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1.
Inorg Chem ; 58(21): 14294-14298, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31599154

RESUMO

Metal complexes to promote oxidative DNA cleavage by H2O2 are desirable as anticancer drugs. A dicopper(II) complex of known p-cresol-derived methylene-tether ligand Hbcc [Cu2(bcc)]3+ did not promote DNA cleavage by H2O2. Here, we synthesized a new p-cresol-derived amide-tether one, 2,6-bis(1,4,7,10-tetrazacyclododecyl-1-carboxyamide)-p-cresol (Hbcamide). A dicopper(II) complex of the new ligand [Cu2(µ-OH)(bcamide)]2+ was structurally characterized. This complex promoted the oxidative cleavage of supercoiled plasmid pUC19 DNA (Form I) with H2O2 at pH 6.0-8.2 to give Forms II and III. The reaction was largely accelerated in a high pH region. A µ-1,1-hydroperoxo species was formed as the active species and spectroscopically identified. The amide-tether complex is more effective in cytotoxicity against HeLa cells than the methylene-tether one.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Cobre/farmacologia , Cresóis/farmacologia , Peróxido de Hidrogênio/farmacologia , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cobre/química , Cresóis/química , Clivagem do DNA , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Peróxido de Hidrogênio/síntese química , Peróxido de Hidrogênio/química , Ligantes , Estrutura Molecular , Oxirredução
2.
J Agric Food Chem ; 67(44): 12182-12190, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31609606

RESUMO

In continuation of our program to develop natural-product-based pesticidal candidates, matrinic/oxymatrinic amides were obtained through structural optimization of matrine. N'-(4-Fluoro)phenyl-N-(4-bromo)phenylsulfonyloxymatrinic amide (IIm) showed potent insecticidal activity against Mythimna separata. N-(Un)substituted phenylsulfonylmatrinic acids (3a-c) exhibited promising acaricidal activity against Tetranychus cinnabarinus. By qRT-PCR analysis of nAChR subunits and AChE genes and determination of AChE activity of (un)treated T. cinnabarinus, it suggested that the open lactam ring of matrine and carboxyl group and (4-methyl)phenylsulfonyl of N-(4-methyl)phenylsulfonylmatrinic acid (3b) were necessary for action with α2, α4, α5, and ß3 nAChR subunits; compound 3b was an inhibitor of AChE in T. cinnabarinus, and AChE was one possible target of action in T. cinnabarinus against 3b; and compound 3b may be an antagonist of nAChR and AChE in T. cinnabarinus.


Assuntos
Acaricidas/química , Alcaloides/química , Amidas/química , Inseticidas/química , Quinolizinas/química , Acaricidas/síntese química , Acaricidas/farmacologia , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Alcaloides/farmacologia , Amidas/farmacologia , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Feminino , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Inseticidas/síntese química , Inseticidas/farmacologia , Estrutura Molecular , Mariposas/efeitos dos fármacos , Mariposas/genética , Mariposas/crescimento & desenvolvimento , Mariposas/metabolismo , Quinolizinas/farmacologia , Relação Estrutura-Atividade , Tetranychidae/efeitos dos fármacos , Tetranychidae/genética , Tetranychidae/crescimento & desenvolvimento , Tetranychidae/metabolismo
3.
Acta Virol ; 63(3): 309-315, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507197

