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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 264: 120287, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34455386

RESUMO

Duvelisib (DUV) is a is a small-molecule with inhibitory action for phosphoinositide 3-kinase (PI3K). It has been recently approved for the effective treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Novel charge transfer complex (CTC) between DUV, as electron donor, with chloranilic acid (CLA), as π electron acceptor has been synthesized and characterized using different spectroscopic and thermogravimetric techniques. UV-visible spectroscopy ascertained the formation of the CTC in different solvents of varying polarity indexes and dielectric constants via formation of new broad absorption band with maximum absorption peak (λmax) in the range of 488-532 nm. The molar absorptivity of the CTC was dependent on the polarity index and dielectric constant of the solvent; the correlation coefficients were 0.9955 and 0.9749, respectively. The stoichiometric ratio of DUV:CLA was 1:1. Electronic spectral analysis was conducted for characterization of the complex in terms of its electronic constants. Computational calculation for atomic charges of energy minimized DUV was conducted and the site of interaction on DUV molecule was assigned. The solid-state CTC of DUV:CLA (1:1) was synthesized, and its structure was characterized by UV-visible, mass, FT-IR, and 1H NMR spectroscopic techniques. Both FT-IR and 1H NMR confirmed that both CT and hydrogen bonding contributed to the molecular composition of the complex. The reaction was adopted as a basis for developing a novel 96-microwell spectrophotometric assay (MW-SPA) for DUV. The assay limits of detection and quantitation were 0.57 and 1.72 µg/well, respectively. The assay was validated and all validation parameters were acceptable. The method was implemented successfully with great precision and accuracy to the analysis of the DUV in its bulk and capsules.


Assuntos
Hidrogênio , Fosfatidilinositol 3-Quinases , Benzoquinonas , Isoquinolinas , Purinas , Espectroscopia de Infravermelho com Transformada de Fourier
2.
J Mol Graph Model ; 109: 108028, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34649146

RESUMO

Owing to the shortage of specific medicines, the global pandemic of COVID-19 caused by SARS-CoV-2 has been the greatest challenge for the science community. Researchers from all over the world developed some drugs which failed to completely suppress the contiguous disease. SARS-CoV-2 main protease (Mpro), an important component in viral pathogenesis, is considered as a prospective drug target to stop SARS-CoV-2 infection. Since identification of phytochemicals with anti-Mpro activity has been carried out to develop the potential drugs against SARS-CoV-2. Therefore, the present study was conducted to screen phytochemicals of Berberis asiatica for anti-SARS-CoV-2 activity. Through text mining, thirty phytochemicals were reported from B. asiatica, of which, three phytochemicals (Berbamine, Oxyacanthine, and Rutin) show high affinity with the SARS-CoV-2 Mpro and exhibited favorable intermolecular interactions with the catalytic residues (His41 and Cys145) and other essential residues. The molecular dynamics simulation showed that Mpro-phytochemical complexes are more stable, less fluctuating, more compact, and moderately extended than the Mpro-X77 (Reference) complex. The number of H-bonds and MMPBSA results also demonstrates that Berbamine, Oxyacanthine, and Rutin are potent Mpro inhibitors having free energy of -20.79, -33.35, and -31.12 kcal mol-1 respectively. The toxicity risk prediction supports all phytochemicals for drug-like and non-toxic nature. From the result, we propose that binding of these phytochemicals could hamper the function of Mpro. This work suggests that selected phytochemicals could be used as novel anti-COVID-19 drug candidates, and might act as novel compounds for in vitro and in vivo study.


Assuntos
Berberis , COVID-19 , Benzilisoquinolinas , Humanos , Isoquinolinas , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases , Rutina , SARS-CoV-2
3.
Invest Ophthalmol Vis Sci ; 62(13): 12, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34661609

