RESUMO
Disruption of copper homeostasis is closely involved in neurodegenerative disorders. This study examined whether a hybrid copper-binding compound, (E)-2-(4-(dimethylamino)phenylimino)methyl)quinolin-8-ol (DPMQ), is able to protect NG108-15 cells against oxidative stress. We found that treatment of cells with rotenone or hydrogen peroxide increased cellular oxidative stress and resulted in mitochondrial dysfunction and apoptosis. The cellular levels of Nrf2 and the Cu2+ chaperone DJ-1 were also decreased. These oxidative detrimental effects were all inhibited when cells were cotreated with DPMQ. DPMQ increased cellular Cu2+ content, DJ-1 protein level, superoxide dismutase (SOD) activity, and Nrf2 nuclear translocation under basal state. The activity of SOD decreased under redox imbalance and this decrease was blocked by DPMQ treatment, while the protein level of SOD1 remained unaltered regardless of the oxidative stress and DPMQ treatment. Using endogenous proteins, coimmunoprecipitation showed that DJ-1 bound with SOD1 and Nrf2 individually. The amount of Nrf2, bound to DJ-1, consistently reflected its cellular level, while the amount of SOD1, bound to DJ-1, was potentiated by DPMQ, being greater in the basal state than under redox imbalance. Simultaneous inclusion of nonpermeable Cu2+ chelator tetrathiomolybdate or triethylenetetramine during DPMQ treatment blocked all aforementioned effects of DPMQ, showing that the dependency of the effect of DPMQ on extracellular Cu2+. In addition, silencing of DJ-1 blocked the protection of DPMQ against oxidative stress. Taken all together, our results suggest that DPMQ stabilizes DJ-1 in a Cu2+-dependent manner, which then brings about SOD1 activation and Nrf2 nuclear translocation; these together alleviate cellular oxidative stress.
Assuntos
Antioxidantes/farmacologia , Quelantes/farmacologia , Cobre/metabolismo , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Proteína Desglicase DJ-1/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Glioma/enzimologia , Glioma/patologia , Humanos , Hibridomas , Peróxido de Hidrogênio/toxicidade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Mitocôndrias/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Neuroblastoma/enzimologia , Neuroblastoma/patologia , Neurônios/enzimologia , Neurônios/patologia , Proteína Desglicase DJ-1/genética , Ratos , Rotenona/toxicidade , Superóxido Dismutase-1/metabolismoRESUMO
Proteolytic processing of amyloid precursor protein (APP) C-terminal fragments (CTFs) by γ-secretase underlies the pathogenesis of Alzheimer's disease (AD). An RNA interference screen using APP-CTF [99-residue CTF (C99)]- and Notch-specific γ-secretase interaction assays identified a unique ErbB2-centered signaling network that was predicted to preferentially govern the proteostasis of APP-C99. Consistently, significantly elevated levels of ErbB2 were confirmed in the hippocampus of human AD brains. We then found that ErbB2 effectively suppressed autophagic flux by physically dissociating Beclin-1 from the Vps34-Vps15 complex independent of its kinase activity. Down-regulation of ErbB2 by CL-387,785 decreased the levels of C99 and secreted amyloid-ß in cellular, zebrafish, and mouse models of AD, through the activation of autophagy. Oral administration of an ErbB2-targeted CL-387,785 for 3 wk significantly improves the cognitive functions of APP/presenilin-1 (PS1) transgenic mice. This work unveils a noncanonical function of ErbB2 in modulating autophagy and establishes ErbB2 as a therapeutic target for AD.
