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1.
Nat Commun ; 11(1): 3848, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737286

RESUMO

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the degeneration of upper and lower motor neurons (MNs). We find a significant reduction of the retromer complex subunit VPS35 in iPSCs-derived MNs from ALS patients, in MNs from ALS post mortem explants and in MNs from SOD1G93A mice. Being the retromer involved in trafficking of hydrolases, a pathological hallmark in ALS, we design, synthesize and characterize an array of retromer stabilizers based on bis-guanylhydrazones connected by a 1,3-phenyl ring linker. We select compound 2a as a potent and bioavailable interactor of VPS35-VPS29. Indeed, while increasing retromer stability in ALS mice, compound 2a attenuates locomotion impairment and increases MNs survival. Moreover, compound 2a increases VPS35 in iPSCs-derived MNs and shows brain bioavailability. Our results clearly suggest the retromer as a valuable druggable target in ALS.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Hidrazonas/farmacologia , Neurônios Motores/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas de Transporte Vesicular/genética , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Diferenciação Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Hidrazonas/síntese química , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Ligação Proteica/efeitos dos fármacos , Multimerização Proteica , Relação Estrutura-Atividade , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Proteínas de Transporte Vesicular/metabolismo
2.
PLoS One ; 15(6): e0233993, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32484843

RESUMO

Multidrug resistance (MDR) to chemotherapeutic drugs remains one of the major impediments to the treatment of cancer. Discovery and development of drugs that can prevent and reverse the acquisition of multidrug resistance constitute a foremost challenge in cancer therapeutics. In this work, we screened a library of 1,127 compounds with known targets for their ability to overcome Pgp-mediated multidrug resistance in cancer cell lines. We identified four compounds (CHIR-124, Elesclomol, Tyrphostin-9 and Brefeldin A) that inhibited the growth of two pairs of parental and Pgp-overexpressing multidrug-resistant cell lines with similar potency irrespective of their Pgp status. Mechanistically, CHIR-124 (a potent inhibitor of Chk1 kinase) inhibited Pgp activity in both multidrug-resistant cell lines (KB-V1 and A2780-Pac-Res) as determined through cell-based Pgp-efflux assays. Other three inhibitors on the contrary, were effective in Pgp-overexpressing resistant cells without increasing the cellular accumulation of a Pgp substrate, indicating that they overcome resistance by avoiding efflux through Pgp. None of these compounds modulated the expression of Pgp in resistant cell lines. PIK-75, a PI3 Kinase inhibitor, was also determined to inhibit Pgp activity, despite being equally potent in only one of the two pairs of resistant and parental cell lines. Strong binding of both CHIR-124 and PIK-75 to Pgp was predicted through docking studies and both compounds inhibited Pgp in a biochemical assay. The inhibition of Pgp causes accumulation of these compounds in the cells where they can modulate the function of their target proteins and thereby inhibit cell proliferation. In conclusion, we have identified compounds with various cellular targets that overcome multidrug resistance in Pgp-overexpressing cell lines through mechanisms that include Pgp inhibition and efflux evasion. These compounds, therefore, can avoid challenges associated with the co-administration of Pgp inhibitors with chemotherapeutic or targeted drugs such as additive toxicities and differing pharmacokinetic properties.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Neoplasias/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Brefeldina A/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hidrazinas/farmacologia , Hidrazonas/farmacologia , Neoplasias/genética , Neoplasias/patologia , Quinolinas/farmacologia , Quinuclidinas/farmacologia , Sulfonamidas/farmacologia , Tirfostinas/farmacologia
3.
Adv Exp Med Biol ; 1195: 137-148, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468468

RESUMO

In the present work a series of N'-arylidene-2-(benzamido)-3-(naphthalen-2-yl)acrylohydrazides were synthesized by refluxing the intermediate 2-(benzamido)-3-(naphthalen-2-yl)acrylohydrazide with various substituted benzaldehyde in the presence of glacial acetic acid. The intermediate 2-(benzamido)-3-(naphthalen-2-yl)acrylohydrazide 2 was prepared by stirring 4-((naphthalen-2-yl)methylene)-2-phenyloxazol-5(4H)-one with hydrazine hydrate in the presence of absolute ethanol. The chemical structures of the compounds were established by IR, 1H NMR and mass spectral data. All the compounds were evaluated for anti-inflammatory (in vivo, in vitro) activity and performed docking against COX-2. The compounds 3a, 3c and 3o showed good inhibition of COX-2 in in vitro studies (0.75 µM, 0.5 µM and 0.7 µM as IC50, respectively). The compounds 3c, 3e and 3f were found to be more active than standard drug phenylbutazone at equidose. Molecular docking studies showed that compound 3 m exhibited good binding affinity against COX-2 with docking score 9.328 kcal/mol, when compared to the standard celecoxib.


Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Hidrazonas/síntese química , Hidrazonas/farmacologia , Simulação de Acoplamento Molecular , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Hidrazonas/química , Hidrazonas/uso terapêutico , Estrutura Molecular , Relação Estrutura-Atividade
4.
Adv Exp Med Biol ; 1195: 189-198, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468477

RESUMO

In the present work, new indole derivatives, i.e., 5-[N,N-di alkyl amino alkoxy] azaindole 2,3- di-one derivatives, are synthesized and characterized. These compounds were subjected to acute toxicity and then screened for antiepileptic activity on maximal electroshock seizure (MES) model in albino Wistar rats. In that study 5-[2-dimethyl amino ethoxy] Azaindole-3-hydrazone,2-one and 5-[2- dimethyl amino ethoxy] Azaindole 2-one,3-thiothiosemicarbazone(IIIa) showed good antiepileptic activity and less neurotoxicity compared to phenytoin. The purpose of the present study is to investigate the effect of 5-[2-dimethyl amino ethoxy] Indole 2,3- di one and 5-[2-dimethyl amino ethoxy] Azaindole 2-one,3-thiosemicarbazone(IIIa) derivatives on biogenic amines concentrations in rat brain after induction of seizures by MES method. The aim of study was relationship between seizure activities and altered the monoamines such as Noradrenaline (NA), Dopamine (DA), Serotonin (5-HT) in forebrain of rats in MES seizure models. In MES model, study of 5-[2-dimethyl amino ethoxy] Azaindole 3-hydrazone,2-one(Va) and 5-[2-dimethyl amino ethoxy]Azaindole 2-one,3-thiosemicarbazone(IIIa) (100 mg/kg) showed significant restoration of the decreased levels of brain monoamines such as noradrenaline, dopamine, and 5-hydroxytryptamine. Thus, this study suggests that 5-[2-Dimethyl amino ethoxy] Azaindole 3-hydrazone,2-one (V) and 5-[2-dimethyl amino ethoxy] Azaindole 2-one,3-thiosemicarbazone (IIIa) increased the monoamines on rat brain, which may decrease the susceptibility to MES-induced seizure in rats.


Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/uso terapêutico , Indóis/síntese química , Indóis/uso terapêutico , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/uso terapêutico , Álcoois/síntese química , Álcoois/química , Álcoois/farmacologia , Álcoois/uso terapêutico , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Modelos Animais de Doenças , Hidrazonas/síntese química , Hidrazonas/química , Hidrazonas/farmacologia , Hidrazonas/uso terapêutico , Indóis/química , Indóis/farmacologia , Ratos , Ratos Wistar , Convulsões/tratamento farmacológico , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia
5.
J Med Chem ; 63(6): 3090-3103, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32142285

RESUMO

Targeting G-quadruplex structures is currently viewed as a promising anticancer strategy. Searching for potent and selective G-quadruplex binders, here we describe a small series of new monohydrazone derivatives designed as analogues of a lead which was proved to stabilize G-quadruplex structures and increase R loop levels in human cancer cells. To investigate the G-quadruplex binding properties of the new molecules, in vitro biophysical studies were performed employing both telomeric and oncogene promoter G-quadruplex-forming sequences. The obtained results allowed the identification of a highly selective G-quadruplex ligand that, when studied in human cancer cells, proved to be able to stabilize both G-quadruplexes and R loops and showed a potent cell killing activity associated with the formation of micronuclei, a clear sign of genome instability.


