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1.
Eur J Med Chem ; 188: 112022, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31901744

RESUMO

Due to the occurrence of antibiotic resistance, bacterial infectious diseases have become a serious threat to public health. To overcome antibiotic resistance, novel antibiotics are urgently needed. N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides are a potential new class of antibacterial agents, as one of its derivatives was identified as an antibacterial agent against S. aureus. However, no potency-directed structural optimization has been performed. In this study, we designed and synthesized 37 derivatives, and evaluated their antibacterial activity against S. aureus ATCC29213, which led to the identification of ten potent antibacterial agents with minimum inhibitory concentration (MIC) values below 1 µg/mL. Next, we performed bacterial growth inhibition assays against a panel of drug-resistant clinical isolates, including methicillin-resistant S. aureus, and cytotoxicity assays with HepG2 and HUVEC cells. One of the tested compounds named 1-ethyl-4-hydroxy-2-oxo-N-(5-(thiazol-2-yl)-1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-3-carboxamide (g37) showed 2 to 128-times improvement compared with vancomycin in term of antibacterial potency against the tested strains (MICs: 0.25-1 µg/mL vs. 1-64 µg/mL) and an optimal selective toxicity (HepG2/MRSA, 110.6 to 221.2; HUVEC/MRSA, 77.6-155.2). Further, comprehensive evaluation indicated that g37 did not induce resistance development of MRSA over 20 passages, and it has been confirmed as a bactericidal, metabolically stable, orally active antibacterial agent. More importantly, we have identified the S. aureus DNA gyrase B as its potential target and proposed a potential binding mode by molecular docking. Taken together, the present work reports the most potent derivative of this chemical series (g37) and uncovers its potential target, which lays a solid foundation for further lead optimization facilitated by the structure-based drug design technique.


Assuntos
Antibacterianos/farmacologia , Quinolonas/farmacologia , Tiadiazóis/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/toxicidade , DNA Girase/metabolismo , Desenho de Drogas , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecium/efeitos dos fármacos , Feminino , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/enzimologia , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/toxicidade , Staphylococcus epidermidis/efeitos dos fármacos , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/toxicidade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase II/toxicidade
2.
Biosci Biotechnol Biochem ; 84(1): 187-197, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31566092

RESUMO

Walnut is a nutritious food material, but only a few studies have been conducted on the mechanisms of its functions and the technique for quality evaluation. Therefore, we analyzed the components in aqueous methanol extract of walnut, and characterized 30 components, including three new compounds, glansreginin C, ellagic acid 4-O-(3'-O-galloyl)-ß-D-xyloside, and platycaryanin A methyl ester. We analyzed the extracts of other nuts using HPLC and clarified that a characteristic peak corresponding to glansreginin A was mainly observed in walnut. These results suggested that glansreginin A might be an indicator component of the quality of walnut. We then examined whether glansreginin A has neuroprotective effect, using lipopolysaccharide (LPS)-induced inflammatory model mice. The results revealed that oral administration of glansreginin A prevented LPS-induced abnormal behavior and LPS-induced hyper-activation of microglia in the hippocampus. These results suggested that glansreginin A has the ability to exert neuroprotective effect via anti-inflammation in the brain.


Assuntos
Anti-Inflamatórios/farmacologia , Juglans/química , Fármacos Neuroprotetores/farmacologia , Valor Nutritivo , Extratos Vegetais/farmacologia , Quinolinas/farmacologia , Quinolonas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Ácido Elágico/farmacologia , Hipocampo/patologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Lipopolissacarídeos/farmacologia , Masculino , Metanol/química , Éteres Metílicos/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Microglia/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Quinolinas/uso terapêutico
3.
Eur J Med Chem ; 185: 111845, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31718941

RESUMO

The three series of 5-mono- and 2,5-bis-1,2,3-triazolyl-substituted benzimidazo[1,2-a]quinolines as potential antitumor agents were synthesized. Their growth-inhibitory activity is influenced by the introduction of fluorine at C-2 and the mono-triazolyl nuclei at C-5 of the tetracyclic skeleton, particularly if the 1,2,3-triazole moiety contains a short aliphatic side-chain. Thus, the chloropropyl side-chain in all three series had the highest impact on the inhibitory effect. 1,2,3-Triazolyl-2-fluorobenzimidazo[1,2-a]quinoline conjugates 8a and 8b with 3-chloropropyl and 2-hydroxyethyl substituents, respectively, exhibited the most pronounced cytostatic effect on colon cancer (HCT116) cells in the submicromolar range. The compound 8a emerged as the most promising candidate because of its higher potency and some selectivity in the non-tumor aneuploid immortal keratinocyte (HaCaT) cells. Fluorescence and CD spectroscopy, as well as the thermal denaturation assays, revealed moderate to high DNA/RNA binding affinities of the selected compounds and identified intercalation as a dominant binding mode to both polynucleotides. However, results of intracellular distribution assay in human lung carcinoma (H460) cells suggest that both 8a and 8b do not target nuclear DNA and that their non-specific cytotoxic effect may be attributed to the damage of intercellular membranes.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , DNA/química , Quinolonas/farmacologia , RNA/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Sítios de Ligação/efeitos dos fármacos , Bovinos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-Atividade
4.
BMC Infect Dis ; 19(1): 979, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752702

