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1.
Eur J Med Chem ; 192: 112156, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32114360

RESUMO

Androgen receptor (AR) plays important roles in the development of prostate cancer (PCa), and therefore it has been regarded as the most important therapeutic target for both hormone-sensitive prostate cancer (HSPC) and advanced PCa. In this study, a novel hit (C18) with IC50 of 2.4 µM against AR transcriptional activity in LNCaP cell was identified through structure-based virtual screening based on molecular docking and free energy calculations. The structure-activity relationship analysis and structural optimization of C18 resulted in the discovery of a structural analogue (AT2), a more potent AR antagonist with 16-fold improved anti-AR potency. Further assays indicated that AT2 was capable of effectively inhibiting the transcriptional function of AR and blocking the nuclear translocation of AR like the second-generation AR antagonists. The antagonists discovered in this study may be served as the promising lead compounds for the development of AR-driven PCa therapeutics.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Quinolonas/farmacologia , Células 3T3 , Antagonistas de Receptores de Andrógenos/síntese química , Antagonistas de Receptores de Andrógenos/química , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
2.
Bioorg Chem ; 96: 103626, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32007719

RESUMO

We, herein, describe the synthesis of a series of novel aryl tethered 7,8-dihydroquinolin-5(6H)-ylidenehydrazinecarbothioamides 4a-v, which showed in vitro and in vivo antimycobacterial activity against Mycobacterium tuberculosis (Mtb) H37Rv. The intermediates dihydro-6H-quinolin-5-ones 3a-v were synthesized from ß-enaminones, reacting with cyclochexane-1,3-dione/5,5-dimethylcyclohexane-1,3-dione and ammonium acetate using a modified Bohlmann-Rahtz reaction conditions. They were further reacted with thiosemicarbazide to give the respective hydrazine carbothioamides 4a-v. All the new analogues 4a-v, were characterized by their NMR and mass spectral data analysis. Among the twenty-two compounds screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294), two compounds, 4e and 4j, exhibited the highest inhibition with an MIC of 0.39 µg/mL. Compounds 4a, 4g, and 4k were found to inhibit Mtb at an MIC of 0.78 µg/mL. Hydrazinecarbothioamides 4a-k, exhibited enhanced activity than dihydroquinolinones 3a-k. The observed increase in potency provides a clear evidence that hydrazinecarbothioamide is a potential pharmacophore, collectively imparting synergistic effect in enhancing antitubercular activity of the dihydroquinolinone core. The in vivo (Zebra fish) antimycobacterial screening of the in vitro active molecules led to the identification of a hit compound, 4j, with significant activity in the Mtb nutrient starvation model (2.2-fold reduction). Docking studies of 4j showed a hydrogen bond with the P156 residue of the protein.


Assuntos
Antituberculosos/química , Antituberculosos/uso terapêutico , Hidrazinas/química , Hidrazinas/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Tioamidas/química , Tioamidas/uso terapêutico , Tuberculose/tratamento farmacológico , Animais , Antituberculosos/síntese química , Modelos Animais de Doenças , Desenho de Fármacos , Humanos , Hidrazinas/síntese química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Quinolonas/síntese química , Quinolonas/química , Quinolonas/uso terapêutico , Relação Estrutura-Atividade , Tioamidas/síntese química , Peixe-Zebra
3.
AAPS PharmSciTech ; 20(1): 26, 2019 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-30604333