Assuntos
Antineoplásicos/farmacologia , Dano ao DNA/efeitos dos fármacos , DNA/efeitos dos fármacos , Quadruplex G/efeitos dos fármacos , Instabilidade Genômica/efeitos dos fármacos , Hidrazonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , DNA/genética , DNA/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Genoma/efeitos dos fármacos , Humanos , Hidrazonas/síntese química , Hidrazonas/metabolismo , Ligantes , Estruturas R-Loop/efeitos dos fármacos
6.
Parasit Vectors ; 13(1): 59, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32046788

RESUMO

BACKGROUND: Trichomonas vaginalis is the causative agent of trichomoniasis, which is one of the most common sexually transmitted diseases worldwide. Trichomoniasis has a high incidence and prevalence and is associated with serious complications such as HIV transmission and acquisition, pelvic inflammatory disease and preterm birth. Although trichomoniasis is treated with oral metronidazole (MTZ), the number of strains resistant to this drug is increasing (2.5-9.6%), leading to treatment failure. Therefore, there is an urgent need to find alternative drugs to combat this disease. METHODS: Herein, we report the in vitro and in silico analysis of 12 furanyl N-acylhydrazone derivatives (PFUR 4, a-k) against Trichomonas vaginalis. Trichomonas vaginalis ATCC 30236 isolate was treated with seven concentrations of these compounds to determine the minimum inhibitory concentration (MIC) and 50% inhibitory concentration (IC50). In addition, compounds that displayed anti-T. vaginalis activity were analyzed using thiobarbituric acid reactive substances (TBARS) assay and molecular docking. Cytotoxicity analysis was also performed in CHO-K1 cells. RESULTS: The compounds PFUR 4a and 4b, at 6.25 µM, induced complete parasite death after 24 h of exposure with IC50 of 1.69 µM and 1.98 µM, respectively. The results showed that lipid peroxidation is not involved in parasite death. Molecular docking studies predicted strong interactions of PFUR 4a and 4b with T. vaginalis enzymes, purine nucleoside phosphorylase, and lactate dehydrogenase, while only PFUR 4b interacted in silico with thioredoxin reductase and methionine gamma-lyase. PFUR 4a and 4b led to a growth inhibition (< 20%) in CHO-K1 cells that was comparable to the drug of choice, with a promising selectivity index (> 7.4). CONCLUSIONS: Our results showed that PFUR 4a and 4b are promising molecules that can be used for the development of new trichomonacidal agents for T. vaginalis.


Assuntos
Antiprotozoários , Hidrazonas , Trichomonas vaginalis/efeitos dos fármacos , Animais , Antiprotozoários/farmacologia , Antiprotozoários/toxicidade , Células CHO , Cricetulus , Humanos , Hidrazonas/farmacologia , Hidrazonas/toxicidade , Técnicas In Vitro , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular/métodos , Tricomoníase/tratamento farmacológico
7.
Eur J Med Chem ; 189: 112045, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31951961

RESUMO

The two series of thiazolidine-2,4-dione (TZD) based hybrids with halogenbenzohydrazones and pyridinecarbohydrazones substituents were designed and synthesized. Target hydrazones were evaluated for their antimycobacterial activity by broth microdilution method with resazurin as an indicator of the metabolic activity of mycobacteria. Conducted studies revealed antimycobacterial activity in the concentration range of 1-512 µg/ml for 23 synthesized TZD-based derivatives. The highest antimycobacterial activity (MIC = 1 µg/ml) was demonstrated for the new group of compounds: TZD-based derivatives with pyridine-4-carbohydrazone substituent. Furthermore, all the tested compounds within this group were characterized by low cytotoxicity. On the basis of the results obtained, three compounds with the highest SI were selected. High effectiveness and safety of these synthesized derivatives makes them promising candidates as antimycobacterial agents.


Assuntos
Antituberculosos/farmacologia , Hidrazonas/farmacologia , Tiazolidinedionas/farmacologia , Animais , Antituberculosos/síntese química , Chlorocebus aethiops , Desenho de Fármacos , Hidrazonas/síntese química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Tiazolidinedionas/síntese química , Células Vero
8.
Molecules ; 25(2)2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31963649

RESUMO

New thienyl- or chlorophenyl-substituted thiazolopyrimidine derivatives and their derived sugar hydrazones incorporating acyclic d-galactosyl or d-xylosyl sugar moieties in addition to their per-O-acetylated derivatives were synthesized. Heterocyclization of the formed sugar hydrazones afforded the derived acyclic nucleoside analogues possessing the 1,3,4-oxadiazoline as modified nucleobase via acetylation followed by the cyclization process. The cytotoxic activity of the synthesized compounds was studied against human breast cancer MCF7 and MDA-MB-231 cell lines as well as human colorectal cancer HCT 116 and Caco-2 cell lines. High activities were revealed by compounds 1, 8, 10, 11, and 13 against Caco-2 and MCF7 cells in addition to moderate activities exhibited by other compounds against HCT116 or MDA-MB-231 cells.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Hidrazonas/síntese química , Hidrazonas/farmacologia , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Humanos , Estrutura Molecular , Nucleosídeos/análogos & derivados
9.
Res Vet Sci ; 128: 86-89, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31760317

