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1.
J Agric Food Chem ; 68(10): 3017-3025, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32059105

RESUMO

Chlorsulfuron has been applied in wheat fields as a recognized herbicide worldwide, yet it was officially banned in China since 2014 for its soil persistence problem. On the basis of our previous research that 5-dimethylamino distinctively accelerated degradation rate in soils, a modified amino moiety (Ia-c) and monosubstituted amino group (Id-e) were introduced onto the fifth position of the benzene ring in sulfonylurea structures, as well as heterocyclic amino substituents (If-g) to seek a suitable soil degradation rate during such an in situ crop rotation system. Referring to the biological data and ScAHAS inhibition and ScAHAS docking results, they turned out to be AHAS inhibitors with high potent herbicidal activities. The various influence on soil degradation rate along with crop safety indicated that different substituents on the fifth position have exerted an apparent impact. Their united study of structure-activity-safety-degradation relationship has great potential to provide valuable information for further development of eco-friendly agrochemicals.


Assuntos
Acetolactato Sintase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Herbicidas/farmacologia , Proteínas de Plantas/antagonistas & inibidores , Poluentes do Solo/química , Compostos de Sulfonilureia/farmacologia , Acetolactato Sintase/metabolismo , Amaranthus/efeitos dos fármacos , Amaranthus/enzimologia , Brassica/efeitos dos fármacos , Brassica/enzimologia , Inibidores Enzimáticos/química , Herbicidas/química , Cinética , Modelos Moleculares , Proteínas de Plantas/metabolismo , Poluentes do Solo/farmacologia , Relação Estrutura-Atividade , Compostos de Sulfonilureia/química
2.
J Agric Food Chem ; 68(3): 826-837, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31895558

RESUMO

A total of five strains of nicosulfuron-degrading bacteria were isolated from a continuously cultivated microbial consortium using culturomics. Among them, a novel Pseudomonas strain, LAM1902, with the highest degradation efficiency was investigated in detail. The characteristics of nicosulfuron-degradation by LAM1902 were investigated and optimized by response surface analysis. Furthermore, non-targeted metabolomic analysis of extracellular and intracellular biodegradation of nicosulfuron by LAM1902 was carried out by liquid chromatography/mass spectroscopy (LC-MS) and gas chromatography-time-of-flight/mass spectroscopy (GC-TOF/MS). It was found that nicosulfuron was degraded by LAM1902 mainly via breaking the sulfonylurea bridge, and this degradation might be attributed to oxalate accumulation. The results of GC-TOF/MS also showed that the intracellular degradation of nicosulfuron did not occur. However, nicosulfuron exerted a significant influence on the metabolism of inositol phosphate, pyrimidine, arginine/proline, glyoxylate, and dicarboxylate metabolism and streptomycin biosynthesis. The changes of myo-inositol, trehalose, and 3-aminoisobutanoic acid were proposed as a mechanism of self-protection against nicosulfuron stress.


Assuntos
Herbicidas/metabolismo , Pseudomonas/metabolismo , Piridinas/metabolismo , Compostos de Sulfonilureia/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biodegradação Ambiental , Herbicidas/química , Concentração de Íons de Hidrogênio , Metabolômica , Filogenia , Pseudomonas/classificação , Pseudomonas/genética , Pseudomonas/isolamento & purificação , Piridinas/química , Compostos de Sulfonilureia/química
3.
Sci Total Environ ; 702: 134767, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31726335

RESUMO

The aim of the present study was to investigate the sorption of atrazine and nicosulfuron onto several experimentally produced biochars, as well as to understand the influence of biochar structure on sorption mechanisms. Nine biochars were generated by pyrolyzing peanut shell at 300, 450, or 600 °C and exposing samples to each of the several deashing treatments: none, water or HCl. The sorption of atrazine and nicosulfuron by the nine biochars were evaluated. Biochars were characterized via elemental analyzer, BET-N2 surface area, FTIR and XPS. Three kinetic models were used to fit the sorption kinetics data and both the Freundlich and dual-mode models described the sorption isotherms well. All the biochar samples exhibited high sorption affinity for both atrazine and nicosulfuron. The sorption mechanisms of the biochar included hydrophobic partition, π-π electron donor-acceptor interactions, H-bonding, and pore-filling mechanism, and these mechanisms were dependent on both the degree of biochar carbonization and the concentration of atrazine or nicosulfuron. Ash could bind to atrazine and nicosulfuron by specific interactions but played a negative role in the sorption, especially on high pyrolyzing temperature biochars. These results will facilitate the production of efficient and cheap adsorbents for reducing the risk of atrazine and nicosulfuron.


Assuntos
Carvão Vegetal/química , Piridinas/química , Compostos de Sulfonilureia/química , Poluentes Químicos da Água/química , Adsorção , Arachis , Atrazina
4.
Molecules ; 24(20)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640214

RESUMO

A multidrug crystal based on drug combinations was synthesized by the solvent evaporation method. This multicomponent crystal consisted of antidiabetic drugs Glimepiride (Gli) and Metformin (Met), which was performed by single crystal X-ray structure analysis. The results showed an enhancement of the pharmaceutical properties such as lower hygroscopicity and greater accelerated stability than the parent drug Met, and a higher solubility and dissolution rate than Gli.