RESUMO

BACKGROUND: Fluoroquinolones are commonly recommended as treatment for urinary tract infections (UTIs). The development of resistance to these agents, particularly in gram-negative microorganisms complicates treatment of infections caused by these organisms. This study aimed to investigate antimicrobial resistance of different Enterobacteriaceae species isolated from hospital- acquired and community-acquired UTIs against fluoroquinolones and correlate its levels with the existing genetic mechanisms of resistance. METHODS: A total of 440 Enterobacteriaceae isolates recovered from UTIs were tested for antimicrobial susceptibility. Plasmid-mediated quinolone resistance (PMQR) genes and mutations in the quinolone resistance-determining regions (QRDRs) of gyrA and parC genes were examined in quinolone-resistant strains. RESULTS: About (32.5%) of isolates were resistant to quinolones and (20.5%) were resistant to fluoroquinolones. All isolates with high and intermediate resistance phenotypes harbored one or more PMQR genes. QnrB was the most frequent gene (62.9%) of resistant isolates. Co-carriage of 2 PMQR genes was detected in isolates (46.9%) with high resistance to ciprofloxacin (CIP) (MICs > 128 µg/mL), while co-carriage of 3 PMQR genes was detected in (6.3%) of resistant isolates (MICs > 512 µg/mL). Carriage of one gene only was detected in intermediate resistance isolates (MICs of CIP = 1.5-2 µg/mL). Neither qnrA nor qnrC genes were detected. The mutation at code 83 of gyrA was the most frequent followed by Ser80-Ile in parC gene, while Asp-87 Asn mutation of gyrA gene was the least, where it was detected only in high resistant E. coli isolates (MIC ≥128 µg/mL). A double mutation in gyrA (Lys154Arg and Ser171Ala) was observed in high FQs resistant isolates (MIC of CIP < 128 µg/mL). CONCLUSION: FQs resistance is caused by interact between PMQR genes and mutations in both gyrA and parC genes while a mutation in one gene only can explain quinolone resistance. Accumulation of PMQR genes and QRDR mutations confers high resistance to FQs.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Infecção Hospitalar/microbiologia , Farmacorresistência Bacteriana , Infecções por Enterobacteriaceae/microbiologia , Enterobacteriaceae/genética , Quinolonas/farmacologia , Infecções Urinárias/microbiologia , Adulto , Proteínas de Bactérias/metabolismo , Ciprofloxacino/farmacologia , Enterobacteriaceae/classificação , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/isolamento & purificação , Feminino , Fluoroquinolonas/farmacologia , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mutação , Plasmídeos/genética , Plasmídeos/metabolismo , Adulto Jovem
5.
Nihon Yakurigaku Zasshi ; 154(5): 275-287, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31735758

RESUMO

Brexpiprazole (Rexulti®) is the second antipsychotic agent in the world with dopamine D2 receptor partial agonist which was developed by Otsuka Pharmaceutical Co. Ltd. It is categorized as 〝Serotonin- dopamine Activity Modulator (SDAM)〟 that regulates both serotoninergic and dopaminergic systems by acting as a partial agonist for serotonin 5-HT1A receptors and D2 receptors and as an antagonist for 5-HT2A receptors. In preclinical pharmacological studies, brexpiprazole showed the equivalent antipsychotic-like effects to those of other atypical antipsychotics. And it was suggested that brexpiprazole has the low potentials to induce extrapyramidal symptoms, hyperprolactinemia and tardive dyskinesia, with improvement effects on cognitive dysfunction. Furthermore, brexpiprazole has the weak effects on histamine H1 receptors which are associated with sedation and weight gain in clinical. In the clinical trials in patients with schizophrenia in both acute and maintenance phase, brexpiprazole showed improvement of antipsychotic effects against placebo, and low incidence of adverse events, e.g., extrapyramidal symptoms, hyperprolactinemia, and weight gain, as suggested in preclinical studies. Furthermore, brexpiprazole showed low incidence of metabolic abnormalities. In particular, brexpiprazole showed relatively low incidences of akathisia, insomnia and agitation which has been commonly reported with aripiprazole. This would be based on the pharmacological features of brexpiprazole that is more potent antagonism at 5-HT2A receptors and D2 receptors partial agonism with lower intrinsic activity compared to those of aripiprazole. In conclusion, brexpiprazole could be one of the antipsychotics with the most rational mechanism of action, and the better efficacy and safety/tolerability profiles would contribute to the treatment of patients with schizophrenia.