RESUMO

Purpose: The purpose of this study was to develop a preclinical compound, ITRI-E-(S)4046, a dual synergistic inhibitor of myosin light chain kinase 4 (MYLK4) and Rho-related protein kinase (ROCK), for reducing intraocular pressure (IOP). Methods: ITRI-E-(S)4046 is an amino-pyrazole derivative with physical and chemical properties suitable for ophthalmic formulation. In vitro kinase inhibition was evaluated using the Kinase-Glo Luminescent Kinase Assays. A comprehensive kinase selectivity analysis of ITRI-E-(S)4046 was performed using the KINOMEscan assay from DiscoverRx. The IOP reduction and tolerability of ITRI-E-(S)4046 were assessed in ocular normotensive rabbits, ocular normotensive non-human primates, and ocular hypertensive rabbits. In vivo studies were conducted to assess drug concentrations in ocular tissue. The adverse ocular effects of rabbit eyes were evaluated following the OECD405 guidelines. Results: ITRI-E-(S)4046 showed highly selective kinase inhibitory activity against ROCK1/2, MYLK4, and mitogen-activated protein kinase kinase kinase 19 (MAP3K19), with high specificity against protein kinase A, G, and C families. In ocular normotensive rabbits and non-human primates, the mean IOP reductions of 0.1% ITRI-E-(S)4046 eye drops were 29.8% and 28.5%, respectively. In hypertonic saline-induced and magnetic beads-induced ocular hypertensive rabbits, the mean IOP reductions of ITRI-E-(S)4046 0.1% eye drops were 46.9% and 22.0%, respectively. ITRI-E-(S)4046 was well tolerated with only temporary and minor signs of hyperemia. Conclusions: ITRI-E-(S)4046 is a novel type of highly specific ROCK1/2 and MYLK4 inhibitor that can reduce IOP in normotensive and hypertensive animal models. It has the potential to become an effective and well-tolerated treatment for glaucoma.


Assuntos
Benzoatos/farmacologia , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Pressão Intraocular/efeitos dos fármacos , Isoquinolinas/farmacologia , Quinase de Cadeia Leve de Miosina/antagonistas & inibidores , Hipertensão Ocular/tratamento farmacológico , Sulfonamidas/farmacologia , beta-Alanina/análogos & derivados , Animais , Modelos Animais de Doenças , Humanos , Macaca , Masculino , Hipertensão Ocular/fisiopatologia , Coelhos , Tonometria Ocular , beta-Alanina/farmacologia , Quinases Associadas a rho/antagonistas & inibidores
4.
Molecules ; 26(19)2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34641558

RESUMO

Peroxisome proliferator-activated receptors (PPARs) play crucial roles in glucose and lipid metabolism and inflammation. Sanguinarine is a natural product that is isolated from Sanguinaria Canadensis, a potential therapeutic agent for intervention in chronic diseases. In this study, biochemical and cell-based promoter-reporter gene assays revealed that sanguinarine activated both PPARα and PPARγ, and enhanced their transcriptional activity; thus, sanguinarine was identified as a dual agonist of PPARα/γ. Similar to fenofibrate, sanguinarine upregulates the expression of PPARα-target genes in hepatocytes. Sanguinarine also modulates the expression of key PPARγ-target genes and promotes adipocyte differentiation, but with a lower adipogenic activity compared with rosiglitazone. We report the crystal structure of sanguinarine bound to PPARα, which reveals a unique ligand-binding mode of sanguinarine, dissimilar to the classic Y-shaped binding pocket, which may represent a new pharmacophore that can be optimized for selectively targeting PPARα. Further structural and functional studies uncover the molecular basis for the selectivity of sanguinarine toward PPARα/γ among all three PPARs. In summary, our study identifies a PPARα/γ dual agonist with a unique ligand-binding mode, and provides a promising and viable novel template for the design of dual-targeting PPARs ligands.


Assuntos
Benzofenantridinas/química , Isoquinolinas/química , PPAR alfa/agonistas , PPAR gama/agonistas , Adipogenia/efeitos dos fármacos , Adipogenia/genética , Animais , Benzofenantridinas/farmacologia , Cristalografia por Raios X , Regulação da Expressão Gênica , Genes Reporter , Células HEK293 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Isoquinolinas/farmacologia , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Relação Estrutura-Atividade
5.
Adv Ther ; 38(10): 5345-5360, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34523074