RESUMO

Rebamipide has low oral bioavailability (10%) due to its low solubility and permeability. Lipid nanoemulsions (LNEs) were prepared in order to improve its oral bioavailability. Rebamipide-loaded lipid nanoemulsions were formulated by hot homogenization and ultrasonication method. Olive oil and egg lecithin in various concentrations as emulsifier were used in the preparation of LNEs. The lipid nanoemulsions were evaluated for various parameters. The globule size, polydispersity index (PDI), and zeta potential (ZP) of the formulations ranged from 230.3 ± 3.88 to 279.8 ± 5.76 nm, 0.204 ± 0.008 to 0.246 ± 0.029, and - 27.7 ± 2.05 to - 31.0 ± 1.87 mV, respectively. Entrapment efficiency and assay values ranged from 99.90 ± 0.006 to 99.92 ± 0.002% and 99.3 ± 0.808 to 99.6 ± 0.360, respectively. Physical stability test results revealed that the optimized LNEs were stable for 2 months at both room (25°C) and refrigerated temperature (4°C). The optimized LNE showed 4.32-fold improvement in the oral bioavailability in comparison to a marketed tablet suspension. In vivo anti ulcer activity of rebamipide LNE was studied by testing the prophylactic effect in preventing the mucosal damage in stomach region. The mucosa of stomach in animals was damaged by per oral administration of 80% alcohol. Maximum prophylactic antiulcer activity was observed by per oral delivery of rebamipide as LNE. Our results indicated that LNEs were a promising approach for the oral delivery of rebamipide for systemic effects along with local effects in protecting gastric region, which gets damaged during peptic ulcers.


Assuntos
Alanina/análogos & derivados , Antiulcerosos/farmacocinética , Emulsificantes/farmacocinética , Nanopartículas/metabolismo , Quinolonas/farmacocinética , Administração Oral , Alanina/síntese química , Alanina/farmacocinética , Animais , Antiulcerosos/síntese química , Avaliação Pré-Clínica de Medicamentos/métodos , Emulsificantes/síntese química , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Lipídeos , Masculino , Nanopartículas/química , Tamanho da Partícula , Quinolonas/síntese química , Ratos , Ratos Wistar
4.
Bioorg Chem ; 78: 236-248, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29614435

RESUMO

The synthesis of ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylates (4, 5) was performed via the reaction of corresponding anilines with diethyl ethoxymethylenemalonate under conventional and also microwave promoted conditions. The treatment of 4 and 5 afforded the corresponding hydrazides (6 and 7). These hydrazides were converted to the corresponding carbo(thio)amides (9a-f and 10a-e) which were then subjected to an intramolecular cyclisation leading to the formation of quinolone-triazole hybrids (11a-f and 12a-e). The newly synthesized compounds were screened for their biological activities such as antioxidant capacity (AC) and acetylcholinesterase Activity. Inhibition of cholinesterases is an effective method to curb Alzheimer's disease, a progressive and fatal neurological disorder. A series of some novel quinolonederivatives were designed, synthesized, and their inhibitory effects on AChE were evaluated. We obtained our compounds and determined their anticholinesterase activities according to the Ellman's method. 9b and 10c showed the best AChE inhibition with 0.48 ±â€¯0.02 and 0.52 ±â€¯0.07, respectively. Docking studies were performed for the most active compounds (9b, 10c) and interaction modes with enzyme active sites were determined. As a result of these studies, a strong interaction between these compounds and the active sites of AChE enzyme was revealed.


Assuntos
Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Micro-Ondas , Simulação de Acoplamento Molecular , Quinolonas/farmacologia , Triazóis/farmacologia , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Bifenilo/antagonistas & inibidores , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Electrophorus , Radicais Livres/antagonistas & inibidores , Estrutura Molecular , Picratos/antagonistas & inibidores , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
5.
Br J Pharmacol ; 174(7): 525-539, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28094839