Assuntos
Antipsicóticos/farmacologia , Quinolonas/farmacologia , Tiofenos/farmacologia , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Esquizofrenia/tratamento farmacológico , Comprimidos , Resultado do Tratamento
6.
Anticancer Res ; 39(9): 4817-4828, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519584

RESUMO

BACKGROUND/AIM: Although epidermal growth factor receptor (EGFR) is frequently activated in lung and pancreatic cancers, the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) is limited. Recently, brexpiprazole, an antipsychotic drug, was reported to chemosensitize glioma cells to osimertinib, a third-generation EGFR-TKI, by suppressing survivin, an anti-apoptotic protein, but their combinational effects on lung and pancreatic cancers remain unknown. The aim of this study was to examine the combinational effects of brexpiprazole and osimertinib on lung and pancreatic cancer cells in vitro and in vivo. MATERIALS AND METHODS: YM155, a suppressor of survivin, siRNA, and immunoblot were used to examine the role of survivin in osimertinib-resistance. The effect of drugs on cell viability in vitro was examined by trypan blue staining. The in vivo effects of drugs on tumor growth were examined using a xenograft mouse model. RESULTS: Brexpiprazole exerted combinational effects with osimertinib in vitro. Pharmacological and genetic suppression of survivin chemosensitized the cells to osimertinib. Moreover, the combination of brexpiprazole and osimertinib effectively suppressed tumor growth in a mouse xenograft model. CONCLUSION: Brexpiprazole is a promising drug for lung and pancreatic cancer in combination with osimertinib.


Assuntos
Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases/farmacologia , Quinolonas/farmacologia , Survivina/genética , Tiofenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Humanos , Masculino , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , RNA Interferente Pequeno/genética , Ensaios Antitumorais Modelo de Xenoenxerto
7.
PLoS Negl Trop Dis ; 13(9): e0007620, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31513580

RESUMO

Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever, a systemic human infection with a burden exceeding 20 million cases each year that occurs disproportionately among children in low and middle income countries. Antimicrobial therapy is the mainstay for treatment, but resistance to multiple agents is common. Here we report genotypes and antimicrobial resistance (AMR) determinants detected from routine whole-genome sequencing (WGS) of 533 S. Typhi isolates referred to Public Health England between April 2014 and March 2017, 488 (92%) of which had accompanying patient travel information obtained via an enhanced surveillance questionnaire. The majority of cases involved S. Typhi 4.3.1 (H58) linked with travel to South Asia (59%). Travel to East and West Africa were associated with genotypes 4.3.1 and 3.3.1, respectively. Point mutations in the quinolone resistance determining region (QRDR), associated with reduced susceptibility to fluoroquinolones, were very common (85% of all cases) but the frequency varied significantly by region of travel: 95% in South Asia, 43% in East Africa, 27% in West Africa. QRDR triple mutants, resistant to ciprofloxacin, were restricted to 4.3.1 lineage II and associated with travel to India, accounting for 23% of cases reporting travel to the country. Overall 24% of isolates were MDR, however the frequency varied significantly by region and country of travel: 27% in West Africa, 52% in East Africa, 55% in Pakistan, 24% in Bangladesh, 3% in India. MDR determinants were plasmid-borne (IncHI1 PST2 plasmids) in S. Typhi 3.1.1 linked to West Africa, but in all other regions MDR was chromosomally integrated in 4.3.1 lineage I. We propose that routine WGS data from travel-associated cases in industrialised countries could serve as informal sentinel AMR genomic surveillance data for countries where WGS is not available or routinely performed.


Assuntos
Farmacorresistência Bacteriana/genética , Salmonella typhi/genética , Febre Tifoide/epidemiologia , Genótipo , Humanos , Testes de Sensibilidade Microbiana , Quinolonas/farmacologia , Inquéritos e Questionários , Doença Relacionada a Viagens , Febre Tifoide/microbiologia , Sequenciamento Completo do Genoma
8.
Inorg Chem ; 58(16): 10778-10790, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31386351