RESUMO

Influenza virus is activated by proteolytic cleavage of hemagglutinin by trypsin. After determining the optimal trypsin concentration, intracellular and extracellular influenza A/PR/8/34 (H1N1) and A/Victoria/361/2011 (H3N2) virus productions were compared in cultures treated with T-705 (favipiravir) and GS 4071 (an active form of oseltamivir). Although both drugs efficiently inhibited extracellular viral RNA release in a dose-dependent manner, T-705 inhibited it to the level of the inoculum without trypsin treatment, while GS 4071 inhibited it to a final level 10 times higher than that without trypsin. T-705 inhibited intracellular viral RNA production to the level of input virus in both trypsin-treated and untreated cells. In contrast, GS 4071 dose-dependently inhibited intracellular viral RNA production in cells treated with trypsin but allowed viral RNA synthesis. The level of maximum inhibition by GS 4071was 10 times higher than that of cells without trypsin and 1,000 times greater than the inoculum titer in cells without trypsin. T-705 inhibited both intracellular and extracellular virus production 1,000 and 10 times more strongly, respectively, than GS 4071. T-705 has powerful anti-influenza activity in the absence of trypsin and even in the trypsin-optimized growth condition, suggesting the therapeutic advantage in treatment of influenza complicated with bacterial pneumonia. Keywords: influenza; T-705; Tamiflu; trypsin; bacterial trypsin-like protease.


Assuntos
Amidas , Antivirais , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N2 , Pirazinas , Tripsina , Amidas/farmacologia , Antivirais/farmacologia , Linhagem Celular , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Oseltamivir/farmacologia , Pirazinas/farmacologia , RNA Viral/biossíntese , Tripsina/farmacologia
4.
Eur J Med Chem ; 181: 111564, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31376563

RESUMO

The P2Y14 receptor (P2Y14R) plays a key role in the modulation of inflammatory process, but very few classes of antagonists have been reported. A series of 3-amide benzoic acid derivatives were identified as novel and potent P2Y14R antagonists. The most potent antagonist, 16c, showed comparable activity (IC50 = 1.77 nM) to PPTN, the most potent P2Y14R antagonist reported. Compound 16c demonstrated dramatically improved aqueous solubility and excellent metabolic stability in rat and human microsomes. Investigation of the anti-inflammatory effect of 16c was performed in MSU treated THP-1 cells by flow cytometry, Western Blot and immunofluorescence labeling technology, which exhibited that 16c might be a promising candidate for further research.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Ácido Benzoico/química , Ácido Benzoico/farmacologia , Antagonistas do Receptor Purinérgico P2/química , Antagonistas do Receptor Purinérgico P2/farmacologia , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Animais , Anti-Inflamatórios/síntese química , Ácido Benzoico/síntese química , Linhagem Celular , Desenho de Drogas , Humanos , Simulação de Acoplamento Molecular , Antagonistas do Receptor Purinérgico P2/síntese química , Ratos , Receptores Purinérgicos P2/metabolismo
5.
Eur J Med Chem ; 181: 111580, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400708

RESUMO

A series of peptidomimetic compounds incorporating an electrophilic moiety was synthesized using the Ugi reaction. These compounds (termed the Ugi Michael acceptors or UMAs) were designed to target the selenocysteine catalytic residue of thioredoxin reductase 1 (TrxR1), a promising cancer target. The compounds were assessed for their potential to inhibit TrxR1 using human neuroblastoma (SH-SY5Y) cell lysate. Based on this initial screening, six compounds were selected for testing against recombinant rat TrxR1 and in the insulin assay to reveal low-micromolar to submicromolar potency of these inhibitors. The same frontrunner compounds were evaluated for their ability to exert antiproliferative activity and induce cell death and this activity was compared to the UMA effects on the levels of reactive oxygen and nitrogen species (RONS). Collectively, the UMA compounds class presented itself as a rich source of leads for TrxR1 inhibitor discovery for anticancer application. Compound 7 (DVD-445) was nominated a lead for further optimization.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Tiorredoxina Redutase 1/antagonistas & inibidores , Tiorredoxinas/metabolismo , Amidas/química , Antineoplásicos/química , Domínio Catalítico/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/metabolismo , Tiorredoxina Redutase 1/química , Tiorredoxina Redutase 1/metabolismo
6.
Curr Top Med Chem ; 19(18): 1650-1675, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31424369