RESUMO

BACKGROUND AND PURPOSE: Cystic fibrosis (CF) is a debilitating disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which codes for a Cl-/HCO3 - channel. F508del, the most common CF-associated mutation, causes both gating and biogenesis defects in the CFTR protein. This paper describes the optimization of two fluorescence assays, capable of measuring CFTR function and cellular localization, and their use in a pilot drug screen. EXPERIMENTAL APPROACH: HEK293 cells expressing YFP-F508del-CFTR, in which halide sensitive YFP is tagged to the N-terminal of CFTR, were used to screen a small library of compounds based on the VX-770 scaffold. Cells expressing F508del-CFTR-pHTomato, in which a pH sensor is tagged to the fourth extracellular loop of CFTR, were used to measure CFTR plasma membrane exposure following chronic treatment with the novel potentiators. KEY RESULTS: Active compounds with efficacy ~50% of VX-770, micromolar potency, and structurally distinct from VX-770 were identified in the screen. The F508del-CFTR-pHTomato assay suggests that the hit compound MS131A, unlike VX-770, does not decrease membrane exposure of F508del-CFTR. CONCLUSIONS AND IMPLICATIONS: Most known potentiators have a negative influence on F508del-CFTR biogenesis/stability, which means membrane exposure needs to be monitored early during the development of drugs targeting CFTR. The combined use of the two fluorescence assays described here provides a useful tool for the identification of improved potentiators and correctors. The assays could also prove useful for basic scientific investigations on F508del-CFTR, and other CF-causing mutations.


Assuntos
Aminofenóis/análise , Aminofenóis/farmacologia , Proteínas de Bactérias/análise , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Fluorescência , Proteínas Luminescentes/análise , Quinolonas/análise , Quinolonas/farmacologia , Bibliotecas de Moléculas Pequenas/análise , Bibliotecas de Moléculas Pequenas/farmacologia , Aminofenóis/síntese química , Aminofenóis/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Células HEK293 , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química
6.
Eur J Med Chem ; 121: 747-757, 2016 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-27429255

RESUMO

Smoothened (Smo) is the signal transducer of the Hedgehog (Hh) pathway and its stimulation is considered a potential powerful tool in regenerative medicine to treat severe tissue injuries. Starting from GSA-10, a recently reported Hh activator acting on Smo, we have designed and synthesized a new class of quinolone-based compounds. Modification and decoration of three different portions of the original scaffold led to compounds able to induce differentiation of multipotent mesenchymal cells into osteoblasts. The submicromolar activity of several of these new quinolones (0.4-0.9 µM) is comparable to or better than that of SAG and purmorphamine, two reference Smo agonists. Structure-activity relationships allow identification of several molecular determinants important for the activity of these compounds.


Assuntos
Desenho de Fármacos , Osteogênese/efeitos dos fármacos , Quinolonas/química , Quinolonas/farmacologia , Animais , Técnicas de Química Sintética , Avaliação Pré-Clínica de Medicamentos , Proteínas Hedgehog/metabolismo , Camundongos , Modelos Moleculares , Células NIH 3T3 , Quinolonas/síntese química , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 25(24): 5808-12, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26546216

RESUMO

2-Benzylisoquinolin-1(2H)-ones has been proposed as vasodilative agents on the basis of scaffold hopping. In the present study, a series of 2-benzylisoquinolin-1(2H)-ones were synthesized. Their vasodilative effects were evaluated by wire myograph on isolated rat mesenteric arterial ring induced contraction with 60mM KCl. The structure-activity relationships of target compounds were discussed. Among these compounds, C7 and C8 displayed potent vasodilative effects and significantly inhibited the contraction of rat mesenteric arterial rings induced by phenylephrine. The antihypertensive effects of compounds C7 and C8 on SHR were further evaluated. The results indicated that oral administrational C7 and C8 can significantly reduce both diastolic and systolic blood pressure in a dose-dependent manner. Moreover, C7 maintained the effects for 4h at a dosage of 4.0mg/kg. These findings suggest that the title compounds can serve as novel vasodilative agents and promising antihypertensive agents.