RESUMO

A new family of cyclometalated ruthenium(II) complexes [Ru(N^N)2(C^N)]+ derived from the π-extended benzo[h]imidazo[4,5-f]quinolone ligand appended with thienyl groups (n = 1-4, compounds 1-4) was prepared and its members were characterized for their chemical, photophysical, and photobiological properties. The lipophilicities of 1-4, determined as octanol-water partition coefficients (log Po/w), were positive and increased with the number of thienyl units. The absorption and emission bands of the C^N compounds were red-shifted by up to 200 nm relative to the analogous Ru(II) diimine systems. All of the complexes exhibited dual emission with the intraligand fluorescence (1IL, C^N-based) shifting to lower energies with increasing n and the metal-to-ligand charge transfer phosphorescence (3MLCT, N^N-based) remaining unchanged. Compounds 1-3 exhibited excited state absorption (ESA) profiles consistent with lowest-lying 3MLCT states when probed by nanosecond transient absorption (TA) spectroscopy with 532 nm excitation and had contributions from 1IL(C^N) states with 355 nm excitation. These assignments were supported by the lifetimes observed (<10 ns for the 1IL states and around 20 ns for the 3MLCT states) as well as a noticeable ESA for 3 with 355 nm excitation that did not occur with 532 nm excitation. Compound 4 was the only member of the family with two 3MLCT emissive lifetimes (15, 110 ns), and the TA spectra collected with both 355 and 532 nm excitation was assigned to the 3IL state, which was corroborated by its 4-6 µs lifetime. The ESA for 4 had a rise time of approximately 10 ns and an initial decay of 110 ns, which suggests a possible 3MLCT-3IL excited state equilibrium that results in delayed emission from the 3MLCT state. Compound 4 was nontoxic toward human skin melanoma cells (SKMEL28) in the dark (EC50 = >300 µM); 1-3 were cytotoxic and yielded EC50 values between 1 and 20 µM. The photocytotoxicites with visible light ranged from 87 nM with a phototherapeutic index (PI) of 13 for 1 to approximately 1 µM (PI = >267) for 4. With red light, EC50 values varied from 270 nM (PI = 21) for 3 to 12 µM for 4 (PI = >25). The larger PIs for 4, especially with visible light, were attributed to the much lower dark cytotoxicity for this compound. Because the dark cytotoxicity contributes substantially to the observed photocytotoxicity for 1-3, it was not possible to assess whether the 3IL state of 4 led to a much more potent phototoxic mechanism in the absence of dark toxicity. There was no stark contrast in cellular uptake and accumulation by laser scanning confocal and differential interference contrast microscopy to explain the large differences in dark toxicities between 1-3 and 4. Nevertheless, the study highlights a new family of Ru(II) C^N complexes where π-conjugation beyond a certain point results in low dark cytotoxicity with high photocytotoxicity, opposing the notion that cyclometalated Ru(II) systems are too toxic to be phototherapeutic agents.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Quinolonas/farmacologia , Rutênio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Luz , Estrutura Molecular , Processos Fotoquímicos , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Quinolonas/química , Rutênio/química
9.
Mol Carcinog ; 58(11): 2052-2064, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31397499

RESUMO

Recent studies have indicated that using statins to inhibit the mevalonate pathway induces mutant p53 degradation by impairing the interaction of mutant p53 with DnaJ subfamily A member 1 (DNAJA1). However, the role of the C-terminus of DNAJA1 with a CAAX box for farnesylation in the binding, folding, and translocation of client proteins such as mutant p53 is not known. In the present study, we used a genetically engineered mouse model of pancreatic carcinoma and showed that atorvastatin significantly increased animal survival and inhibited pancreatic carcinogenesis. There was a dramatic decrease in mutant p53 protein accumulation in the pancreatic acini, pancreas intraepithelial neoplasia lesions, and adenocarcinoma. Supplementation with farnesyl pyrophosphate, a substrate for protein farnesylation, rescued atorvastatin-induced mutant p53 degradation in pancreatic cancer cells. Tipifarnib, a farnesyltransferase inhibitor, mirrored atorvastatin's effects on mutant p53, degraded mutant p53 in a dose-dependent manner, and converted farnesylated DNAJA1 into unfarnesylated DNAJA1. Farnesyltransferase gene knockdown also significantly promoted mutant p53 degradation. Coimmunoprecipitation either by an anti-DNAJA1 or p53 antibody confirmed the direct interaction of mutant p53 and DNAJA1 and higher doses of atorvastatin treatments converted more farnesylated DNAJA1 into unfarnesylated DNAJA1 with much less mutant p53 pulled down by DNAJA1. Strikingly, C394S mutant DNAJA1, in which the cysteine of the CAAX box was mutated to serine, was no longer able to be farnesylated and lost the ability to maintain mutant p53 stabilization. Our results show that farnesylated DNAJA1 is a crucial chaperone in maintaining mutant p53 stabilization and targeting farnesylated DNAJA1 by atorvastatin will be critical for inhibiting p53 mutant cancer.