RESUMO

INTRODUCTION: This integrated phase 3 analysis examined efficacy and cardiovascular safety for roxadustat vs erythropoiesis-stimulating agents (ESAs) in dialysis-dependent patients. METHODS: Efficacy and safety results from four phase 3, randomized, open-label studies comparing roxadustat to ESAs (PYRENEES, SIERRAS, HIMALAYAS, ROCKIES) in dialysis-dependent patients with anemia of chronic kidney disease (CKD) were evaluated by study, pooled population and in two subgroups: incident dialysis and stable dialysis. The primary efficacy endpoint per study was hemoglobin change from baseline (CFB) to weeks 28-36 using least-squares mean difference (LSMD) without rescue therapy. Pooled safety endpoints included time to major adverse cardiovascular event (MACE; myocardial infarction, stroke, and all-cause mortality [ACM]) and MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization), ACM, and treatment-emergent adverse events (TEAEs). MACE and MACE+ were evaluated for non-inferiority at 1.8 and 1.3 margins using hazard ratios (HRs) and 95% confidence intervals (CIs). TEAEs were descriptively summarized. RESULTS: In total, 4714 patients were randomized (2354 roxadustat; 2360 ESA). Hemoglobin CFB to weeks 28-36 achieved non-inferiority for roxadustat vs ESA in each study. Roxadustat was non-inferior to ESA for risks for MACE and MACE+ in the entire cohort (MACE: HR 1.09, 95% CI 0.95-1.26; MACE+ : HR 0.98, 95% CI 0.86-1.11) and similar to the incident dialysis and stable dialysis subgroups; ACM results were consistent with MACE and MACE+ (HR 1.13, 95% CI 0.95-1.34). TEAEs were generally comparable between groups. CONCLUSION: Roxadustat improved hemoglobin similarly to ESA while demonstrating comparable cardiovascular and overall safety profiles in a wide spectrum of dialysis-dependent patients with anemia of CKD. Roxadustat represents an oral alternative to ESAs for achieving a target hemoglobin for anemia of CKD in dialysis-dependent patients.


Assuntos
Eritropoetina , Hematínicos , Insuficiência Renal Crônica , Glicina/efeitos adversos , Glicina/análogos & derivados , Hemoglobinas , Humanos , Isoquinolinas/efeitos adversos , Diálise Renal , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia
6.
Adv Ther ; 38(10): 5361-5380, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34537926

RESUMO

INTRODUCTION: Roxadustat is an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for the treatment of anemia of chronic kidney disease (CKD). This European, phase 3, randomized, open-label, active-controlled study investigated efficacy and safety of roxadustat in patients with end-stage kidney disease on dialysis for at least 4 months. METHODS: Patients were randomized to switch from an erythropoiesis-stimulating agent (ESA) (epoetin alfa or darbepoetin alfa) to roxadustat three times/week or to continue their previous ESA. Roxadustat and ESA doses were adjusted to maintain hemoglobin within 10.0-12.0 g/dL during the treatment period (day 1 up to 52-104 weeks). Primary endpoints were hemoglobin change from baseline (CFB) to the average of weeks 28-36 without rescue therapy and hemoglobin CFB to the average of weeks 28-52 regardless of rescue therapy. Treatment-emergent adverse events (TEAEs) were assessed descriptively. RESULTS: Of 1081 screened patients, 836 were randomized and received treatment (roxadustat, n = 415; ESA, n = 421). The least squares means (95% CI) of the treatment difference (roxadustat - ESA) for hemoglobin CFB to weeks 28-36 (without rescue therapy) and CFB to weeks 28-52 (regardless of rescue therapy) were 0.235 (0.132, 0.339) g/dL and 0.171 (0.082, 0.261) g/dL, respectively, demonstrating non-inferiority of roxadustat to ESA (non-inferiority margin of - 0.75 g/dL). The proportions of patients who achieved target hemoglobin without rescue therapy during weeks 28-36 were 84.2% (roxadustat) and 82.4% (ESA). Roxadustat was superior to ESA in decreasing LDL cholesterol from baseline to the average of weeks 12-28. Serious TEAEs occurred in 50.7% (roxadustat) and 45.0% (ESA) of patients. Common TEAEs in both treatment groups included hypertension, arteriovenous fistula thrombosis, headache, and diarrhea. CONCLUSION: Roxadustat was non-inferior to ESAs in maintaining hemoglobin levels in this cohort of patients with anemia of CKD on dialysis for at least 4 months who were previously treated with ESAs. Observed TEAEs were consistent with previous studies.


Assuntos
Anemia , Hematínicos , Falência Renal Crônica , Insuficiência Renal Crônica , Anemia/tratamento farmacológico , Anemia/etiologia , Glicina/análogos & derivados , Hematínicos/uso terapêutico , Hemoglobinas/análise , Humanos , Isoquinolinas , Diálise Renal , Insuficiência Renal Crônica/complicações , Projetos de Pesquisa
7.
J Org Chem ; 86(19): 13420-13445, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34546053