Assuntos
Anti-Hipertensivos/química , Quinolonas/química , Vasodilatadores/química , Administração Oral , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Hipertensão/tratamento farmacológico , Artérias Mesentéricas/efeitos dos fármacos , Quinolonas/síntese química , Quinolonas/farmacologia , Ratos , Ratos Endogâmicos SHR , Relação Estrutura-Atividade , Vasodilatadores/síntese química , Vasodilatadores/farmacologia
8.
Molecules ; 19(9): 14204-20, 2014 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-25211002

RESUMO

A diverse array of 4-(1H)-quinolone derivatives bearing substituents at positions 1 and 2 were synthesized and evaluated for antiprotozoal activities against Plasmodium falciparum and Trypanosoma brucei rhodesiense, and cytotoxicity against L-6 cells in vitro. Furthermore, selectivity indices were also determined for both parasites. All compounds tested showed antimalarial activity at low micromolar concentrations, with varied degrees of selectivity against L-6 cells. Compound 5a was found to be the most active against P. falciparum, with an IC50 value of 90 nM and good selectivity for the malarial parasite compared to the L-6 cells. Compound 10a, on the other hand, showed a strong antitrypanosomal effect with an IC50 value of 1.25 µM. In this study side chain diversity was explored by varying the side chain length and substitution pattern on the aliphatic group at position-2 and a structure-antiprotozoal activity study revealed that the aromatic ring introduced at C-2 contributed significantly to the antiprotozoal activities.


Assuntos
Antimaláricos/farmacologia , Quinolonas/farmacologia , Tripanossomicidas/farmacologia , Acetilação , Animais , Antimaláricos/síntese química , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Concentração Inibidora 50 , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Quinolonas/síntese química , Ratos , Tripanossomicidas/síntese química , Trypanosoma brucei rhodesiense/efeitos dos fármacos
9.
Eur J Med Chem ; 85: 107-18, 2014 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-25078314

RESUMO

A series of azaisoflavone analogs were designed and synthesized and their transactivation activities and binding affinities for ERα and ERß were investigated. Among these compounds, 2b and 3a were the most potent with 6.5 and 1.1 µM of EC50, respectively. Molecular modeling study showed putative binding modes of the compound 3a in the active site of ERα and ERß, which were similar with that of genistein and provided insight of the effect of N-alkyl substitution of azaisoflavones on ERß activity. Also, a biphasic effect of azaisoflavone analogs on MCF-7 cell growth depending on their concentrations was investigated.


Assuntos
Desenho de Fármacos , Flavonas/síntese química , Flavonas/farmacologia , Fitoestrógenos/síntese química , Fitoestrógenos/farmacologia , Quinolonas/síntese química , Quinolonas/farmacologia , Domínio Catalítico , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/química , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Flavonas/química , Flavonas/metabolismo , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Fitoestrógenos/química , Fitoestrógenos/metabolismo , Quinolonas/química , Quinolonas/metabolismo , Relação Estrutura-Atividade , Ativação Transcricional/efeitos dos fármacos
10.
Clin Chim Acta ; 425: 242-58, 2013 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-23954776

RESUMO

Beta2-adrenergic agonists, or ß2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of ß2-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006-2012) literature concerning the development of novel ß2-agonists molecules either by modifying the molecule of known ß2-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging ß2-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/isolamento & purificação , Anti-Inflamatórios/isolamento & purificação , Drogas Desenhadas/isolamento & purificação , Suplementos Nutricionais , Dopagem Esportivo/prevenção & controle , Agonistas de Receptores Adrenérgicos beta 2/síntese química , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Bovinos , Drogas Desenhadas/síntese química , Etanolaminas/síntese química , Etanolaminas/isolamento & purificação , Substâncias de Crescimento/síntese química , Substâncias de Crescimento/isolamento & purificação , Humanos , Indóis/síntese química , Indóis/isolamento & purificação , Quinolonas/síntese química , Quinolonas/isolamento & purificação , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/isolamento & purificação
11.
Chem Pharm Bull (Tokyo) ; 61(6): 631-6, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23558565

RESUMO

A novel series of quinolone derivatives (6a-n) were designed and synthesized, and their biological activities were evaluated as potential antitumor topoisomerase I (Top I) inhibitors. Among these compounds, 6j exhibited the most potent antitumor activities against multiple cancer cell lines. Docking simulation was performed to insert compound 6j into the crystal structure of DNA-Top I to determine the probable binding model.