Assuntos
Atorvastatina/farmacologia , Proteínas de Choque Térmico HSP40/genética , Neoplasias Pancreáticas/tratamento farmacológico , Proteína Supressora de Tumor p53/genética , Animais , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Farnesiltranstransferase/antagonistas & inibidores , Farnesiltranstransferase/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Chaperonas Moleculares/genética , Proteínas Mutantes/genética , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Prenilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas p21(ras)/genética , Quinolonas/farmacologia
10.
Int J Mol Sci ; 20(16)2019 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-31426602

RESUMO

Rebamipide ophthalmic solution is a mucin secretagogue which is an important therapeutic agent in the treatment of dry eye. It has been noted that dry eye in office workers is associated with a decrease in secretory mucin. This study aimed to evaluate the effects of 2% rebamipide ophthalmic solution in mice subjected to environmental dry eye stress (EDES), which mimics the conditions of office workers. Thirty eyes from thirty BALB/c mice (eight-week-old males) were divided into three treatment groups: artificial tear (vehicle), 2% rebamipide ophthalmic solution, and 0.1% hyaluronic acid (HA) ophthalmic solution. After four days of pretreatment, mice were exposed to EDES for three days. The corneal subbasal nerve and inflammatory cells were then examined using in vivo confocal microscopy. Following EDES exposure, the lissamine green staining score was significantly lower and corneal sensitivity was more preserved in the 2% rebamipide group than in the HA group. In addition, the subbasal nerve fiber density was significantly higher and the DC density was significantly lower in the 2% rebamipide group than in the HA group. Overall, the topical rebamipide ophthalmic solution showed more favorable therapeutic effects when compared to the HA ophthalmic solution in a mouse model of EDES, likely owing to its anti-inflammatory and neuroprotective effects.


Assuntos
Alanina/análogos & derivados , Anti-Inflamatórios/uso terapêutico , Córnea/efeitos dos fármacos , Síndromes do Olho Seco/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Nervos Periféricos/efeitos dos fármacos , Quinolonas/farmacologia , Alanina/farmacologia , Alanina/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Córnea/inervação , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fármacos Neuroprotetores/uso terapêutico , Quinolonas/uso terapêutico
11.
J Steroid Biochem Mol Biol ; 194: 105458, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31465845

RESUMO

Human and rat reproductive systems differ significantly with respect to hormonal cyclicity and endometrial cell behavior. However, species-differences in endometrial cell responses upon hormonal stimulation and exposure to potentially toxic compounds are poorly characterized. In this study, human and rat endometrial hormonal responses were assessed in vitro using a 3D co-culture model of primary human and rat endometrial cells. The models were exposed to the aryl hydrocarbon receptor (AHR) ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), laquinimod, and its AHR active metabolite DELAQ. In both the human and rat endometrial models, estrogen receptor and progesterone receptor gene expression was modulated by the hormonal treatments, comparable to the in vivo situation. AHR gene expression in the human endometrial model did not change when exposed to hormones. In contrast, AHR expression decreased 2-fold in the rat model when exposed to predominantly progesterone, which resulted in a 2.8-fold attenuation of gene expression induction of cytochrome P450 1A1 (CYP1A1) by TCDD. TCDD and DELAQ, but not laquinimod, concentration-dependently induced CYP1A1 gene expression in both human and rat endometrial models. Interestingly, the relative degree of DELAQ to induce CYP1A1 was higher than that of TCDD in the human model, while it was lower in the rat model. These data clearly show species-differences in response to hormones and AHR ligands between human and rat endometrial cells in vitro, which might greatly affect the applicability of the rat as translational model for human endometrial effects. This warrants further development of human relevant, endometrium-specific test methods for risk assessment purposes.


Assuntos
Endométrio/citologia , Células Epiteliais/efeitos dos fármacos , Dibenzodioxinas Policloradas/farmacologia , Quinolonas/farmacologia , Receptores de Hidrocarboneto Arílico/genética , Células Estromais/efeitos dos fármacos , Animais , Aromatase/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Técnicas de Cocultura , Citocromo P-450 CYP1A1/metabolismo , Células Epiteliais/metabolismo , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Ligantes , Ratos Sprague-Dawley , Células Estromais/metabolismo
12.
Mol Pharmacol ; 96(4): 515-525, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31427400

RESUMO

ORKAMBI, a combination of the corrector, lumacaftor, and the potentiator, ivacaftor, partially rescues the defective processing and anion channel activity conferred by the major cystic fibrosis-causing mutation, F508del, in in vitro studies. Clinically, the improvement in lung function after ORKAMBI treatment is modest and variable, prompting the search for complementary interventions. As our previous work identified a positive effect of arginine-dependent nitric oxide signaling on residual F508del-Cftr function in murine intestinal epithelium, we were prompted to determine whether strategies aimed at increasing arginine would enhance F508del-cystic fibrosis transmembrane conductance regulator (CFTR) channel activity in patient-derived airway epithelia. Now, we show that the addition of arginine together with inhibition of intracellular arginase activity increased cytosolic nitric oxide and enhanced the rescue effect of ORKAMBI on F508del-CFTR-mediated chloride conductance at the cell surface of patient-derived bronchial and nasal epithelial cultures. Interestingly, arginine addition plus arginase inhibition also enhanced ORKAMBI-mediated increases in ciliary beat frequency and mucociliary movement, two in vitro CF phenotypes that are downstream of the channel defect. This work suggests that strategies to manipulate the arginine-nitric oxide pathway in combination with CFTR modulators may lead to improved clinical outcomes. SIGNIFICANCE STATEMENT: These proof-of-concept studies highlight the potential to boost the response to cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators, lumacaftor and ivacaftor, in patient-derived airway tissues expressing the major CF-causing mutant, F508del-CFTR, by enhancing other regulatory pathways. In this case, we observed enhancement of pharmacologically rescued F508del-CFTR by arginine-dependent, nitric oxide signaling through inhibition of endogenous arginase activity.