RESUMO

An efficient diastereoselective route is developed to get access to novel spiropyrrolo[1,2-a]isoquinoline-oxindole skeletons by a one-pot three-component [3 + 2] cycloaddition reaction of (Z)-5-arylidene-1,3-thiazolidine-2,4-diones, isatin derivatives, and 1,2,3,4-tetrahydroisoquinoline (THIQ). Interestingly, the regioselectivity of the reaction is both temperature- and solvent-dependent, allowing the synthesis of two regioisomeric endo-dispiropyrrolo[2,1-a]isoquinolineoxindoles in excellent yield. Unprecedentedly, each isomeric dispiropyrrolo[2,1-a]isoquinolineoxindole endured retro-1,3-dipolar cycloaddition/recycloaddition reactions under thermal or catalytic conditions to regenerate the corresponding regioisomeric counterpart. In addition, DFT calculations were performed at the M062X/6-31++g(d,p) level of theory to unravel the origin of the reversal of regioselectivity and endo-stereoselectivity of the title 1,3-dipolar cycloaddition reactions. Upon treatment of Isatin, THIQ with (Z)-4-arylidene-5-thioxo-thiazolidin-2-ones as dipolarophiles, unusual rhodanine analogues were formed, along with smaller amounts of a dispirooxindole-piperazine. The structure and the relative configuration of these N-heterocycles were unambiguously assigned by spectroscopic techniques and confirmed by four single-crystal structures. In vitro and in vivo studies reveal that the novel rhodanine derivatives exert antidiabetic activity. The binding affinity with the active site of the enzyme α-amylase was studied by molecular docking. Furthermore, the bioavailability assessed through virtual ADME parameters (Absorption, Distribution, Metabolism, Elimination pharmacokinetics) and the excellent fit with the Lipinski and Veber rules predict good drug-likeness properties for a bromo-substituted 2-sulfanylidene-1,3-thiazolidin-4-one.


Assuntos
Rodanina , Reação de Cicloadição , Hipoglicemiantes , Isoquinolinas , Simulação de Acoplamento Molecular
8.
FASEB J ; 35(10): e21850, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34569654

RESUMO

Children with hypoplastic lung disease associated with congenital diaphragmatic hernia (CDH) continue to suffer significant morbidity and mortality secondary to progressive pulmonary disease. Recently published work from our lab demonstrated the potential of Roxadustat (FG-4592), a prolyl hydroxylase inhibitor, as a treatment for CDH-associated pulmonary hypoplasia. Treatment with Roxadustat led to significantly accelerated compensatory lung growth (CLG) through downregulation of pigment epithelium-derived factor (PEDF), an anti-angiogenic factor, rather than upregulation of vascular endothelial growth factor (VEGF). PEDF and its role in pulmonary development is a largely unexplored field. In this study, we sought to further evaluate the role of PEDF in accelerating CLG. PEDF-deficient mice demonstrated significantly increased lung volume, total lung capacity, and alveolarization compared to wild type controls following left pneumonectomy without increased VEGF expression. Furthermore, Roxadustat administration in PEDF-deficient mice did not further accelerate CLG. Human microvascular endothelial lung cells (HMVEC-L) and human pulmonary alveolar epithelial cells (HPAEC) similarly demonstrated decreased PEDF expression with Roxadustat administration. Additionally, downregulation of PEDF in Roxadustat-treated HMVEC-L and HPAEC, a previously unreported finding, speaks to the potential translatability of Roxadustat from small animal studies. Taken together, these findings further suggest that PEDF downregulation is the primary mechanism by which Roxadustat accelerates CLG. More importantly, these data highlight the critical role PEDF may have in pulmonary growth and development, a previously unexplored field.


Assuntos
Células Endoteliais/citologia , Células Epiteliais/citologia , Proteínas do Olho/fisiologia , Glicina/análogos & derivados , Isoquinolinas/farmacologia , Pulmão/crescimento & desenvolvimento , Fatores de Crescimento Neural/fisiologia , Serpinas/fisiologia , Animais , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Glicina/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
10.
Mol Cells ; 44(9): 688-695, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34518443