Assuntos
Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Autofagia , Encéfalo/patologia , Presenilina-1/metabolismo , Receptor ErbB-2/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Encéfalo/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Presenilina-1/genética , Proteostase , Receptor ErbB-2/genética , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismoRESUMO
Dengue virus (DENV) and Zika virus (ZIKV) are mosquito-borne flaviviruses that cause severe illness after infection. Currently, there are no specific or effective treatments against DENV and ZIKV. Previous studies have shown that tyrosine kinase activities and signal transduction are involved in flavivirus replication, suggesting a potential therapeutic strategy for DENV and ZIKV. In this study, we found that compound L3 can significantly reduce viral protein expression and viral titers in HEK-293, MCF-7, HepG2, and Huh-7 cells and exhibits superior therapeutic efficacy against flaviviral infection compared to other tyrosine kinase inhibitors. In addition, compound L3 can decrease endogenous HER2 activation and inhibit the phosphorylation of the HER2 downstream signaling molecules Src and ERK1/2, the levels of which have been associated with viral protein expression in MCF-7 cells. Moreover, silencing HER2 diminished DENV-2 and ZIKV expression in MCF-7 cells, which suggests that HER2 activity is involved in flavivirus replication. Furthermore, in DENV-2-infected AG129 mice, treatment with compound L3 increased the survival rates and reduced the viremia levels. Overall, compound L3 demonstrates therapeutic efficacy both in vitro and in vivo and could be developed as a promising antiviral drug against emerging flaviviruses or for concurrent DENV and ZIKV outbreaks.
Assuntos
Antivirais/farmacologia , Vírus da Dengue/efeitos dos fármacos , Zika virus/efeitos dos fármacos , Afatinib/química , Afatinib/farmacologia , Animais , Antivirais/química , Células Cultivadas , Dengue/virologia , Relação Dose-Resposta a Droga , Receptores ErbB/metabolismo , Células HEK293 , Humanos , Concentração Inibidora 50 , Camundongos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Replicação Viral/efeitos dos fármacos , Infecção por Zika virus/virologiaRESUMO
Copper is more likely than iron to generate reactive oxygen species (ROS) in a redox reaction due to its higher electrochemical reactivity. This study examined the effect of a newly synthesized Cu2+ binding compound, (E)-2-(4-(dimethylamino)phenylimino)methyl)quinolin-8-ol (DPMQ), on ultraviolet B (UVB) irradiation-induced cytotoxicity in human dermal fibroblasts. DPMQ induced Cu2+ influx as effectively as disulfiram, a Cu2+ ionophore anticancer drug. However, disulfiram induced ROS generation, mitochondrial dysfunction, and apoptosis in fibroblasts in a Cu2+ -dependent manner, whereas DPMQ was not only nontoxic, but protected cells against UVB irradiation-induced apoptosis in a Cu2+ -independent manner. UVB irradiation induced a Ca2+ -dependent increase in ROS generation, a decrease in Nrf2 levels, and activation of the mitochondrial apoptotic pathway, and these effects were prevented by DPMQ, which also increased Nrf2 nuclear translocation in a Cu2+ -independent manner. UVB irradiation activated 12-lipoxygenase and 12-hydroxyeicosatetraenoic acid (12-HETE), a product of 12-lipoxygenase, activated the TRPV1 channel. DMPQ did not act as a Ca2+ chelator, but inhibited the cytosolic Ca2+ increase induced by 12-HETE or capsaicin, but not that induced by bradykinin or ATP. Blockade of Ca2+ influx by pharmacological inhibition or silencing of the TRPV1 channel or chelation of cytosolic Ca2+ inhibited the UVB irradiation-induced Nrf2 reduction, ROS generation, mitochondrial dysfunction, and apoptosis. Taken together, our results suggest that Ca2+ influx via the TRPV1 channel is responsible for UVB irradiation-induced cytotoxicity and that DPMQ protects cells against UVB irradiation by inhibiting the TRPV1 channel and stabilizing Nrf2, and could thus be a potentially useful compound for the treatment of free radical-induced diseases.