Assuntos
Antineoplásicos/síntese química , DNA Topoisomerases Tipo I/química , Desenho de Fármacos , Quinolonas/química , Inibidores da Topoisomerase I/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Quinolonas/síntese química , Quinolonas/toxicidade , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/toxicidade
12.
Bioorg Med Chem Lett ; 23(11): 3267-72, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23602443

RESUMO

A novel series of quinolone triazoles were synthesized and characterized by IR, NMR, MS and HRMS spectra. All the newly prepared compounds were screened for their antimicrobial activities against seven bacteria and four fungi. Bioactive assay manifested that most of new compounds exhibited good or even stronger antibacterial and antifungal activities against the tested strains including multi-drug resistant MRSA in comparison with reference drugs Norfloxacin, Chloromycin and Fluconazole. The preliminary interactive investigations of compound 6b with calf thymus DNA by fluorescence and UV-vis spectroscopic methods revealed that compound 6b could effectively intercalate DNA to form compound 6b-DNA complex which might block DNA replication and thus exert its antimicrobial activities.


Assuntos
Anti-Infecciosos/síntese química , DNA/metabolismo , Substâncias Intercalantes/síntese química , Quinolonas/química , Quinolonas/síntese química , Triazóis/química , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Bovinos , DNA/química , DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Fungos/efeitos dos fármacos , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Quinolonas/farmacologia , Espectrofotometria Ultravioleta , Triazóis/síntese química , Triazóis/farmacologia
13.
Bioorg Med Chem Lett ; 23(6): 1684-8, 2013 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-23414838

RESUMO

High throughput screening led to the identification of a novel series of quinolone α7 nicotinic acetylcholine receptor (nAChR) agonists. Optimization of an HTS hit (1) led to 4-phenyl-1-(quinuclidin-3-ylmethyl)quinolin-2(1H)-one, which was found to be potent and selective. Poor brain penetrance in this series was attributed to transporter-mediated efflux, which was in turn due to high pKa. A novel 4-fluoroquinuclidine significantly lowered the pKa of the quinuclidine moiety, reducing efflux as measured by a Caco-2 assay.


Assuntos
Agonistas Nicotínicos/química , Quinolonas/química , Receptores Nicotínicos/química , Animais , Células CACO-2 , Avaliação Pré-Clínica de Medicamentos , Humanos , Cinética , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/metabolismo , Quinolonas/síntese química , Quinolonas/metabolismo , Ratos , Receptores Nicotínicos/metabolismo , Relação Estrutura-Atividade , Receptor Nicotínico de Acetilcolina alfa7
14.
Am J Chin Med ; 40(5): 1063-71, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22928835

RESUMO

A bicyclic chemical structure, such as that found in flavonoids, was discovered to have anti-cancer activity. Further synthetic structural modification created a series of 2-phenyl-4-quinolone analogs, especially KHC-4, with the same bicyclic chemical structure. This new structure was reported to have stronger anti-cancer activity. In KHC-4 treatments for 72 h on human prostate cancer PC3 cells, cytotoxic effects (IC(50) =0.1 µM) increased dose dependently, causing Cdk1/cyclin B1 complex activity mannered cell cycle and proliferation. KHC-4 treatments suppressed Bcl-2 and Bcl-xL protein levels and upregulated Bax. At the same concentration, pro-caspase 9 protein was cleaved to an activated form, leading to cell apoptosis. Furthermore, the MMP-2 protein levels also decreased through KHC-4 treatment in PC3. In conclusion, KHC-4 presents great prostate cancer therapeutic effects for cell proliferation inhibition, induction of apoptosis and protection against tumor migration.