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has become a global health concern. Various SARS-CoV-2 vaccines have been developed and are being used for vaccination worldwide. However, no therapeutic agents against coronavirus disease 2019 (COVID-19) have been developed so far; therefore, new therapeutic agents are urgently needed. In the present study, we evaluated several hepatitis C virus direct-acting antivirals as potential candidates for drug repurposing against COVID-19. Theses include asunaprevir (a protease inhibitor), daclatasvir (an NS5A inhibitor), and sofosbuvir (an RNA polymerase inhibitor). We found that asunaprevir, but not sofosbuvir and daclatasvir, markedly inhibited SARS-CoV-2-induced cytopathic effects in Vero E6 cells. Both RNA and protein levels of SARS-CoV-2 were significantly decreased by treatment with asunaprevir. Moreover, asunaprevir profoundly decreased virion release from SARS-CoV-2-infected cells. A pseudoparticle entry assay revealed that asunaprevir blocked SARS-CoV-2 infection at the binding step of the viral life cycle. Furthermore, asunaprevir inhibited SARS-CoV-2 propagation in human lung Calu-3 cells. Collectively, we found that asunaprevir displays broad-spectrum antiviral activity and therefore might be worth developing as a new drug repurposing candidate for COVID-19.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Isoquinolinas/farmacologia , SARS-CoV-2/crescimento & desenvolvimento , Sulfonamidas/farmacologia , Inibidores de Protease Viral/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Carbamatos/farmacologia , Linhagem Celular , Chlorocebus aethiops , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Células HEK293 , Hepacivirus/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Pirrolidinas/farmacologia , SARS-CoV-2/efeitos dos fármacos , Sofosbuvir/farmacologia , Valina/análogos & derivados , Valina/farmacologia , Células Vero , Proteínas não Estruturais Virais/antagonistas & inibidores
11.
Sci Rep ; 11(1): 17997, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504274

RESUMO

Nucleotide excision repair (NER) and cell cycle checkpoints impact the ability of the anti-cancer drug cisplatin to inhibit cell proliferation and induce cell death. Genetic studies have shown that both NER and cell cycle progression are impacted by the circadian clock, which has emerged as a novel pharmacological target for the treatment of various disease states. In this study, cultured human cell lines were treated with combinations of cisplatin and the circadian clock modulating compounds KS15 and SR8278, which enhance circadian clock transcriptional output by inhibiting the activities of the cryptochrome and REV-ERB proteins, respectively. Treatment of cells with KS15 and SR8278 protected cells against the anti-proliferative effects of cisplatin and increased the expression of NER factor XPA and cell cycle regulators Wee1 and p21 at the mRNA and protein level. Correlated with these molecular changes, KS15 and SR8278 treatment resulted in fewer unrepaired cisplatin-DNA adducts in genomic DNA and a higher fraction of cells in the G1 phase of the cell cycle. Thus, the use of pharmacological agents targeting the circadian clock could be a novel approach to modulate the responses of normal and cancer cells to cisplatin chemotherapy regimens.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Criptocromos/antagonistas & inibidores , Adutos de DNA/efeitos dos fármacos , Adutos de DNA/farmacologia , Reparo do DNA/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Células A549 , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relógios Circadianos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células HaCaT , Humanos , Isoquinolinas/farmacologia , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tiofenos/farmacologia , Proteína de Xeroderma Pigmentoso Grupo A/metabolismo
12.
Poult Sci ; 100(11): 101423, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34534853

RESUMO

Spotty liver disease (SLD) is a serious condition affecting extensively housed laying hens. The causative bacterium was described in 2015 and characterized in 2016 and named Campylobacter hepaticus. Antibiotics are the only tool currently available to combat SLD. However, antimicrobial resistance has already been detected, so finding therapeutic alternatives is imperative. Isoquinoline alkaloids (IQA), such as sanguinarine and chelerythrine, have been shown to have immunomodulatory effects. It has been hypothesized that IQA could ameliorate some of the deleterious effects of SLD. This study aimed to address that hypothesis in an experimental disease induction model. Birds were fed with diets containing 2 different doses of an IQA containing product, 100 mg of product/kg of feed (0.5 ppm of sanguinarine) and 200 mg of product/kg of feed (1.0 ppm of sanguinarine). Two additional groups remained untreated (a challenged positive control and an unchallenged negative control). After 4 wk of treatment, birds from all groups except the negative control group were exposed to C. hepaticus strain HV10. The IQA treated groups showed a reduction in the number of miliary lesions on the liver surface and reduced lesion scores compared with untreated hens. A significant reduction of egg mass was detected 6 d after exposure to C. hepaticus in the untreated group (P = 0.02). However, there was not a significant drop in egg-mass in the IQA groups, especially those fed with a high dose of IQA (P = 0.93). IQA supplementation did not produce significant changes in intestinal villus height and crypt depth but did result in a significant reduction in the proinflammatory cytokine, interleukin-8, in the blood (P < 0.01). Microbiota analysis showed that IQA treatment did not alter the alpha diversity of the cecal microbiota but did produce changes in the phylogenetic structure, with the higher dose of IQA increasing the Firmicutes/Bacteroidetes ratio. Other minor changes in production indicators included an increase in feed consumption (P < 0.01) and an increase in body weight of the treated hens (P < 0.0001). The present study has demonstrated that IQA confers some protection of chickens from the impact of SLD.