Assuntos
Cobre/farmacologia , Citoproteção , Ionóforos/farmacologia , Quinolinas/farmacologia , Canais de Cátion TRPV/metabolismo , Raios Ultravioleta , Acetilcisteína/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Araquidonato 12-Lipoxigenase/metabolismo , Caspase 3/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Citoproteção/efeitos dos fármacos , Citoproteção/efeitos da radiação , Derme/citologia , Dissulfiram/farmacologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/efeitos da radiação , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Inativação Gênica/efeitos dos fármacos , Inativação Gênica/efeitos da radiação , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Ativação do Canal Iônico/efeitos da radiação , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiação , Fator 2 Relacionado a NF-E2/metabolismo , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Chikungunya is a severe disease that results from infection with the chikungunya virus (CHIKV), an arbovirus. Thus, we (1) explored a new approach to combining previously researched drugs that have shown the potential to inhibit CHIKV infection; and (2) demonstrated the antiviral effects of (-)-Epigallocatechin-3-gallate (EGCG) and the underlying mechanisms. Specifically, we used U2OS cells infected with CHIVK to assess the synergistic antiviral activities of EGCG and suramin. EGCG presented the ability to inhibit the viral RNA, progeny yield, and cytopathic effect (CPE) of CHIKV and also demonstrated the ability to protect against virus entry, replication, and release. Moreover, the results confirmed that EGCG and suramin can have synergistic effects against CHIKV strain S27 infection and two other clinical isolates of CHIKV. Our findings suggest that treatment with a combination of EGCG and suramin could provide a basis for the development of novel stretages against CHIKV infection.
Assuntos
Catequina/análogos & derivados , Febre de Chikungunya/tratamento farmacológico , Febre de Chikungunya/virologia , Vírus Chikungunya/efeitos dos fármacos , Vírus Chikungunya/fisiologia , Suramina/administração & dosagem , Antivirais/administração & dosagem , Catequina/administração & dosagem , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Sinergismo Farmacológico , Humanos , Resultado do TratamentoRESUMO
PURPOSE: To analyze and characterize data regarding the prevalence and types of outpatient drug-related problems (DRPs) found by clinical pharmacists after implementation of the Virtual Medicine Record in Cloud System (VMRCS). METHODS: A cross-sectional study regarding outpatient pharmaceutical care was conducted at a medical center in Taiwan. Patients aged >20 years old with multiple chronic diseases and polypharmacy were enrolled. In Stage I (1 October-31 December 2014), patients received pharmaceutical care according to prescription data accessed online in the VMRCS. In Stage II (1 June-31 August 2015), the VMRCS were pre-download and arranged to the institute's required format, facilitated DRP detection. Clinical pharmacists then reviewed and evaluated the prescription data through pre-downloaded VMRCS. Overall, 1539 and 1600 prescriptions were evaluated in these two stages, respectively. DRPs were recorded using the Pharmaceutical Care Network Europe (PCNE)-DRP. RESULTS: DRPs were found for 50.2% of patients in Stage I and 55.2% in Stage II (p < 0.05) and were most frequently encountered for "Drugs for the cardiovascular system" and caused by "Inappropriate duplication of therapeutic group or active ingredient." In terms of problems, incidence of "Unnecessary drug treatment" was highest. Duplicate medications were most frequently seen for "Drugs for acid-related disorders." The efficiency to identify DRPs was at least 2.4 times higher with pre-downloaded prescription data than with real-time online queries. CONCLUSIONS: With VMRCS, DRPs were more easily identified whether patients received medical care in the same hospital or not. DRPs could be efficiently prevented through the use of pre-downloaded patient prescription data. Copyright © 2016 John Wiley & Sons, Ltd.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Assistência Farmacêutica/organização & administração , Farmacêuticos/organização & administração , Polimedicação , Adulto , Idoso , Idoso de 80 Anos ou mais , Assistência Ambulatorial/organização & administração , Computação em Nuvem , Estudos Transversais , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Humanos , Prescrição Inadequada/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Padrões de Prática Médica/estatística & dados numéricos , Prevalência , TaiwanRESUMO
Copper and zinc have been found to contribute to the burden of amyloid-ß (Aß) aggregations in neurodegenerative Alzheimer's disease (AD). Dysregulation of these metals leads to the generation of reactive oxygen species (ROS) and eventually results in oxidative damage and accumulation of the Aß peptide, which are the key elements of the disease. Aiming to pursue the discovery of new modulators for the disease, we here rationally focused on conjugating the core hydroxyquinoline of the metal-protein attenuating compound PBT2 and the N-methylanilide analogous moiety of the Aß imaging agent to build a new type of multi-target modulators of Aß aggregations. We found that the N,N-dimethylanilinyl imines 7a, 8a, and the corresponding amines 7b, 8b exerted efficient inhibition of Cu(2+) - or Zn(2+) -induced Aß aggregations and significant disassembly of metal-mediated Aß aggregated fibrils. Further, 7a and 7b also exhibited significant ROC scavenging effects compared to PBT2. The results suggested that 7a and 7b are promising lead compounds for the development of a new therapy for AD.