Assuntos
Antineoplásicos/uso terapêutico , Flavonoides/química , Morfolinas/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Quinolonas/uso terapêutico , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 9/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina B1/metabolismo , Relação Dose-Resposta a Droga , Humanos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Morfolinas/síntese química , Morfolinas/farmacologia , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Quinolonas/síntese química , Quinolonas/farmacologia , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/metabolismo
15.
ChemMedChem ; 6(5): 804-15, 2011 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-21374821

RESUMO

Heat shock protein 90 (Hsp90) is a significant target in the development of rational cancer therapy, due to its role at the crossroads of multiple signaling pathways associated with cell proliferation and viability. Here, a novel series of Hsp90 inhibitors containing a quinolein-2-one scaffold was synthesized and evaluated in cell proliferation assays. Results from these structure-activity relationships studies enabled identification of the simplified 3-aminoquinolein-2-one analogue 2 b (6BrCaQ), which manifests micromolar activity against a panel of cancer cell lines. The molecular signature of Hsp90 inhibition was assessed by depletion of standard known Hsp90 client proteins. Finally, processing and activation of caspases 7, 8, and 9, and the subsequent cleavage of PARP by 6BrCaQ, suggest stimulation of apoptosis through both extrinsic and intrinsic pathways.


Assuntos
Antineoplásicos/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Quinolonas/química , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Apoptose , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Novobiocina/toxicidade , Complexo de Endopeptidases do Proteassoma/metabolismo , Dobramento de Proteína , Quinolonas/síntese química , Quinolonas/toxicidade
16.
Eur J Med Chem ; 46(6): 2091-101, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21429630

RESUMO

In an effort to improve biological activities and to examine antimycobacterial-lipophilicity relationships of 2-[(1E)-alkenyl)]-4-(1H)-quinolones, we have synthesized a series of 30 quinolones by introducing several alkyl groups, an alkenyl and an alkynyl group at N-1. All synthetic compounds were first tested in vitro against Mycobacterium smegmatis and the most active compounds (MIC values ∼3.0-7.0 µM) were further examined against three other rapidly growing strains of mycobacteria using a microtiter broth dilution assay. The Clog P values of the synthetic compounds were calculated to provide an estimate of their lipophilicity. Compounds 18e, 19a and 19b displayed the most potent inhibitory effect against M. smegmatis mc(2)155 with an MIC value of ∼1.5 µM, which was twenty fold and thirteen fold more potent than isoniazid and ethambutol, respectively. On the other hand, compounds 17e, 18e and 19a were most active against Mycobacterium fortuitum and Mycobacterium phlei with an MIC value of ∼3.0 µM. In the human diploid embryonic lung cell line MRC-5 cytotoxicity assay, the derivatives showed moderate to strong cytotoxic activity. Although the antimycobacterial activity of our synthetic compounds could not be correlated with the calculated log P values, an increase in lipophilicity enhances the antimycobacterial activity and C13-C15 total chain length at positions 1 and 2 is required to achieve optimal inhibitory effect against the test strains.


Assuntos
Antibacterianos/farmacologia , Mycobacterium/efeitos dos fármacos , Quinolonas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/química , Estereoisomerismo , Relação Estrutura-Atividade
17.
Bioorg Med Chem Lett ; 20(24): 7414-20, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21055932

RESUMO

A novel series of quinolinone-based adenosine A(2B) receptor antagonists was identified via high throughput screening of an encoded combinatorial compound collection. Synthesis and assay of a series of analogs highlighted essential structural features of the initial hit. Optimization resulted in an A(2B) antagonist (2i) which exhibited potent activity in a cAMP accumulation assay (5.1 nM) and an IL-8 release assay (0.4 nM).