RESUMO

Chemotherapeutic drugs are given parenterally to treat various canine tumors. A limitation of parenteral administration is low drug penetration into the tumor, which reduces tumoricidal activity. Various drug carriers have been used to enhance tumor delivery, including albumin, liposomes and nanoparticles. A novel peptide-based nanofiber precursor (NFP) has been developed that is designed to take advantage of the leaky tumor neovasculature to promote drug delivery after parenteral administration. In this study, we loaded aldoxorubicin, an albumin-bound prodrug version of doxorubicin, onto NFP and tested the in vitro cytotoxicity in canine mammary carcinoma (CMT12, CMT25) and osteosarcoma (HMPOS, D-17, Abrams) cell lines. The half maximal inhibitory concentration (IC50) was determined with a luminescence-based cell viability assay. The IC50 for aldoxorubicin-loaded NFP was lower than free aldoxorubicin or doxorubicin in all cell lines, whereas non-drug loaded NFP had no cytotoxic effects. There were differences in IC50 between the osteosarcoma lines, with lower and higher IC50 for HMPOS and D-17 cells, respectively, with all drugs (aldoxorubicin-loaded NFP, free aldoxorubicin or free doxorubicin). Our results indicate that drug-loaded NFPs are cytotoxic for various canine mammary carcinoma and osteosarcoma cell lines in vitro and hold promise as a mechanism for enhancing delivery of chemotherapeutic agents to canine tumors.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doenças do Cão/tratamento farmacológico , Doxorrubicina/análogos & derivados , Hidrazonas/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Nanofibras , Osteossarcoma/veterinária , Animais , Linhagem Celular Tumoral , Cães , Doxorrubicina/farmacologia , Osteossarcoma/tratamento farmacológico
10.
Arch Biochem Biophys ; 680: 108239, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31881189

RESUMO

c-Met receptor is frequently overexpressed in hepatocellular carcinoma and thus considered as an attractive target for pharmacological intervention with small molecule tyrosine kinase inhibitors. Albeit with the development of multiple c-Met inhibitors, none reached clinical application in the treatment of hepatoma so far. To improve the efficacy of c-Met inhibitors towards hepatocellular carcinoma, we investigated the combined effects of the dynamin inhibitor dynasore with several c-Met inhibitors, including tivantinib, PHA-665752, and JNJ-38877605. We provide several lines of evidence that dynasore enhanced the inhibitory effects of these inhibitors on hepatoma cell proliferation and migration, accompanied with increased cell cycle arrest and apoptosis. Mechanically, the combinatorial treatments decreased c-Met levels and hence markedly disrupted downstream signaling, as revealed by the dramatically declined phosphorylation of AKT and MEK. Taken together, our findings demonstrate that the candidate agent dynasore potentiated the inhibitory effects of c-Met inhibitors against hepatoma cells and will shed light on the development of novel therapeutic strategies to target c-Met in the clinical management of hepatocellular carcinoma patients.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Hidrazonas/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Carcinoma Hepatocelular/metabolismo , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo
11.
Oxid Med Cell Longev ; 2019: 8169125, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827703

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and there is no cure for it at present. We have previously reported that the tetramethylpyrazine (TMP) derivative T-006 exhibited beneficial effects in Alzheimer's disease (AD) models. However, its effect on PD remains unclear. In the present study, we investigated the neuroprotective effects and underlying mechanisms of T-006 against 6-hydroxydopamine- (6-OHDA-) induced lesions in in vivo and in vitro PD models. Our results demonstrated that T-006 alleviated mitochondrial membrane potential loss and restored the energy metabolism and mitochondrial biogenesis that were induced by 6-OHDA in PC12 cells. In addition, animal experiments showed that administration of T-006 significantly attenuated the 6-OHDA-induced loss of tyrosine hydroxylase- (TH-) positive neurons in the SNpc, as well as dopaminergic nerve fibers in the striatum, and also increased the concentration of dopamine and its metabolites (DOPAC, HVA) in the striatum. Functional deficits were restored following T-006 treatment in 6-OHDA-lesioned mice, as demonstrated by improved motor coordination and rotational behavior. In addition, we found that the neuroprotective effects of T-006 were mediated, at least in part, by the activation of both the PKA/Akt/GSK-3ß and CREB/PGC-1α/NRF-1/TFAM pathways. In summary, our findings demonstrate that T-006 could be developed as a novel neuroprotective agent for PD, and the two pathways might be promising therapeutic targets for PD.