Assuntos
Peptídeos beta-Amiloides/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Hidroxiquinolinas/química , Hidroxiquinolinas/uso terapêutico , Agregação Patológica de Proteínas/tratamento farmacológico , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/ultraestrutura , Quelantes/síntese química , Quelantes/farmacologia , Quelantes/uso terapêutico , Clioquinol/análogos & derivados , Clioquinol/química , Clioquinol/farmacologia , Clioquinol/uso terapêutico , Cobre/efeitos adversos , Hidroxiquinolinas/síntese química , Hidroxiquinolinas/farmacologia , Relação Estrutura-Atividade , Zinco/efeitos adversosRESUMO
BACKGROUND: Simethicone and N-acetylcysteine have been widely used in improving endoscopic visibility. However, the optimal dose, volume, and dosing time for the premedication regimen are still unclear. AIM: Our aim was to assess the efficacy of premedication in improving endoscopic visibility and determine the contributions of dose, volume, and premedication time. METHODS: A total of 1849 patients were prospectively treated in three groups: group A: 100-mg simethicone suspension in 5 mL water; group B: 100-mg simethicone suspension in 100 mL water; and group C: 100-mg simethicone suspension in 100 mL water containing 200 mg N-acetylcysteine. Mucosa visibility was assessed at seven sites of upper gastrointestinal tract. The sum of scores was considered as total mucosal visibility score (TMVS). RESULTS: The upper body of stomach had the worst visibility score for all groups. TMVS of groups B and C were significantly lower than those of group A. Group C had a significantly fewer patients requiring endoscopic flushing than groups A and B. The TMVS for groups B and C were significantly lower than for group A within 30 min of beginning premedication. Beyond 30 min of premedication, there was no significant difference in the TMVS among groups. CONCLUSIONS: Premedication using 100 mg simethicone in 100 mL of water improves endoscopic visibility. Addition of N-acetylcysteine to simethicone in 100 mL of water reduces the need for endoscopic flushing. For patients unable to tolerate a large fluid volume, a 5-mL simethicone suspension administered more than 30 min prior to upper endoscopy is suggested.
Assuntos
Acetilcisteína/administração & dosagem , Endoscopia do Sistema Digestório/métodos , Aumento da Imagem/métodos , Pré-Medicação/métodos , Simeticone/administração & dosagem , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Método Simples-Cego , Suspensões , Fatores de Tempo , ÁguaRESUMO
Synthesis and evaluation of difluorophenylglycinols as new modulators of proteolytic processing of the amyloid-ß precursor proteins for Alzheimer's therapies were described. A range of N-substituted (R)- and (S)-difluorophenylglycinols, structured on the amino alcohol framework, were explored by incorporating the arylsulfonyl moieties and various N-substituents. Evans' chiral auxiliary strategy was employed for the asymmetric synthesis of these enantiomeric difluorophenylglycinols. Compounds with effects on the γ-secretase inhibition and ERK-mediated signaling pathways were evaluated on cell-based assays. Among them, N-cyclopropylmethyl derivatives R-12c and R-13c showed modest γ-secretase inhibition as well as ERK-dependent activation.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/metabolismo , Etanolaminas/farmacologia , Inibidores de Proteases/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Ativação Enzimática , Etanolaminas/síntese química , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células HEK293 , Humanos , Estrutura Molecular , Inibidores de Proteases/síntese química , Proteólise , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , TransfecçãoRESUMO
Fluoroquinolones have been a class of important synthetic antimicrobial agents broadly and effectively used in clinic for infectious diseases. In this study, the synthesis of a range of fluoroquinolone derivatives with 4-(carbopiperazin-1-yl)piperazinyl moieties at the C7 position and their inhibition of bacterial pathogens commonly disseminated in hospital environment were described. The results indicated that a 7-[4-(4-(benzoyl)carbopiperazin-1-yl)]piperazinyl derivative 5h and two 7-[4-(4- (benzenesulfonyl)carbopiperazin-1-yl)]piperazinyl derivatives 5k and 5l showed more promising growth inhibition of ciprofloxacin-resistant P. aeruginosa (CRPA) with MIC values as low as 16 µg/mL which is 16-fold more potent than ciprofloxacin, while most of other derivatives maintained potency against methicillin-resistant Staphylococcus aureus (MRSA).