RESUMO

Human immunodeficiency virus type-1 (HIV-1) is the causative agent responsible for the acquired immunodeficiency syndrome (AIDS) pandemic. More than 60 million infections and 25 million deaths have occurred since AIDS was first identified in the early 1980s. Advances in available therapeutics, in particular combination antiretroviral therapy, have significantly improved the treatment of HIV infection and have facilitated the shift from high mortality and morbidity to that of a manageable chronic disease. Unfortunately, none of the currently available drugs are curative of HIV. To deal with the rapid emergence of drug resistance, off-target effects, and the overall difficulty of eradicating the virus, an urgent need exists to develop new drugs, especially against targets critically important for the HIV-1 life cycle. Viral entry, which involves the interaction of the surface envelope glycoprotein, gp120, with the cellular receptor, CD4, is the first step of HIV-1 infection. Gp120 has been validated as an attractive target for anti-HIV-1 drug design or novel HIV detection tools. Several small molecule gp120 antagonists are currently under investigation as potential entry inhibitors. Pyrrole, piperazine, triazole, pyrazolinone, oxalamide, and piperidine derivatives, among others, have been investigated as gp120 antagonist candidates. Herein, we discuss the current state of research with respect to the design, synthesis and biological evaluation of oxalamide derivatives and five-membered heterocycles, namely, the pyrrole-containing small molecule as inhibitors of gp120 and HIV entry.


Assuntos
Amidas/farmacologia , Fármacos Anti-HIV/farmacologia , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Inibidores da Fusão de HIV/farmacologia , Pirróis/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Amidas/química , Fármacos Anti-HIV/química , Descoberta de Drogas , Proteína gp120 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/química , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Pirróis/química , Bibliotecas de Moléculas Pequenas/química
7.
Eur J Med Chem ; 179: 404-422, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31265934

RESUMO

A comprehensive study was performed for the first time to compare two structurally related substance classes, namely indazole-5-carboxamides (11-16) and (indazole-5-yl)methanimines (17-22). Both chemical entities are potent, selective and reversible MAO-B inhibitors and, therefore, may serve as promising lead structures for the development of drug candidates against Parkinson's disease (PD) and other neurological disorders. Compounds 15 (Ki = 170 pM, SI = 25907) and 17 (Ki = 270 pM, SI = 16340) were the most potent and selective MAO-B inhibitors in both series. To investigate the multi-target inhibitory activity, all compounds were further screened for their potency against human AChE and BuChE enzymes. Compound 15 was found to be the most potent and selective AChE inhibitor in all series (hAChE IC50 = 78.3 ±â€¯1.7 µM). Moreover, compounds 11 and 17 showed no risk of drug-induced hepatotoxicity and a wider safety window, as determined in preliminary cytotoxicity screening. Molecular modeling studies into the human MAO-B enzyme-binding site supported by a HYDE analysis suggested that the imine linker similarly contributes to the total binding energy in methanimines 17-22 as the amide spacer in their carboxamide analogs 11-16. Amplified photophysical evaluation of compounds 17 and 20, including single X-ray analysis, photochemical experiments, and quantum-chemical calculations, provided insights into their more favourable isomeric forms and structural features, which contribute to their biologically active form and promising drug-like properties.


Assuntos
Acetilcolinesterase/metabolismo , Amidas/farmacologia , Inibidores da Colinesterase/farmacologia , Iminas/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Amidas/química , Proliferação de Células/efeitos dos fármacos , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Iminas/química , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
8.
Acta Pharm ; 69(2): 233-248, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31259728

RESUMO

The paper is focused on the synthesis and screening of the antiplasmodial activity of novel fumardiamides 5-10 with the mefloquine pharmacophore and a Michael acceptor motif. Multi-step reactions leading to the title compounds included two amide bond formations. The first amide bond was achieved by the reaction of (E)-ethyl 4-chloro-4-oxobut-2-enoate (1) and N1-(2,8-bis(trifluoromethyl)quinolin-4-yl) butane-1,4-diamine (2). The obtained ester 3 was hydrolyzed and gave acid 4, which then reacted with the selected halogenanilines in the presence of HATU/DIEA and formed products 5-10. Title compounds showed marked, dose dependent activity in vitro against hepatic stages of Plasmodium berghei. IC50 values of the most active compounds 5, 7 and 9 bearing 3-fluoro, 3-chloro and 3-trifluoromethyl substituents were 3.04-4.16 µmol L-1, respectively. On the other hand, the compounds exerted only weak activity against the erythrocytic stages of two P. falciparum strains (Pf3D7 and PfDd2) in vitro, with the exception of compound 5 (IC50 = 2.9 µmol L-1).