Assuntos
Adrenérgicos/toxicidade , Modelos Animais de Doenças , Hidrazonas/farmacologia , Fármacos Neuroprotetores/farmacologia , Oxidopamina/toxicidade , Doença de Parkinson/prevenção & controle , Pirazinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Sobrevivência Celular , Células Cultivadas , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Biogênese de Organelas , Consumo de Oxigênio/efeitos dos fármacos , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia
12.
Respir Res ; 20(1): 285, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852500

RESUMO

BACKGROUND: ß2 receptor agonists induce airway smooth muscle relaxation by increasing intracellular cAMP production. PKA is the traditional downstream signaling pathway of cAMP. Exchange protein directly activated by cAMP (Epac) was identified as another important signaling molecule of cAMP recently. The role of Epac in asthmatic airway inflammation and airway remodeling is unclear. METHODS: We established OVA-sensitized and -challenged acute and chronic asthma mice models to explore the expression of Epac at first. Then, airway inflammation and airway hyperresponsiveness in acute asthma mice model and airway remodeling in chronic asthma mice model were observed respectively after treatment with Epac-selective cAMP analogue 8-pCPT-2'-O-Me-cAMP (8pCPT) and Epac inhibitor ESI-09. Next, the effects of 8pCPT and ESI-09 on the proliferation and apoptosis of in vitro cultured mouse airway smooth muscle cells (ASMCs) were detected with CCK-8 assays and Annexin-V staining. Lastly, the effects of 8pCPT and ESI-09 on store-operated Ca2+ entry (SOCE) of ASMCs were examined by confocal Ca2+ fluorescence measurement. RESULTS: We found that in lung tissues of acute and chronic asthma mice models, both mRNA and protein expression of Epac1 and Epac2, two isoforms of Epac, were lower than that of control mice. In acute asthma mice model, the airway inflammatory cell infiltration, Th2 cytokines secretion and airway hyperresponsiveness were significantly attenuated by 8pCPT and aggravated by ESI-09. In chronic asthma mice model, 8pCPT decreased airway inflammatory cell infiltration and airway remodeling indexes such as collagen deposition and airway smooth muscle cell proliferation, while ESI-09 increased airway inflammation and airway remodeling. In vitro cultured mice ASMCs, 8pCPT dose-dependently inhibited, whereas ESI-09 promoted ASMCs proliferation. Interestingly, 8pCPT promoted the apoptosis of ASMCs, whereas ESI-09 had no effect on ASMCs apoptosis. Lastly, confocal Ca2+ fluorescence examination found that 8pCPT could inhibit SOCE in ASMCs at 100 µM, and ESI-09 promoted SOCE of ASMCs at 10 µM and 100 µM. In addition, the promoting effect of ESI-09 on ASMCs proliferation was inhibited by store-operated Ca2+ channel blocker, SKF-96365. CONCLUSIONS: Our results suggest that Epac has a protecting effect on asthmatic airway inflammation and airway remodeling, and Epac reduces ASMCs proliferation by inhibiting SOCE in part.


Assuntos
Remodelação das Vias Aéreas , Asma/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Pulmão/metabolismo , Pneumonia/metabolismo , Hipersensibilidade Respiratória/metabolismo , Remodelação das Vias Aéreas/efeitos dos fármacos , Animais , Apoptose , Asma/induzido quimicamente , Asma/tratamento farmacológico , Asma/fisiopatologia , Sinalização do Cálcio , Proliferação de Células , Células Cultivadas , AMP Cíclico/análogos & derivados , AMP Cíclico/farmacologia , Modelos Animais de Doenças , Feminino , Fatores de Troca do Nucleotídeo Guanina/antagonistas & inibidores , Fatores de Troca do Nucleotídeo Guanina/genética , Hidrazonas/farmacologia , Mediadores da Inflamação/metabolismo , Isoxazóis/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Camundongos Endogâmicos BALB C , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Ovalbumina , Pneumonia/induzido quimicamente , Pneumonia/fisiopatologia , Pneumonia/prevenção & controle , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/fisiopatologia
13.
J Agric Food Chem ; 67(48): 13344-13352, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31721573