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Fluoroquinolonas/química , Fluoroquinolonas/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Ciprofloxacina/farmacologia , Farmacorresistência Bacteriana , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
Nanocomposites based on Keggin-type polyoxometalate H5PV2Mo10O40 (POM) and porous bamboo charcoal (BC) were prepared by activation and immobilization processes. The physical properties of the BC/POM composites were examined using FTIR, UV-Vis spectroscope, 31P MAS-NMR, SEM and TEM. These techniques indicated that the POM was intact on the surface of the BC matrix after impregnation. The POM particle size was found to be less than 150 nm based on TEM. The antibacterial effects of the BC/POM composites were assessed from the zone of inhibition, minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and plate-counting method, and an excellent antibacterial performance was discovered.
RESUMO
Previous studies have demonstrated that the ERK MAPK acts as a negative regulator of gamma-secretase. Here, we demonstrate that the activation of ERK MAPK pathway by sodium selenite can inhibit endogenous gamma-secretase activity. Consistently, the gamma-secretase-mediated production of amyloid-beta (Abeta) was dramatically attenuated by sodium selenite in a temporal manner. To substantiate the functional role of ERK MAPK in the regulation of gamma-secretase, we demonstrate that cells transfected with the wild-type MEK1 and a constitutively active mutant of MEK1 also displayed a significant attenuation of gamma-secretase activity. The active purified ERK1/2 can significantly reduce the gamma-secretase-mediated processing of C99, possibly through inducing alterations in the phosphorylation of both nicastrin and presenilin-1. Together, our data suggest that the selenite-elicited ERK activation could effectively reduce Abeta production, supporting that selenium compounds could represent a novel class of nutrient supplements to slow down the progression of Alzheimer's disease.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Selenito de Sódio/farmacologia , Peptídeos beta-Amiloides/metabolismo , Linhagem Celular Transformada , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Humanos , Mutação/fisiologia , Fragmentos de Peptídeos/metabolismo , Fatores de TempoRESUMO
A type of new 1,2,3,4-tetrahydroisoquinoline derivatives was synthesized via concise procedure from commercially available tetrahydroisoquinoline. These derivatives were delicately designed to possess propargyl-related pharmacophores simulated with a monoamine oxidase inhibitor rasagiline. We investigated the effect of these synthetic tetrahydroisoquinoline derivatives on the regulation of proteolytic processing of amyloid precursor protein (APP) by an ERK-dependent signaling pathway. Additionally, these compounds were also evaluated on the prevention of the proteolytic processing of C99 as gamma-secretase inhibitors by using a highly efficient cell-based reporter gene assay for gamma-secretase. The results suggested that certain compounds might be explored to possess both sAPPalpha-releasing stimulation and gamma-secretase inhibitory potency, which may reflect the synergetic potential of neuroprotective activities for the treatment of Alzheimer's disease as they possessed both ERK activation and inhibition of amyloidogenic Abeta release.
Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Peptídeo Hidrolases/metabolismo , Tetra-Hidroisoquinolinas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Hidrólise/efeitos dos fármacos , Fármacos Neuroprotetores , Tetra-Hidroisoquinolinas/químicaRESUMO
The chikungunya virus (CHIKV) is a mosquito-borne virus that belongs to the genus Alphavirus, family Togaviridae. It is the cause of chikungunya fever in humans, which presents a serious global threat due to its high rate of contagion. The clinical symptoms of CHIKV include fever and persistent, severe arthritis. Micafungin has broad-spectrum fungicidal activity against Candida spp. is a promising echinocandin that was recently approved by the U.S. Food and Drug Administration (FDA) and has demonstrated activity against Candida and Aspergillus. Recent studies have demonstrated the antiviral activity of micafungin; however, the inhibitory effects against CHIKV have yet to be investigated. Our objectives in this study were to explore the antiviral effects of micafungin on CHIKV infection and to elucidate the potential molecular mechanisms of inhibition. We determined that micafungin has the ability to counter CHIKV-induced cytopathic effects. We further discovered that micafungin limits virus replication, release, cell-to-cell transmission, and also slightly affected virus stability during high doses treatment. The efficacy of micafungin was further confirmed against two clinical isolates of CHIKV and two alphaviruses: Sindbis virus (SINV) and Semliki Forest virus (SFV). Our findings suggest that micafungin has considerable potential as a novel inhibitor against the viral replication, and intracellular and extracellular transmission of CHIKV, and has a little effect on virus stability. Our findings also suggest that micafungin could have curative effects on other alphavirus infections.
