarbamate. But with the addition of palladium, the ESIPT emission was recovery though the palladium-catalyzed deallylation reaction and the fluorescence intensity exhibited 40-fold enhancement at 511 nm. In addition, the probe showed excellent selectivity, high sensitivity, fast responds and low limit detection for palladium with a larger Stoke-shift. Moreover, the targetable probe was also successfully applied for detecting palladium in lysosomes of living cells. Hence, the probe though ESIPT modulation is a promising for monitoring palladium in practical samples.


Assuntos
Corantes Fluorescentes/química , Lisossomos/química , Paládio/análise , Ftalimidas/química , Células A549 , Corantes Fluorescentes/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Lisossomos/metabolismo , Microscopia Confocal , Ftalimidas/metabolismo
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