Assuntos
Amidas/farmacologia , Antimaláricos/farmacologia , Mefloquina/farmacologia , Amidas/síntese química , Amidas/química , Antimaláricos/síntese química , Antimaláricos/química , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Mefloquina/síntese química , Mefloquina/química , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-Atividade
9.
Eur J Med Chem ; 180: 41-50, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31299586

RESUMO

In this work, a series of novel indole-2-amide compounds were designed, synthesized, characterized and the anti-inflammatory activity in vivo were evaluated. Compounds 8a, 10b, 12h, and 12l exhibited marked anti-inflammatory activity in 2,4-Dinitrofluorobenzenethe (DNFB) - induced mice auricle edema model. Further, compounds 8a, 10b and 12h exhibited potential in vitro COX-2 inhibitory activity (IC50 = 21.86, 23.3 and 23.21 nM, respectively), while the reference drug celecoxib was 11.20 nM. The most promising compound 10b was exhibited the highest selectivity for COX-2 (selectivity index (COX-1/COX-2) = 17.45) and moderate 5-LOX inhibitory activity (IC50 = 66 nM), which comparable to positive controlled zileuton (IC50 = 38.91 nM). In addition, the test results showed compounds 10b and 12h no significant cytotoxic activity on normal cells (RAW264.7). Further, at the active sites of the COX-1, COX-2 co-crystals, 3b and 4l showed higher binding forces in the molecular docking study, which consistent with the results of in vitro experiments. These results demonstrated that these compounds had dual inhibitory activity of COX/5-LOX, providing clues for further searching for safer and more effective anti-inflammatory drugs.


Assuntos
Amidas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Desenho de Drogas , Indóis/farmacologia , Inibidores de Lipoxigenase/farmacologia , Amidas/síntese química , Amidas/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Araquidonato 5-Lipoxigenase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Relação Dose-Resposta a Droga , Indóis/síntese química , Indóis/química , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Células RAW 264.7 , Relação Estrutura-Atividade
10.
Anticancer Res ; 39(7): 3507-3518, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262875

RESUMO

BACKGROUND/AIM: Very few studies of anticancer activity of azulene amides led us to investigate the cytotoxicity of 21 N-alkylazulene-1-carboxamides introduced either with 3-methyl [1-7], 7-isopropyl-3-methyl [8-14] or 2-methoxy group [15-21] Materials and Methods: Tumor-specificity (TS) was calculated by the ratio of mean 50% cytotoxic concentration (CC50) against three normal human oral mesenchymal cells to that against four human oral squamous cell carcinoma (OSCC) cell lines. Potency-selectivity expression (PSE) was calculated by dividing TS value by CC50 value against OSCC cell lines. Apoptosis-inducing activity was evaluated by caspase-3 activation and appearance of subG1 cell population. RESULTS: [8-14] showed higher TS and PSE values, than [1-7] and [15-21] The most active compound [8-14] induced apoptosis in C9-22 OSCC cells at 4-times higher CC50 Quantitative structure-activity relationship analysis of [1-14] demonstrated that their tumor-specificity was correlated with chemical descriptors that explain the molecular shape and hydrophobicity. CONCLUSION: 7-Isopropyl-3-methyl-N-propylazulene-1-carboxamide [8] can be a potential candidate of lead compound for manufacturing new anticancer drug.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Azulenos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Bucais/tratamento farmacológico , Amidas/química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Azulenos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Relação Quantitativa Estrutura-Atividade
11.
Curr Top Med Chem ; 19(13): 1173-1187, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31244427