RESUMO

A series of novel anthranilic diamide derivatives (5a-5ab) containing moieties of trifluoromethylpyridine and hydrazone was designed and synthesized. The synthesized compounds were evaluated in vivo for their activities against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV). Most of the synthesized compounds displayed good to excellent antiviral activities. The compounds 5i, 5k, 5s, 5w, 5x, and 5z had the curative activity over 65% against TMV at the concentration of 500 µg/mL, which were significantly higher than those of ningnanmycin (55.0%) and ribavirin (37.9%). Notably, the curative activity of compound 5i was up to 79.5%, with the EC50 value of 75.9 µg/mL, whereas the EC50 value of ningnanmycin was 362.4 µg/mL. The pot experiments also further demonstrated the significantly curative effect of 5i. Meanwhile, compounds 5h, 5p and 5x displayed more protective activities on TMV than that of ningnanmycin. Moreover, compounds 5a, 5e, 5f, and 5i showed inactivation activity similar to ningnanmycin at 500 µg/mL, and the EC50 value of 5e (41.5 µg/mL) was lower than ningnanmycin (50.0 µg/mL). The findings of transmission electron microscopic (TEM) indicated that the synthesized compounds exhibited strong and significant binding affinity to TMV coat protein (CP) and could obstruct the self-assembly and increment of TMV particles. Microscale thermophoresis (MST) studies on TMV-CP and CMV CP revealed that some of the active compounds, particularly 5i, exhibited a strong binding capability to TMV-CP or CMV-CP. This study revealed that anthranilic diamide derivatives containing moieties of trifluoromethylpyridine and hydrazone could be used as novel antiviral agents for controlling the plant viruses.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Diamida/química , Hidrazonas/química , Vírus de Plantas/efeitos dos fármacos , Piridinas/química , Antivirais/química , Cucumovirus/efeitos dos fármacos , Cucumovirus/crescimento & desenvolvimento , Diamida/farmacologia , Desenho de Fármacos , Hidrazonas/farmacologia , Testes de Sensibilidade Microbiana , Vírus de Plantas/crescimento & desenvolvimento , Piridinas/síntese química , Piridinas/farmacologia , Relação Estrutura-Atividade , Vírus do Mosaico do Tabaco/efeitos dos fármacos , Vírus do Mosaico do Tabaco/crescimento & desenvolvimento
14.
Molecules ; 24(21)2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31694218

RESUMO

Reaction of 1-adamantyl carbohydrazide (1) with various substituted benzaldehydes and acetophenones yielded the corresponding hydrazide-hydrazones with a 1-adamantane carbonyl moiety. The new synthesized compounds were tested for activities against some Gram-negative and Gram-positive bacteria, and the fungus Candida albicans. Compounds 4a, 4b, 5a, and 5c displayed potential antibacterial activity against tested Gram-positive bacteria and C. albicans, while compounds 4e and 5e possessed cytotoxicity against tested human cancer cell lines.


Assuntos
Adamantano/química , Adamantano/farmacologia , Hidrazinas/química , Hidrazonas/química , Hidrazonas/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Candida albicans/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana
15.
Molecules ; 24(20)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640238

RESUMO

The current study was chiefly designed to examine the antiproliferative and antioxidant activities of some novel quinazolinone(thione) derivatives 6-14. The present work focused on two main points; firstly, comparing between quinazolinone and quinazolinthione derivatives. Whereas, antiproliferative (against two cell lines namely, HepG2 and MCF-7) and antioxidant (by two methods; ABTS and DPPH) activities of the investigated compounds, the best quinazolinthione derivatives were 6 and 14, which exhibited excellent potencies comparable to quinazolinone derivatives 5 and 9, respectively. Secondly, we compared the activity of four series of Schiff bases which included the quinazolinone moiety (11a-d). In addition, the antiproliferative and antioxidant activities of the compounds with various aryl aldehyde hydrazone derivatives (11a-d) analogs were studied. The compounds exhibited potency that increased with increasing electron donating group in p-position (OH > OMe > Cl) due to extended conjugated systems. Noteworthy, most of antiproliferative and antioxidant activities results for the tested compounds are consistent with the DFT calculations.