Assuntos
Aminofenóis/farmacologia , Aminopiridinas/farmacologia , Arginase/antagonistas & inibidores , Arginina/metabolismo , Benzodioxóis/farmacologia , Fibrose Cística/metabolismo , Óxido Nítrico/metabolismo , Quinolonas/farmacologia , Animais , Brônquios/citologia , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Células Cultivadas , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Citosol/metabolismo , Combinação de Medicamentos , Humanos , Mucosa Intestinal/metabolismo , Camundongos , Mutação , Nariz/citologia , Nariz/efeitos dos fármacos
13.
Eur J Med Chem ; 181: 111584, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31419740

RESUMO

Developing new therapeutic strategies to overcome drug resistance of cancer cells is an ongoing endeavor. From among 2 million chemicals, we identified ethyl 4-oxo-2-phenyl-1,4-dihydroquinoline-6-carboxylate (AS1712) as a low-toxicity inhibitor of lung cancer cell proliferation and xenograft tumor growth. We show that AS1712 is active against broad cancer cell lines and is able to bind in the colchicine-binding pocket of ß-tubulin, thereby inhibiting microtubule assembly and, consequently, inducing mitotic arrest and apoptosis. Our cell-based structure-activity relationship study identified a new lead compound, RJ-LC-15-8, which had a greater anti-proliferative potency for H1975 cells than did AS1712, while maintaining a similar mechanism of action. Notably, AS1712 and RJ-LC-15-8 overcame P-glycoprotein efflux pump and ß-tubulin alterations that lead to acquired resistance against microtubule-targeting drugs of cancer cells. AS1712 and RJ-LC-15-8 may be lead compounds that overcome acquired resistance to microtubule-targeting agents of cancer cells.


Assuntos
Quinolonas/química , Quinolonas/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colchicina/metabolismo , Resistencia a Medicamentos Antineoplásicos , Humanos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Tubulina (Proteína)/química
14.
Int J Food Microbiol ; 307: 108274, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31404780

RESUMO

The purpose of this study was to determine the genetic characterization of ciprofloxacin resistant- Escherichia coli recovered from 7 different integrated broiler operations in Korea. Among the 157 E. coli isolated from chicken meat produced by integrated broiler operations, 75 (47.8%) were observed to be ciprofloxacin resistant-E. coli. However, the prevalence varied from 25.0 to 75.0%, in chicken meat, indicating variation in ciprofloxacin resistant E. coli occurrence among the operations. Among the 75 ciprofloxacin resistant-E. coli isolates, 10 showed plasmid-mediated quinolone resistance (PMQR) genes, aac(6')-Ib-cr, qnrS1 and qnrB4. Among the 10 PMQR-positive E. coli, a double amino-acid exchange in both gyrA and parC with ciprofloxacin minimum inhibitory concentrations of ≥16 µg/mL was noted in 8 isolates, and 4 transconjugants (40.0%) expressed similar antimicrobial resistance patterns and revealed the presence of PMQR genes and ß-lactamase genes. Our findings suggest that E. coli with resistance to ciprofloxacin can now be found in association with integrated broiler operations, thus highlighting the need for monitoring and prevention programs in integrated operations.


Assuntos
Ciprofloxacino/farmacologia , Farmacorresistência Bacteriana/genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/isolamento & purificação , Carne/microbiologia , Plasmídeos/genética , Quinolonas/farmacologia , Criação de Animais Domésticos/normas , Animais , Antibacterianos/farmacologia , Galinhas , Escherichia coli/genética , Genes Bacterianos/genética , Testes de Sensibilidade Microbiana , República da Coreia/epidemiologia
15.
Eur J Med Chem ; 180: 340-349, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31325782

RESUMO

Allosteric ligands of GABAA receptors exist in many different chemotypes owing to their great usefulness as therapeutics, with benzodiazepines being among the best known examples. Many allosteric binding sites have been described, among them a site at the extracellular interface between the alpha principal face and the beta complementary face (α+/ß-). Pyrazoloquinolinones have been shown to bind at α+/ß-binding sites of GABAA receptors, exerting chiefly positive allosteric modulation at this location. In order to further explore molecular determinants of this type of allosteric modulation, we synthesized a library of ligands based on the PQ pharmacophore employing a ring-chain bioisosteric approach. In this study we analyzed the structure-activity-relationship (SAR) of these novel ligands based on an azo-biaryl structural motif in α1ß3 GABAA receptors, indicating interesting novel properties of the compound class.