RESUMO

BACKGROUND: Alzheimers Disease (AD) is a neurodegenerative disease which is characterized by the deposition of amyloid plaques in the brain- a concept supported by most of the researchers worldwide. The main component of the plaques being amyloid-beta (Aß42) results from the sequential cleavage of Amyloid precursor protein (APP) by beta and gamma secretase. This present study intends to inhibit the formation of amyloid plaques by blocking the action of gamma secretase protein with Inhibitors (GSI). METHODS: A number of Gamma Secretase Inhibitors (GSI) were targeted to the protein by molecular docking. The inhibitor having the best affinity was used as a subject for further virtual screening methods to obtain similar compounds. The generated compounds were docked again at the same docking site on the protein to find a compound with higher affinity to inhibit the protein. The highlights of virtually screened compound consisted of Pharmacophore Mapping of the docking site. These steps were followed by comparative assessments for both the compounds, obtained from the two aforesaid docking studies, which included interaction energy descriptors, ADMET profiling and PreADMET evaluations. RESULTS: 111 GSI classified as azepines, sulfonamides and peptide isosteres were used in the study. By molecular docking an amorpholino-amide, compound (22), was identified to be the high affinity compound GSI along with its better interaction profiles.The virtually screened pubchem compound AKOS001083915 (CID:24462213) shows the best affinity with gamma secretase. Collective Pharmacophore mapping (H bonds, electrostatic profile, binding pattern and solvent accesibility) shows a stable interaction. The resulting ADMETand Descriptor values were nearly equivalent. CONCLUSION: These compounds identified herein hold a potential as Gamma Secretase inhibitors.According to PreADMET values the compound AKOS001083915 is effective and specific to the target protein. Its BOILED-egg plot analysis infers the compound permeable to blood brain barrier.Comparative study for both the compounds resulted in having nearly equivalent properties. These compounds have the capacity to inhibit the protein which is indirectly responsible for the formation of amyloid plaques and can be further put to in vitro pharmacokinetic and dynamic studies.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Amidas/farmacologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Morfolinas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Doença de Alzheimer/metabolismo , Amidas/síntese química , Amidas/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligações de Hidrogênio , Simulação de Acoplamento Molecular , Morfolinas/síntese química , Morfolinas/química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
12.
Fitoterapia ; 137: 104247, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31247217

RESUMO

A new sesquiterpene glycoside and a new amide have been isolated from the stems of Tinospora sinensis. Their structures were established by 2D NMR spectroscopic techniques (1H,1H-COSY, NOESY, HSQC and HMBC) and mass spectrometry. The isolated compounds were subjected to evaluate neuroprotective activities in vitro. The pre-treatment of two new compounds can significantly ameliorate damage of oxidative stress induced by Aß25-35 and improve PC12 cells survival.


Assuntos
Amidas/farmacologia , Glicosídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Sesquiterpenos/farmacologia , Tinospora/química , Amidas/isolamento & purificação , Animais , Glicosídeos/isolamento & purificação , Estrutura Molecular , Células PC12 , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Caules de Planta/química , Ratos , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos/isolamento & purificação , Tibet
13.
Eur J Med Chem ; 178: 30-38, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31173969