Assuntos
Infecções por Campylobacter , Hepatopatias , Doenças das Aves Domésticas , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Campylobacter , Infecções por Campylobacter/veterinária , Galinhas , Dieta/veterinária , Suplementos Nutricionais , Feminino , Isoquinolinas , Hepatopatias/veterinária , Filogenia , Doenças das Aves Domésticas/prevenção & controle
13.
Bioorg Chem ; 115: 105265, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34426160

RESUMO

In spite of possessing a wide range of pharmacological properties the anti-inflammatory activities of isoquinolin-1(2H)-ones were rarely known or explored earlier. PDE4 inhibitors on the other hand in addition to their usefulness in treating inflammatory diseases have been suggested to attenuate the cytokine storm in COVID-19 especially TNF-α. In our effort, a new class of isoquinolin-1(2H)-ones derivatives containing an aminosulfonyl moiety were designed and explored as potential inhibitors of PDE4. Accordingly, for the first time a CuCl2-catalyzed inexpensive, faster and ligand/additive free approach has been developed for the synthesis of these predesigned isoquinolin-1(2H)-one derivatives via the coupling-cyclization strategy. Thus, the CuCl2-catalyzed reaction of 2-iodobenzamides with appropriate terminal alkynes proceeded with high chemo and regioselectivity affording the desired compounds in 77-84% yield within 1-1.5 h. The methodology also afforded simpler isoquinolin-1(2H)-ones devoid of aminosulfonyl moiety showing a broader generality and scope of this approach. Several of the synthesized compounds especially 3c, 3k and 3s showed impressive inhibition (83-90%) of PDE4B when tested at 10 µM in vitro whereas compounds devoid of aminosulfonyl moiety was found to be less active. In spite of high inhibition showed at 10 µM these compounds did not show proper concertation dependent inhibition below 1 µM that was reflected in their IC50 values e.g. 2.43 ± 0.32, 3.26 ± 0.24 and 3.63 ± 0.80 µM for 3k, 3o and 3s respectively. The anti-inflammatory potential of these compounds was indicated by their TNF-α inhibition (60-50% at 10 µM). The in silico docking studies of these molecules suggested good interactions with PDE4B and selective inhibition of PDE4B by 3k over PDE4D that was supported by in vitro assay results. These observations together with the favorable ADME and safety predicted for 3kin silico not only suggested 3k as an interesting hit molecule for further studies but also reveal the first example of isoquinolin-1(2H)-one based inhibitor of PDE4B.


Assuntos
Anti-Inflamatórios/química , Cobre/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Isoquinolinas/química , Inibidores da Fosfodiesterase 4/química , Animais , Anti-Inflamatórios/síntese química , Catálise , Ciclização , Ensaios Enzimáticos , Humanos , Isoquinolinas/síntese química , Camundongos , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Células RAW 264.7 , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores
14.
Drug Alcohol Depend ; 227: 108930, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34358767

RESUMO

BACKGROUND: The present study investigated the effects of the dual orexin receptor antagonist (DORA) almorexant, a sleep-modulating drug, on the sleep-disrupting effects of methamphetamine in adult rhesus monkeys. METHODS: Monkeys were fitted with primate collars to which actigraphy monitors were attached. To determine the effects of methamphetamine on daytime activity and sleep-like parameters, monkeys were given acute injections of vehicle or methamphetamine (0.03, 0.1 or 0.3 mg/kg, i.m.) in the morning (9:00 h) (n = 4 males). We then determined the ability of almorexant to alter the daytime and/or sleep-like effects of the largest (effective) dose of methamphetamine. Vehicle or almorexant (1, 3 or 10 mg/kg, i.m.) were administered in the evening (16:30 h, 1.5 h before "lights off") following morning (9:00 h) administration of methamphetamine (0.3 mg/kg, i.m.), or as a pretreatment (8:30 h) before methamphetamine injections (9:00 h) (n = 4 males). The ability of almorexant (10 mg/kg) to improve sleep-like behaviors also was assessed in a group of monkeys quantitatively identified with short-duration sleep (n = 2 males, 2 females). RESULTS: Morning methamphetamine administration dose-dependently impaired sleep in rhesus monkeys (0.3 mg/kg significantly increased sleep latency and decreased sleep efficiency). Administration of almorexant, both as a pretreatment or as an evening treatment, improved methamphetamine-induced sleep impairment in a dose dependent manner. Morning pretreatment with almorexant also blocked the daytime stimulant effects of methamphetamine. Evening, but not morning, treatment with almorexant in a group of monkeys with baseline short-duration sleep improved sleep measures. CONCLUSIONS: Our findings indicate that orexin receptor systems are involved in methamphetamine-induced hyperarousal and sleep disruption.