Assuntos
Antineoplásicos/síntese química , Antioxidantes/síntese química , Quinazolinonas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Proliferação de Células/efeitos dos fármacos , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Hidrazonas/farmacologia , Células MCF-7 , Estrutura Molecular , Quinazolinonas/química , Quinazolinonas/farmacologia , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/farmacologia , Relação Estrutura-Atividade , Tionas/química
16.
Arch Pharm (Weinheim) ; 352(12): e1900209, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31621127

RESUMO

A green approach was developed for synthesizing a series of (isatin-3-ylidene)-hydrazonamides 3a-j from the reaction between isatin, (isatin-3-ylidene)malononitrile, or 2-cyano-2-(2-isatin-3-ylidene)acetate and benzohydrazonamide in ethyl acetate solutions at ambient temperature. The structures of the new compounds were confirmed on the basis of spectral data. In this eco-friendly medium, a variety of (isatin-3-ylidene)hydrazonamides were obtained free of catalyst in good to excellent yields. All the synthesized products were evaluated for their antimicrobial activity. Among the compounds tested, 3b and 3d exhibited good antibacterial activity against Staphylococcus aureus, whereas others responded moderately with reference to the standard drug ciprofloxacin.


Assuntos
Antibacterianos/síntese química , Desenho de Fármacos , Hidrazonas/síntese química , Isatina/análogos & derivados , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas , Hidrazonas/química , Hidrazonas/farmacologia , Estrutura Molecular
17.
Eur J Med Chem ; 184: 111742, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31605866

RESUMO

In this work, we report the antileishmanial activity of 15 compounds based on 2-pyrimidinyl hydrazone and N-acylhydrazone derivatives, being 13 new compounds. All compounds were tested against promastigotes and Leishmania amazonensis-GFP amastigotes, as well as murine macrophages. Besides, studies about the mechanism of action of the best antileishmanial compounds and in silico physicochemical and pharmacokinetic properties were performed. Studies about the mechanism of action of representative compounds of each class showed slight differences in mode of action and both are able to cause mitochondrial depolarization and increase of intracellular ROS levels. Through computational tool and further analysis of the physicochemical and pharmacokinetic parameters, the results indicating good oral bioavailability. These results confirm the potential of 2-pyrimidinyl derivatives as lead compounds in antileishmanial drug discovery.


Assuntos
Antiprotozoários/farmacologia , Hidrazonas/farmacologia , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Pirimidinas/farmacologia , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Hidrazonas/síntese química , Hidrazonas/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Pirimidinas/síntese química , Pirimidinas/química , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
18.
J Pharm Pharmacol ; 71(12): 1854-1863, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31595530

RESUMO

OBJECTIVES: The in vitro antileishmanial effect of analogues of resveratrol (AR) present in the N-aryl imines and N-aryl hydrazones series was investigated. In addition, possible parasite targets were evaluated. METHODS: Antipromastigote activity of Leishmania amazonensis, L. braziliensis and L. infantum, as well as the cytotoxicity on macrophages was determined by MTT assay and L. braziliensis-infected macrophages effect by Giemsa stain. After staining, effects on the parasite targets were analysed by flow cytometry or by fluorescence microscopy. KEY-FINDINGS: Among the tested compounds, the derivative AR26 showed the best effect against promastigotes of all Leishmania species (IC50  < 3.0 µg/ml), being more active than miltefosine, the control drug. AR26 was also effective against amastigotes of L. braziliensis (IC50  = 15.9 µg/ml), with low toxicity to mammalian cells. The evaluation of mechanism of action of AR26 on L. braziliensis promastigotes indicates mitochondrial potential depolarization, plasma membrane permeabilization, interference in the progression of the cell cycle and accumulation of autophagic vacuoles. In addition, any increase of the reactive oxygen species levels was detected in the treated L. braziliensis-macrophages. CONCLUSIONS: Data indicate that the antileishmanial activity of AR26 is related to multitarget action, and the resveratrol analogues could be used in future studies as antileishmanial agent.