RESUMO

Several studies that have identified agents that potentiate the antimicrobial activity of antibiotics, but there are limited insights into their structure-activity relationships (SAR). The SAR associated with select N-alkylaryl amide derivatives of ornithine was performed to establish those structural features that were associated with potentiation of the antimicrobial activity of clarithromycin against E. coli ATCC 25922. The data indicate that the N-propyl derivative was slightly more active in reducing the effective MIC of clarithromycin against E. coli ATCC 25922. In addition, the S-enantiomer of compound 9 was somewhat more potent than the R-enantiomer in potentiating clarithromycin activity. No significant enhancement in potentiation activity was observed with the conversion of these secondary amides to their N-methyl tertiary amides. Formation of the N-methyl or N,N-dimethyl derivatives of the primary amine of 9 was associated with the loss of potentiation activity. Conversion of this primary amine to a guanidine was also not associated with an increase in potentiation activity. Among the isomeric diamino pentamides, 15 potentiated the antibacterial activity of clarithromycin to the greatest extent. In addition to these amide derivatives, the desoxy derivatives 16 and 18 were the more potent potentiators within this triamine series. The relative location of the primary amines, as indicated by the relative differences in the potentiation observed with 16 compared to 14, appears to be a critical factor in determining potentiation activity. Cell-based membrane permeabilization and efflux inhibition studies in E. coli ATCC 25922 suggest that the potentiation of clarithromycin activity by 16 reflects its ability to inhibit efflux pump activity and to a lesser extent its actions as a permeabilizer of the outer leaflet of the outer cell membrane.


Assuntos
Amidas/farmacologia , Antibacterianos/farmacologia , Claritromicina/farmacologia , Escherichia coli/efeitos dos fármacos , Ornitina/farmacologia , Amidas/síntese química , Amidas/química , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sinergismo Farmacológico , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ornitina/análogos & derivados , Ornitina/síntese química , Relação Estrutura-Atividade
14.
Dokl Biochem Biophys ; 485(1): 141-144, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31201636

RESUMO

It was established that in neurodegeneration models in the human neuron-like cell line SH-SY5Y, amide derivatives of arachidonic and docosahexaenoic acids were inactive in experiments with MPP+ and CoCl2 but protected from H2O2. The protective activity of neurolipins decreased in the series DHA-DA > AA-SER ≥ AA-GLY > AA-GABA ≥ AA-EA and was manifested starting from a concentration of 0.5 nM.


Assuntos
Amidas , Ácidos Graxos , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores , Transdução de Sinais/efeitos dos fármacos , Amidas/química , Amidas/farmacologia , Linhagem Celular , Ácidos Graxos/química , Ácidos Graxos/farmacologia , Humanos , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/prevenção & controle , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia
15.
Invest Ophthalmol Vis Sci ; 60(6): 2274-2285, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31112612

RESUMO

Purpose: Retraction of the axon terminals of rod photoreceptors after retinal detachment breaks the first synapse in the visual pathway, resulting in visual impairment. Previous work showed that the mechanism of axonal retraction involves RhoA signaling and its downstream effector LIM Kinase (LIMK) activation. We examined the response of the downstream component cofilin, a direct binding protein of actin filaments, as well as the regulation by RhoA-LIMK-Cofilin signaling of actin assembly/disassembly, in the presynaptic ribbon terminal of injured rod cells. Methods: Injury was produced by retinal detachment or rod cell isolation. Detached porcine retina was probed for levels and localization of phosphorylated cofilin with Western blots and confocal microscopy, whereas rod cell cultures of dissociated salamander retina were examined for filamentous actin assembly/disassembly with a barbed end assay and phalloidin staining. Results: A detachment increased phosphorylation of cofilin in retinal explants; phosphorylation occurred in rod terminals in sections of detached retina. Isolation of rod cells resulted in axon retraction accompanied by an increase in actin barbed ends and a decrease in net filament labeling. All changes were significantly reduced by either Rho kinase (ROCK) or LIMK inhibition, using Y27632 or BMS-5, respectively. Cytochalasin D also reduced retraction and stabilized filaments in isolated rod cells. Conclusions: These results indicate that actin depolymerization via activation of RhoA downstream kinases and cofilin contributes to axon retraction. Preventing depolymerization, in addition to actomyosin contraction, may stabilize ribbon synapses after trauma.