Assuntos
Metanfetamina , Acetamidas , Animais , Feminino , Isoquinolinas , Macaca mulatta , Masculino , Metanfetamina/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Sono
16.
Chemistry ; 27(60): 14841-14845, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34398497

RESUMO

An asymmetric three-component 1,3-dipolar cycloaddition of 3,4-dihydroisoquinolines, bromoacetates and α,ß-unsaturated pyrazole amide is realized by using a chiral N,N'-dioxide-Y(OTf)3 complex as the catalyst. The process includes a base-promoted formation of dihydroisoquinolium ylides in situ, and a chiral Lewis acid-catalyzed asymmetric [3+2] cycloaddition with α,ß-unsaturated pyrazole amides. A series of hexahydropyrrolo-isoquinolines are obtained in moderate to good yields with excellent diastereo- and enantioselectivities.


Assuntos
Isoquinolinas , Ácidos de Lewis , Catálise , Reação de Cicloadição , Estereoisomerismo
17.
Int J Mol Sci ; 22(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34445223

RESUMO

Increasing evidence suggests that systemic inflammation triggers a neuroinflammatory response that involves sustained microglia activation. This response has deleterious consequences on memory and learning capability in experimental animal models and in patients. However, the mechanisms connecting systemic inflammation and microglia activation remain poorly understood. Here, we identify the autotaxin (ATX)/lysophosphatidic acid (LPA)/LPA-receptor axis as a potential pharmacological target to modulate the LPS-mediated neuroinflammatory response in vitro (the murine BV-2 microglia cell line) and in vivo (C57BL/6J mice receiving a single i.p. LPS injection). In LPS-stimulated (20 ng/mL) BV-2 cells, we observed increased phosphorylation of transcription factors (STAT1, p65, and c-Jun) that are known to induce a proinflammatory microglia phenotype. LPS upregulated ATX, TLR4, and COX2 expression, amplified NO production, increased neurotoxicity of microglia conditioned medium, and augmented cyto-/chemokine concentrations in the cellular supernatants. PF8380 (a type I ATX inhibitor, used at 10 and 1 µM) and AS2717638 (an LPA5 antagonist, used at 1 and 0.1 µM) attenuated these proinflammatory responses, at non-toxic concentrations, in BV-2 cells. In vivo, we demonstrate accumulation of PF8380 in the mouse brain and an accompanying decrease in LPA concentrations. In vivo, co-injection of LPS (5 mg/kg body weight) and PF8380 (30 mg/kg body weight), or LPS/AS2717638 (10 mg/kg body weight), significantly attenuated LPS-induced iNOS, TNFα, IL-1ß, IL-6, and CXCL2 mRNA expression in the mouse brain. On the protein level, PF8380 and AS2717638 significantly reduced TLR4, Iba1, GFAP and COX2 expression, as compared to LPS-only injected animals. In terms of the communication between systemic inflammation and neuroinflammation, both inhibitors significantly attenuated LPS-mediated systemic TNFα and IL-6 synthesis, while IL-1ß was only reduced by PF8380. Inhibition of ATX and LPA5 may thus provide an opportunity to protect the brain from the toxic effects that are provoked by systemic endotoxemia.


Assuntos
Benzoxazóis/farmacologia , Encéfalo/metabolismo , Endotoxemia , Isoquinolinas/farmacologia , Lipopolissacarídeos/toxicidade , Microglia/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Piperazinas/farmacologia , Piperidinas/farmacologia , Receptores de Ácidos Lisofosfatídicos , Animais , Encéfalo/patologia , Linhagem Celular , Modelos Animais de Doenças , Endotoxemia/induzido quimicamente , Endotoxemia/metabolismo , Endotoxemia/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Microglia/patologia , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Ácidos Lisofosfatídicos/metabolismo
18.
Biomed Res Int ; 2021: 3689829, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34409102