Assuntos
Pirazóis/farmacologia , Quinolonas/farmacologia , Receptores de GABA-A/metabolismo , Regulação Alostérica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Ligantes , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-Atividade
16.
J Drugs Dermatol ; 18(7): 655-661, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31334625

RESUMO

Background: Impetigo, a bacterial infection that is highly contagious, involves the superficial skin. Topical treatment for impetigo includes amongst other bacitracin, gentamycin, mupirocin, retapamulin, and more recently, ozenoxacin 1% cream. For more severe conditions systemic antibiotics are prescribed and may be combined with a topical treatment. The current review explored the challenges in treating impetigo in pediatric and adult populations and examined the role of ozenoxacin 1% cream as a safe and effective treatment option. Methods: We performed PubMed and Google Scholar searches of the English-language literature (2010-2018) using the terms impetigo, bullous impetigo, non-bullous impetigo, antimicrobial and antibiotic resistance, mupirocin, retapamulin, and ozenoxacin. The selected publications were manually reviewed for additional resources. Results: Although guidelines were updated regularly, the recommended treatments have not changed much since 2014. Emerging antimicrobial resistance is a growing concern in dermatology and pediatrics. Impetigo therapy choices should consider the resistance pattern of S. aureus. Ozenoxacin 1% cream is a prescription medicine for topical treatment of impetigo in adults and children 2 months or older. Ozenoxacin has a low probability of selecting spontaneous resistant mutants in quinolone-susceptible or quinolone-resistant bacterial strains and has shown to be active against MRSA isolates. Ozenoxacin 1% cream has potent bactericidal activity and was shown to be effective and safe for the treatment of impetigo in two well-controlled Phase 3 trials. Conclusions: Resistance patterns in a wide range of pathogens against oral or topical antibiotics and antiseptics used for the treatment of dermatological conditions, such as impetigo have been observed. When making treatment decisions for impetigo MRSA and other antimicrobial resistance has to be taken into account. Ozenoxacin 1% cream offers a potent bactericidal activity and has demonstrated clinical efficacy and safety. Combined with its favorable features, such as a low dosing frequency and a 5 days treatment regimen, ozenoxacin 1% cream is an important option for the treatment of impetigo for pediatric and adult populations. J Drugs Dermatol. 2019;18(7):655-661.


Assuntos
Aminopiridinas/farmacologia , Antibacterianos/farmacologia , Impetigo/tratamento farmacológico , Quinolonas/farmacologia , Creme para a Pele/administração & dosagem , Staphylococcus aureus/fisiologia , Aminopiridinas/uso terapêutico , Antibacterianos/uso terapêutico , Gestão de Antimicrobianos/normas , Tomada de Decisão Clínica , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/genética , Humanos , Impetigo/microbiologia , Mutação/efeitos dos fármacos , Seleção de Pacientes , Guias de Prática Clínica como Assunto , Quinolonas/uso terapêutico , Staphylococcus aureus/isolamento & purificação , Resultado do Tratamento
17.
Eur J Med Chem ; 180: 204-212, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31306907

RESUMO

A series of 5-(4-substituted piperazin-1-yl)quinolin-2(1H)-one derivatives (4a-4w) has been designed as chitin synthase inhibitors and antifungal agents. The designed compounds were obtained by an environmentally benign route in four steps starting from 5-amino-3,4-dihydroquinolin-2(1H)-one which was offered by an easily achieved synthetic method. The synthesized compounds were tested for their inhibition potency against chitin synthase. Compounds 4a and 4c exhibited excellent inhibitory activity with IC50 values of 0.10 mM and 0.15 mM, respectively, which is better than that of Polyoxin B whose IC50 value is 0.18 mM. Compounds 4h, 4i, 4j, 4k and 4n exerted moderate inhibition potency with IC50 values of 0.38, 0.36, 0.47, 0.47 and 0.37 mM, respectively. These synthesized compounds were also evaluated for their in vitro antifungal activity against Candida albicans, Crytococcus neoformans, and Aspergillus flavus. Compounds 4a, 4i and 4j exhibited the most potent antifungal activity against C. albicans with MIC of 32 µg/mL, which were similar to that of Polyoxin B. The results of antibacterial activity against selected strains showed that the designed compounds have little potency against bacteria and indicated that these compounds were chitin synthase inhibitors and have selectively antifungal activity.