Assuntos
Actinas/metabolismo , Cofilina 1/metabolismo , Retina/lesões , Descolamento Retiniano/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/fisiologia , Transdução de Sinais/fisiologia , Proteína rhoA de Ligação ao GTP/metabolismo , Amidas/farmacologia , Animais , Axônios/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Quinases Lim/antagonistas & inibidores , Plasticidade Neuronal/fisiologia , Piridinas/farmacologia , Suínos , Quinases Associadas a rho/farmacologia , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores
16.
Biomed Res Int ; 2019: 9209676, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31139660

RESUMO

A series of amides derived from vanillic acid were obtained by coupling reactions using PyBOP ((Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate) and DCC (Dicyclohexylcarbodiimide) coupling reagents. These were submitted to biological evaluation for species of Candida, Staphylococcus, and Pseudomonas. The microdilution method in broth was used for the antimicrobial testing to determine the Minimum Inhibitory Concentration (MIC) and to verify the likely mechanism of action for antifungal activity. The ten amides were obtained with yields ranging from 28.81 to 86.44%, and three compounds were novel. In the antibacterial evaluation, the amides (in their greatest concentrations) were bioactive against Staphylococcus aureus strain ATCC 25925. Meanwhile, all of the tested amides presented antifungal activity against at least one strain. The amide with best antifungal profile was compound 7, which featured an MIC of 0.46 µmol/mL, and a mechanism of action involving the plasma membrane and fungal cell wall. The presence of a methyl group in the para position of the aromatic ring is suggested which enhances the activity of the compound against fungi. Docking studies of the ten compounds using the protein 14α-demethylase as a biological target were also performed. The biological results presented good correlation with molecular docking studies demonstrating that a possible site of antifungal action for bioactive amides is the enzyme 14α-demethylase.


Assuntos
Amidas/farmacologia , Antibacterianos/farmacologia , Simulação de Acoplamento Molecular , Ácido Vanílico/química , Amidas/química , Bactérias/efeitos dos fármacos , Candida/efeitos dos fármacos , Testes de Sensibilidade Microbiana
17.
Eur J Med Chem ; 171: 383-400, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30928710

RESUMO

The use of nitroreductases (NTR) that catalyze the reduction of nitro compounds by using NAD(P)H in GDEPT (Gene-directed enzyme prodrug therapy) studies which minimize toxicity at healthy cells and increases concentration of drugs at cancer cells is remarkable. Discovery of new prodrug/NTR combinations is necessary to be an alternative to known prodrug candidates such as CB1954, SN23862, PR-104A. For this aim, nitro containing aromatic amides (A1-A23)2 were designed, synthesized, performed in silico ADMET and molecular docking techniques in this study. Prodrug candidates were studied on reduction potentials with Ssap-NtrB by HPLC system. Also, cyototoxic properties and prodrug ability of these amides were investigated using different cancer cell lines such as Hep3B and PC3. As a result of theoretical and biological studies, combinations of A5, A6 and A20 with Ssap-NtrB can be suggested as potential prodrugs/enzyme combinations at NTR based cancer therapy compared with CB1954/NfsB.


Assuntos
Amidas/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Nitrorredutases/metabolismo , Pró-Fármacos/farmacologia , Amidas/síntese química , Amidas/química , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular , Nitrorredutases/química , Células PC-3 , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade
18.
Eur J Med Chem ; 173: 32-43, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30981691

RESUMO

The CXCR4/CXCL12 axis plays prominent roles in tumor metastasis and inflammation. CXCR4 has been shown to be involved in a variety of inflammation-related diseases. Therefore, CXCR4 is a promising potential target to develop novel anti-inflammatory agents. Taking our previously discovered CXCR4 modulator RB-108 as the lead compound, a series of derivatives were synthesized structurally modifying and optimizing the amide and sulfamide side chains. The derivatives successfully maintained potent CXCR4 binding affinity. Furthermore, compounds IIb, IIc, IIIg, IIIj, and IIIm were all efficacious in inhibiting the invasion of CXCR4-positive cells, displaying a much more potent effect than the lead compound RB-108. Notably, compound IIIm significantly decreased carrageenan-induced swollen volume and paw thickness in a mouse paw edema model. More importantly, IIIm exhibited satisfying PK profiles with a half-life of 4.77 h in an SD rat model. In summary, we have developed compound IIIm as a new candidate for further investigation based on the lead compound RB-108.