RESUMO

Objective: There is still no effective treatment of neuropathic pain. Sanguinarine is a natural plant medicine with anti-inflammatory effects, but its effect on neuropathic pain remains unclear. This study was aimed at investigating the potential of sanguinarine to attenuate neuropathic pain. Methods: Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Rats were randomly divided into several groups: sham, CCI, CCI+SG (1.00 mg/kg), CCI+SG (2.50 mg/kg), and CCI+SG (6.25 mg/kg). SG was injected intraperitoneally from the day of surgery every three days. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were recorded before surgery and on days 1, 3, 7, and 14 after surgery. The microglia in the spinal dorsal horn were examined by immunofluorescence. p38 MAPK expression in the spinal dorsal horn was detected by PCR and Western blot analysis. Cytokine levels in the spinal dorsal horn were measured by ELISA. Results: MWT and TWL were significantly reduced in the CCI group, but sanguinarine recovered MWT and TWL in the CCI group. In addition, sanguinarine inhibited the activation of microglia and decreased the expression of p-p38 and TNF-α, IL-1ß, and IL-6 in the spinal dorsal horn of the CCI group in a dose-dependent manner. Conclusions: Our results suggest that sanguinarine can attenuate neuropathic pain via inhibiting the activation of microglia and the activation of the p38 MAPK signaling pathway.


Assuntos
Benzofenantridinas/administração & dosagem , Citocinas/metabolismo , Isoquinolinas/administração & dosagem , Nervo Isquiático/lesões , Ciática/tratamento farmacológico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Benzofenantridinas/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Injeções Intraperitoneais , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Isoquinolinas/farmacologia , Masculino , Fosforilação/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo , Ciática/metabolismo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismo
19.
Fitoterapia ; 154: 105021, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34403776

RESUMO

Bark of Phellodendron chinense Schneid. (Rutaceae), called "Huang Bai" in China, is one of the 50 most used Chinese medicines in clinical practice. In this paper, a new isoquinoline alkaloid glycoside was isolated from P. chinense, and its structure was elucidated using spectroscopic method. The compound was eventually identified as (1S, 3"S)-1, 2, 3, 4-tetrahydro-7-hydroxy-1-[(4-hydroxybenzyl) methyl]-2-methyl-8-O-isoquinolinyl-[3-hydroxy-3-methylglutaryl]-ß-D-glucopyranoside and named as Phellodendronoside A (PDA). The results of molecular docking showed that PDA could stably bind to an extracellular signal-regulated kinase (ERK), stress-activated protein kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK) proteins that are closely related to inflammation. Further, the anti-inflammatory activity of PDA was evaluated using the lipopolysaccharide (LPS) induced RAW264.7 macrophage model. We observed that PDA can effectively reduce the levels of nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and decrease the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, we found that PDA inhibits the activation of ERK, JNK and p38MAPK proteins in the MAPK signaling pathway. Collectively, the present study demonstrates that PDA has excellent anti-inflammatory effect in vitro by inhibiting the overproduction of pro-inflammatory mediators, and its mechanism of action involves suppressing the activation of MAPK pathways, suggesting that PDA may be a potential agent for the treatment of inflammatory illness.


Assuntos
Alcaloides/farmacologia , Anti-Inflamatórios/farmacologia , Glicosídeos/farmacologia , Isoquinolinas/farmacologia , Phellodendron/química , Alcaloides/isolamento & purificação , Animais , Anti-Inflamatórios/isolamento & purificação , Medicamentos de Ervas Chinesas , Glicosídeos/isolamento & purificação , Isoquinolinas/isolamento & purificação , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Casca de Planta/química , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
20.
Zhongguo Zhong Yao Za Zhi ; 46(14): 3504-3513, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34402272

RESUMO

Coptidis Rhizoma is a common Chinese medicinal in clinical practice,with the effects of clearing heat,drying dampness,purging fire,and removing toxin. All the medicinal plants of Coptis can be used for clinical treatment,but some species are endangered due to resource destruction and difficulty in planting. The dominant medicinal components in Coptidis Rhizoma are isoquinoline alkaloids. There are various methods for the analysis and detection of alkaloids,such as LC-MS,HPLC,and TLC,among which LC-MS is the most widely applied. Different plants of Coptis vary in the kind and content of alkaloids. C. chinensis,C. deltoidea,C. teeta,C. chinensis var. brevisepala,C. omeiensis,C. quinquefolia,and C. quinquesecta mainly contain berberine,palmatine,coptisine,jatrorrhizine,and columbamine,five effective alkaloid components. Plant isoquinoline alkaloids( PIAs) have strong pharmacological activity but are difficult to prepare. The application of synthetic biology of PIAs will be helpful for the clinical application of PIAs. This paper reviews the research progress on biological resources of Coptis species and structures of alkaloids as well as analysis methods and synthetic biology for isoquinoline alkaloids in the medicinal plants of Coptis in recent years,which will facilitate the protection of Coptis medicinal resources and the application and development of alkaloids.


Assuntos
Alcaloides , Alcaloides de Berberina , Berberina , Coptis , Medicamentos de Ervas Chinesas , Isoquinolinas , Rizoma
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