Assuntos
Antiprotozoários/farmacologia , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Resveratrol/farmacologia , Animais , Antiprotozoários/administração & dosagem , Antiprotozoários/química , Modelos Animais de Doenças , Feminino , Hidrazonas/administração & dosagem , Hidrazonas/química , Hidrazonas/farmacologia , Iminas/administração & dosagem , Iminas/química , Iminas/farmacologia , Concentração Inibidora 50 , Leishmaniose/parasitologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Resveratrol/administração & dosagem , Resveratrol/análogos & derivados
19.
Arch Pharm (Weinheim) ; 352(12): e1900079, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31602690

RESUMO

Novel thiazolyl hydrazonothiazolamines and 1,3,4-thiadiazinyl hydrazonothiazolamines were synthesized by a facile one-pot multicomponent approach by the reaction of 2-amino-4-methyl-5-acetylthiazole, thiosemicarbazide or thiocarbohydrazide and phenacyl bromides or 3-(2-bromoacetyl)-2H-chromen-2-ones in acetic acid with good to excellent yields. These new compounds were screened in vitro for their antimalarial activity; among them, four compounds, 4h, 4i, 4k, 4l, showed moderate activity with half-maximal inhibitory concentration (IC50 ) values of 3.2, 2.7, 2.7, and 2.8 and 3.2, 3.2, 3.1, and 3.5 µM against chloroquine-sensitive and -resistant strains of Plasmodium falciparum, respectively. Compound 4l inhibited the ring stage growth of P. falciparum 3D7 at an IC90 concentration of 12.5 µM in a stage-specific assay method, where the culture is incubated with specific stages of P. falciparum for 12 hr, and no activity was found against the trophozoite and schizont stages, confirming that 4l may have potent action against the ring stage of P. falciparum.


Assuntos
Antimaláricos/síntese química , Hidrazonas/síntese química , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Triazóis/síntese química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Antimaláricos/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Hidrazonas/química , Hidrazonas/farmacologia , Hidrazonas/toxicidade , Concentração Inibidora 50 , Macrófagos/efeitos dos fármacos , Malária Falciparum/microbiologia , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia , Triazóis/toxicidade
20.
Chem Biodivers ; 16(11): e1900315, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31532059

RESUMO

Here, we report the synthesis and characterization of four new aroyl-hydrazone derivatives L1 -L4 , and their structural as well as biological activities have been explored. In addition to docking with bovine serum albumin (BSA) and duplex DNA, the experimental results demonstrate the effective binding of L1 -L4 with BSA protein and calf thymus DNA (ct-DNA) which is in agreement with the docking results. Further biological activities of L1 -L4 have been examined through molecular docking with different proteins which are involved in the propagation of viral or cancer diseases. L1 shows best binding affinity with influenza A virus polymerase PB2 subunit (2VY7) with binding energy -11.42 kcal/mol and inhibition constant 4.23 nm, whereas L2 strongly bind with the hepatitis C virus NS5B polymerase (2WCX) with binding energy -10.47 kcal/mol and inhibition constant 21.06 nm. Ligand L3 binds strongly with TGF-beta receptor 1 (3FAA) and L4 with cancer-related EphA2 protein kinases (1MQB) with binding energy -10.61 kcal/mol, -10.02 kcal/mol and inhibition constant 16.67 nm and 45.41 nm, respectively. The binding energies of L1 -L4 are comparable with binding energies of their proven inhibitors. L1 , L3 and L4 can be considered as both 3FAA and 1MQB dual targeting anticancer agents, while L1 and L3 are both 2VY7 and 2WCX dual targeting antiviral agents. On the other side, L2 and L4 target only one virus related target (2WCX). Furthermore, the geometry optimizations of L1 -L4 were performed via density functional theory (DFT). Moreover, all four ligands (L1 -L4 ) were characterized by NMR, FT-IR, ESI-MS, elemental analysis and their molecular structures were validated by single crystal X-ray diffraction studies.


Assuntos
Antineoplásicos/farmacologia , Antivirais/farmacologia , DNA/antagonistas & inibidores , Desenho de Fármacos , Hidrazonas/farmacologia , Simulação de Acoplamento Molecular , Soroalbumina Bovina/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antivirais/síntese química , Antivirais/química , Bovinos , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , DNA/química , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Hepacivirus/efeitos dos fármacos , Hidrazonas/síntese química , Hidrazonas/química , Vírus da Influenza A/efeitos dos fármacos , Ligantes , Testes de Sensibilidade Microbiana , Estrutura Molecular , Soroalbumina Bovina/química
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