Assuntos
Amidas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Inflamação/tratamento farmacológico , Receptores CXCR4/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Carragenina , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Inflamação/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
19.
Int J Mol Sci ; 20(6)2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30875877

RESUMO

Inflammation is a central aspect of tumour biology and can contribute significantly to both the origination and progression of tumours. The NFκB pathway is one of the most important signal transduction pathways in inflammation and is, therefore, an excellent target for cancer therapy. In this work, we examined the influence of four NFκB inhibitors-Cortisol, MLN4924, QNZ and TPCA1-on proliferation, inflammation and sensitisation to apoptosis mediated by the death ligand FasL in the HNSCC cell lines PCI1, PCI9, PCI13, PCI52 and SCC25 and in the human dermal keratinocyte cell line HaCaT. We found that the selection of the inhibitor is critical to ensure that cells do not respond by inducing counteracting activities in the context of cancer therapy, e.g., the extreme IL-8 induction mediated by MLN4924 or FasL resistance mediated by Cortisol. However, TPCA1 was qualified by this in vitro study as an excellent therapeutic mediator in HNSCC by four positive qualities: (1) proliferation was inhibited at low µM-range concentrations; (2) TNFα-induced IL-8 secretion was blocked; (3) HNSCC cells were sensitized to TNFα-induced cell death; and (4) FasL-mediated apoptosis was not disrupted.


Assuntos
Anti-Inflamatórios/farmacologia , Proteína Ligante Fas/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , NF-kappa B/antagonistas & inibidores , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Amidas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclopentanos/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Hidrocortisona/farmacologia , Interleucina-8/metabolismo , Éteres Fenílicos/farmacologia , Pirimidinas/farmacologia , Quinazolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Tiofenos/farmacologia
20.
Int J Mol Med ; 43(4): 1911-1919, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816436

RESUMO

The present study aimed to evaluate the cardioprotective effects of a Rho­kinase inhibitor, Y­27632, and the underlying mechanisms. A rat model of myocardial ischemia­reperfusion (I/R) injury was generated by ligation of the coronary artery, and global ischemia of isolated rat hearts was conducted using the Langendorff system. Staining with triphenyltetrazolium chloride (TTC) and hematoxylin and eosin was performed to analyze the myocardial infarct size and histopathological alterations of the I/R­induced rat heart. In addition, coronary flow, myocardial contractility and an electrocardiogram were analyzed. The effects of Y­27632 on inflammatory cytokines and cardiac enzymes in the serum were assessed by ELISA. The expression of apoptosis­ and inflammation­associated proteins was also analyzed via western blotting. Rats in the Y­27632 group exhibited alleviated myocardial I/R injury according to TTC staining and histopathological diagnosis. Additionally, Y­27632 restored the ST segment. The data of coronary flow and myocardial contractility in isolated rat hearts indicated that Y­27632 improved heart function following I/R. The levels of inflammatory cytokines and cardiac enzymes in the serum were downregulated by Y­27632. The mitogen­activated protein kinase (MAPK) and nuclear factor (NF)­κB signaling pathways were inhibited by Y­27632. Furthermore, apoptosis­associated protein expression in rats and the isolated hearts was effectively inhibited by Y­27632. In conclusion, the findings of the present study indicated that Y­27632 attenuated myocardial injury via inhibiting the activation of the MAPK and NF­κB signaling pathways; thus, apoptosis and the inflammatory response were suppressed.


Assuntos
Amidas/farmacologia , Amidas/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Piridinas/uso terapêutico , Quinases Associadas a rho/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Citocinas/sangue , Mediadores da Inflamação/metabolismo , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/enzimologia , Miocárdio/metabolismo , Miocárdio/patologia , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteínas rho de Ligação ao GTP/metabolismo , Quinases Associadas a rho/metabolismo
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