Assuntos
Antifúngicos/farmacologia , Quitina Sintase/antagonistas & inibidores , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Piperazinas/farmacologia , Quinolonas/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Aspergillus flavus/efeitos dos fármacos , Aspergillus flavus/metabolismo , Candida albicans/efeitos dos fármacos , Candida albicans/metabolismo , Quitina Sintase/metabolismo , Cryptococcus neoformans/efeitos dos fármacos , Cryptococcus neoformans/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-Atividade
18.
Eur J Med Chem ; 179: 576-590, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279292

RESUMO

A series of novel fluoroquinolone-Safirinium dye hybrids was synthesized by means of tandem Mannich-electrophilic amination reactions from profluorophoric isoxazolones and antibiotics bearing a secondary amino group at position 7 of the quinoline ring. The obtained fluorescent spiro fused conjugates incorporating quaternary nitrogen atoms were characterized by 1H NMR, IR, MS, and elemental analysis. All the synthetic analogues (3a-h and 4a-h) were evaluated for their in vitro antimicrobial, bactericidal, and antibiofilm activities against a panel of Gram positive and Gram-negative pathogenic bacteria. The most active Safirinium Q derivatives of lomefloxacin (4d) and ciprofloxacin (4e) exhibited molar-based antibacterial activities comparable to the unmodified drugs and displayed considerable inhibitory potencies in E. coli DNA gyrase supercoiling assays with IC50 values in the low micromolar range. Zwiterionic hybrids were noticeably less lipophilic than the parent quinolones in micellar electrokinetic chromatography (MECK) experiments. The tests performed in the presence of phenylalanine-arginine ß-naphthylamide (PAßN) or carbonyl cyanide m-chlorophenylhydrazone (CCCP) revealed that the conjugates are to some extent subject to bacterial efflux and cellular accumulation, respectively. Moreover, the hybrids did not exhibit notable cytotoxicity towards the HEK 293 control cell line and demonstrated low propensity for resistance development, as exemplified for compounds 3g and 4b. Finally, molecular docking experiments revealed that the synthesized compounds were able to bind in the fluoroquinolone-binding mode at S. aureus DNA gyrase and S. pneumoniae topoisomerase IV active sites.


Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Compostos de Amônio Quaternário/farmacologia , Quinolonas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , DNA Girase/metabolismo , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Bactérias Gram-Negativas/metabolismo , Bactérias Gram-Positivas/metabolismo , Células HEK293 , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/química , Quinolonas/química , Relação Estrutura-Atividade
19.
Arch Pharm (Weinheim) ; 352(9): e1900045, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31274223

RESUMO

Acquired immune deficiency syndrome (AIDS)/human immunodeficiency virus (HIV) is one of the largest and most devastating public health pandemics throughout the world. The global pandemic of drug-sensitive HIV and the increasing threat from drug-resistant HIV result in an urgent need to develop more effective anti-HIV candidates. Quinolone represents a significant class of privileged heterocycles, and its derivatives possess promising in vitro and in vivo anti-HIV properties. The 4-quinolone elvitegravir has already been approved for the treatment of HIV; thus, quinolone derivatives might be promising candidates with anti-HIV activity. This review emphasizes quinolone derivatives with potential anti-HIV activity, covering articles published between 1992 and 2019. The structure-activity relationship is also discussed to provide insights for further development of more active quinolone derivatives.


Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Quinolonas/farmacologia , Fármacos Anti-HIV/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Descoberta de Drogas , Farmacorresistência Viral Múltipla/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/genética , Humanos , Estrutura Molecular , Quinolonas/química , Relação Estrutura-Atividade
20.
Expert Opin Pharmacother ; 20(15): 1907-1916, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31290344

RESUMO

Background: There is a need for effective, safe and well-tolerated pharmacotherapies for patients with major depressive disorder (MDD) who have inadequate response to antidepressant treatments (ADTs). This analysis aimed to summarize the short-term efficacy and safety of adjunctive brexpiprazole in adults with MDD. Research design and methods: A pooled analysis of data from the 6-week, randomized, double-blind treatment phases of four studies of adjunctive brexpiprazole 1-3 mg/day versus placebo in outpatients with MDD and inadequate response to ADTs (n = 1,853). Efficacy was measured by Montgomery-Åsberg Depression Rating Scale (MADRS) scores, and safety by treatment-emergent adverse events (TEAEs). Results: ADT + brexpiprazole 2-3 mg/day showed greater improvement in MADRS Total score from baseline to Week 6 than ADT + placebo (least squares mean difference: -2.15; confidence limits: -2.82, -1.48; p < 0.0001; Cohen's d effect size: 0.33). TEAEs with incidence ≥5% with ADT + brexpiprazole 1-3 mg/day were akathisia (8.0% versus 2.6% with ADT + placebo), headache (5.8% versus 6.0%), and weight increased (5.8% versus 1.6%). Conclusions: Adjunctive brexpiprazole is an efficacious and well-tolerated treatment option for adult patients with MDD and inadequate response to ADTs. Study limitations included a lack of active comparator.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Quinolonas/uso terapêutico , Tiofenos/uso terapêutico , Adulto , Antidepressivos/farmacologia , Transtorno Depressivo Maior/patologia , Feminino , Humanos , Masculino , Quinolonas/farmacologia , Tiofenos/farmacologia , Resultado do Tratamento
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