Assuntos
Alphavirus/efeitos dos fármacos , Antivirais/farmacologia , Vírus Chikungunya/efeitos dos fármacos , Micafungina/farmacologia , Infecções por Alphavirus/tratamento farmacológico , Febre de Chikungunya/tratamento farmacológico , Febre de Chikungunya/virologia , Vírus da Floresta de Semliki/efeitos dos fármacos , Sindbis virus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
BACKGROUND: The frequent use of antibacterial agents and the exposure of the patients to lifesaving intervention processes are consistently associated with the increased chance of nosocomial infections and the emergence of multidrug resistant microorganisms in the hospital environment. Thus, new antimicrobial agents are of unmet need to treat the severe nosocomial infections caused by these putative pathogens resistant to currently available agents. METHOD: Design, synthesis, and biological evaluation of analogues of nitazoxanide (NTZ), an FDA approved thiazolide antiparasitic, as new antimicrobial agents against nosocomial pathogens were described. The NTZ analogues were rationally explored on the basis of either increasing the electronic resonance effects at the nitrothiazolide moiety or improving the anionic form of the whole NTZ structure. RESULTS: The MICs and MBCs values of these NTZ analogues against prevalent nosocomial pathogens were measured. The benzologous analogues 3a and 4a and p-chlorobenzenesulfonamides 8d and 9d exhibited tremendous antimicrobial activities, which were 100- to 2000-fold more potent than NTZ and ciprofloxacin. CONCLUSION: The results demonstrated that delicate manipulation of the NTZ core structure could lead to promising antimicrobial agents against the nosocomial pathogens.
Assuntos
Antibacterianos/farmacologia , Tiazóis/farmacologia , Antibacterianos/síntese química , Ciprofloxacina/farmacologia , Infecção Hospitalar/microbiologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bacilos Gram-Positivos Formadores de Endosporo/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Nitrocompostos , Ftalimidas/síntese química , Ftalimidas/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Tiazóis/síntese químicaRESUMO
In the search for highly selective and potent derivatives of tacrine (1a), a number of homodimeric tacrine congeners were synthesized and conducted for their effects on rat acetylcholinesterase (AChE) and human butyrylcholinesterase (BChE) inhibitions. Heptylene-linked bis-(6-chloro)tacrine (3h) was found up to 3000- and 3-fold more potent in inhibiting rat AChE than tacrine and the unsubstituted bis-tacrine 3b, respectively. Changes in the size of the carbocyclic ring of the dimeric tacrine reduced both the selectivity and the potency of AChE inhibition as compared to 3b. Inserting an aza into the tacrine nucleus as the desired isosteres 3j-m resulted in moderate potency but tended to be detrimental to selectivity. The pronounced enhancement of AChE inhibition potency and AChE/BChE selectivity was achieved with incorporation of a halogen at the 6-position of homodimeric tacrines. The assay results of 3a-m also provided evidence that the 7-methylene tether tended to be optimal to AChE inhibition potency.
Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Tacrina/síntese química , Animais , Encéfalo/enzimologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Dimerização , Humanos , Técnicas In Vitro , Ratos , Relação Estrutura-Atividade , Tacrina/química , Tacrina/farmacologiaRESUMO
This article describes the synthesis and antioxidative properties of melatonin derivatives. Tryptamines and cysteinyl or mercaptopropionyl derivatives were deliberately condensed with coupling reagents to give melatonin derivatives 4a-d and 5a, b. The preliminary evaluation indicated that compound 4c showed improved scavenging activity compared with vitamin C (IC50 43 microM vs 65 microM, where IC50 is the concentration of the test compound that induced a change of 50% in absorbance during the 30 min observation) on diphenyl-p-picrylhydrazyl (DPPH) tests. Derivative 5b, which possesses the thiolactyl moiety, showed moderate potency compared with melatonin (IC50 235 microM vs 690 microM) in the H(2)O(2) scavenging test. Intriguingly, 4c displayed 2-fold more potency than melatonin (IC50 51 microM vs 125 microM) in scavenging NO in the macrophage model. These results suggested that the cysteinyl-conjugated derivative 4c may be a suitable lead to further optimize potent antioxidants for certain oxidative stress conditions.
Assuntos
Antioxidantes/farmacologia , Melatonina/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Células Cultivadas , Interações Medicamentosas , Peróxido de Hidrogênio/química , Melatonina/análogos & derivados , Melatonina/química , Relação Estrutura-AtividadeRESUMO
We have investigated the developdment of potential antioxidants based on magnolol, a naturally occurring biphenolic obtained from the bark of Magnolia officinalis. A series of aminomethylated derivatives of magnolol were synthesized under the aromatic Mannich reaction. In-vitro testing for diphenyl-p-picrylhydrazyl (DPPH) scavenging and chemiluminescence assays in whole cell models revealed that the pyrrolidyl-containing magnolols (2b (5,5'-diallyl-3-(pyrrolidin-1-ylmethyl)-biphenyl-2,2'-diol), 3a (5,5'-diallyl-3,3'-bis-(pyrrolidin-1-ylmethyl)-biphenyl-2,2'-diol) and 4c (5,5'-diallyl-3-(morphorin-4-ylmethyl)-3'-(pyrrolidin-1-ylmethyl)-biphenyl-2,2'-diol)) displayed promising free radical scavenging effects as compared with magnolol. The results from compound 4c indicated that the naturally occurring component was suitable to be a lead compound toward promising antioxidants.
Assuntos
Compostos de Bifenilo/química , Compostos de Bifenilo/síntese química , Sequestradores de Radicais Livres/síntese química , Hidrazinas/química , Lignanas , Compostos de Bifenilo/isolamento & purificação , Sequestradores de Radicais Livres/química , Medições Luminescentes , Magnolia/química , Picratos , Casca de Planta/química , Óleos de Plantas/químicaRESUMO
Structural optimization of the prior lead 3 led to the small molecular (D)-leucinamides with potent modulating activity and Notch-sparing selectivity on the proteolytic processing of amyloid-ß precursor proteins. The N-(R)-epoxypropyl analog 10c exhibited potent γ-secretase modulation compared to DAPT and showed substantial substrate selection for APP cleavage over Notch cleavage, while N-(2-fluoro)benzyl analog 10e showed the most potent γ-secretase inhibition with dull selectivity. The exceptional suppression of ERK-mediated activation suggested that these potent γ-secretase modulators may adapt an alternative pathway to prominently induce the differential inhibition of C99 cleavage by γ-secretase.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Descoberta de Drogas , Leucina/análogos & derivados , Bibliotecas de Moléculas Pequenas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Leucina/síntese química , Leucina/química , Leucina/farmacologia , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Mutations in presenilin-1 (PS1) are tightly associated with early-onset familial Alzheimer's disease (FAD), which is characterized by extracellular amyloid plaques and the accumulation of intracellular Tau. In addition to being the catalytic subunit of γ-secretase, PS1 has been shown to regulate diverse cellular functions independent of its proteolytic activity. We found that cells deficient in PS1 exhibit reduced levels of p62 protein, a cargo-receptor shuttling Tau for degradation. The downregulation of PS1 led to a significant decrease in both the protein and mRNA transcript of p62, concomitant with attenuated p62 promoter activity. This PS1-dependent regulation of p62 expression was mediated through an Akt/AP-1 pathway independent of the proteolytic activity of PS1/γ-secretase. This p62-mediated Tau degradation was significantly impaired in PS1-deficient cells, which can be rescued by ectopic expression of either p62 or wild-type PS1 but not mutant PS1 containing FAD-linked mutations. Our study suggests a novel function for PS1 in modulating p62 expression to control the proteostasis of Tau.