Assuntos
Antagonistas do Receptor A2 de Adenosina/química , Quinolonas/química , Receptor A2B de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/farmacologia , Técnicas de Química Combinatória , Avaliação Pré-Clínica de Medicamentos , Humanos , Microssomos Hepáticos/metabolismo , Quinolonas/síntese química , Quinolonas/farmacologia , Receptor A2B de Adenosina/metabolismo , Relação Estrutura-Atividade
18.
Eur J Med Chem ; 45(7): 3162-8, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20434240

RESUMO

A series of novel ketoprofen derivatives 4a-j bearing both amide and carbamate functionalities were prepared using benzotriazole. Selective reduction of ketoprofen produced hydroxy derivative 2, which reacts with one or 2 mol of 1-benzotriazole carboxylic acid chloride (1) gave benzotriazole derivatives 3a and 3b respectively. Antioxidative screenings revealed that the prepared compounds 3b and 4a-j possess excellent lipid peroxidation inhibition at 0.1 mM concentration. Two of the compounds 3b and 4 g also showed high soybean lipoxygenase inhibition activity, where as the amidocarbamate derivatives of ketoprofen showed only weak reducing activity against 1,1-diphenyl-2-picrylhydrazyl radicals. No selective antiviral effects were noted for the tested compounds against a broad variety of DNA and RNA viruses.


Assuntos
Carbamatos/química , Quinolonas/química , Quinolonas/farmacologia , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Compostos de Bifenilo/química , Linhagem Celular , Citostáticos/síntese química , Citostáticos/química , Citostáticos/farmacologia , Vírus de DNA/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Concentração Inibidora 50 , Ácido Linoleico/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Picratos/química , Quinolonas/síntese química , Vírus de RNA/efeitos dos fármacos , Glycine max/enzimologia
19.
ChemMedChem ; 5(5): 739-48, 2010 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-20379990

RESUMO

A small set of aggrecanase inhibitors based on the pyrrolo[3,4-c]quinolin-1-one or oxoisoindoline frameworks bearing a 4-(benzyloxy)phenyl substituent and different zinc binding groups were rationally designed and evaluated in silico by docking studies using the crystal structure of the ADAMTS-5 catalytic domain (PDB code: 3B8Z). The designed compounds were synthesized via straightforward routes and tested for their potential inhibitory activity against ADAMTS-5 and ADAMTS-4. Among the compounds containing the pyrrolo[3,4-c]quinolinone tricyclic system, hydroxamate derivative 2 b inhibited both ADAMTS-5 and ADAMTS-4, with IC(50) values in the submicromolar range and an inhibitory profile very similar to that of reference carboxylate derivative 11. Conversely, the corresponding carboxylate derivative 2 a was significantly less active and unable to discriminate between ADAMTS-5 and -4. The structure-activity relationship analysis of pyrroloquinolinone derivatives 2 a-i suggests that the carboxylate or hydroxamate groups of compounds 2 a,b play a key role in the interaction of these compounds with ADAMTS-5 and -4. On the other hand, the oxoisoindoline derivatives 3 a,b lack significant ADAMTS-4 inhibitory activity and inhibit ADAMTS-5 showing IC(25) values in the micromolar range.


Assuntos
Endopeptidases/química , Indóis/química , Inibidores de Proteases/síntese química , Quinolonas/química , Proteínas ADAM/química , Sítios de Ligação , Domínio Catalítico , Simulação por Computador , Cristalografia por Raios X , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Endopeptidases/metabolismo , Indóis/síntese química , Indóis/farmacologia , Conformação Molecular , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Quinolonas/síntese química , Quinolonas/farmacologia
20.
Bioorg Med Chem Lett ; 19(23): 6582-4, 2009 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-19875282

RESUMO

We developed a synthetic route to prepare isoquinoline analogs of the cancer drug clinical candidate tipifarnib. We show that these compounds kill Trypanosoma cruzi amastigotes grown in mammalian host cells at concentrations in the low nanomolar range. These isoquinolines represent new leads for the development of drugs to treat Chagas disease.


Assuntos
Antineoplásicos/farmacologia , Quinolonas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Doença de Chagas/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Camundongos , Conformação Molecular , Testes de Sensibilidade Parasitária , Quinolonas/síntese química , Quinolonas/química , Estereoisomerismo , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Trypanosoma cruzi/crescimento & desenvolvimento
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