Assuntos
Hipoglicemiantes/síntese química , Metformina/química , Compostos de Sulfonilureia/química , Química Farmacêutica , Cristalografia por Raios X , Combinação de Medicamentos , Hipoglicemiantes/química , Solubilidade , Molhabilidade
5.
Int J Nanomedicine ; 14: 6287-6296, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496686

RESUMO

Purpose: We aimed to enhance the solubility, dissolution rate, oral bioavailability, and α-glucosidase inhibition of glimepiride (Glm) by fabricating its nanosuspension using a precipitation-ultrasonication approach. Methods: Glm nanosuspensions were fabricated using optimized processing conditions. Characterization of Glm was performed using Malvern Zetasizer, scanning electron microscopy, transmission electron microscopy, differential scanning calorimetry, and powder X-ray diffraction. Minimum particle size and polydispersity index (PDI) values were found to be 152.4±2.42 nm and 0.23±0.01, respectively, using hydroxypropyl methylcellulose: 6 cPs, 1% w/v, polyvinylpyrrolidone K30 1% w/v, and sodium lauryl sulfate 0.12% w/v, keeping ultrasonication power input at 400 W, with 15 minutes' processing at 3-second pauses. In vivo oral bioavailability was assessed using rabbits as a model. Results: The saturation solubility of the Glm nanosuspensions was substantially enhanced 3.14-fold and 5.77-fold compared to unprocessed drug in stabilizer solution and unprocessed active pharmaceutical ingredient. Also, the dissolution rate of the nanosuspensions ws substantially boosted when compared to the marketed formulation and unprocessed drug candidate. The results showed that >85% of Glm nanosuspensions dissolved in the first 10 minutes compared to 10.17% of unprocessed Glm), 42.19% of microsuspensions, and 19.94% of marketed tablets. In-vivo studies conducted in animals, i.e. rabbits, demonstrated that maximum concentration and AUC0-24 with oral dosing were twofold (5 mg/kg) and 1.74-fold (2.5 mg/kg) and 1.80-fold (5 mg/kg) and 1.63-fold (2.5 mg/kg), respectively, and compared with the unprocessed drug formulation. In-vitro α-glucosidase inhibition results showed that fabricated nanosuspensions had a pronounced effect compared to unprocessed drug. Conclusion: The optimized batch fabricated by ultrasonication-assisted precipitation can be useful in boosting oral bioavailability, which may be accredited to enhanced solubility and dissolution rate of Glm, ultimately resulting in its faster rate of absorption due to nanonization.


Assuntos
Precipitação Química , Inibidores de Glicosídeo Hidrolases/farmacologia , Nanopartículas/química , Compostos de Sulfonilureia/farmacologia , Ultrassom , alfa-Glucosidases/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Derivados da Hipromelose/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Coelhos , Solubilidade , Compostos de Sulfonilureia/administração & dosagem , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacocinética , Suspensões , Difração de Raios X
6.
Eur J Pharmacol ; 861: 172598, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31408647

RESUMO

Type 2 diabetes mellitus (T2DM) is associated with a higher risk of cancer and cancer-related mortality. Increased blood glucose and insulin levels in T2DM patients may be, at least in part, responsible for this effect. Indeed, lowering glucose and/or insulin levels pharmacologically appears to reduce cancer risk and progression, as has been demonstrated for the biguanide metformin in observational studies. Studies investigating the influence of sulfonylurea derivatives (SUs) on cancer risk have provided conflicting results, partly due to comparisons with metformin. Furthermore, little attention has been paid to within-class differences in systemic and off-target effects of the SUs. The aim of this systematic review is to discuss the available preclinical and clinical evidence on how the different SUs influence cancer development and risk. Databases including PubMed, Cochrane, Database of Abstracts on Reviews and Effectiveness, and trial registries were systematically searched for available clinical and preclinical evidence on within-class differences of SUs and cancer risk. The overall preclinical and clinical evidence suggest that the influence of SUs on cancer risk in T2DM patients differs between the various SUs. Potential mechanisms include differing affinities for the sulfonylurea receptors and thus differential systemic insulin exposure and off-target anti-cancer effects mediated for example through potassium transporters and drug export pumps. Preclinical evidence supports potential anti-cancer effects of SUs, which are of interest for further studies and potentially repurposing of SUs. At this time, the evidence on differences in cancer risk between SUs is not strong enough to guide clinical decision making.


Assuntos
Neoplasias , Compostos de Sulfonilureia/química , Animais , Carcinogênese/efeitos dos fármacos , Humanos , Neoplasias/induzido quimicamente , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Risco , Compostos de Sulfonilureia/farmacologia , Compostos de Sulfonilureia/uso terapêutico
7.
Chemosphere ; 236: 124333, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31319303

RESUMO

The use of herbicides in Brazil has been carried out based on the manufacturer's recommendation, often disregarding the high variability of soil attributes. The use of statistical methods to predict the herbicide retention processes in the soil can contribute to the improvement of weed control efficiency associated with the lower risk of environmental contamination. This research evaluated the use of Artificial Neural Networks (ANNs) to predict soil sorption and desorption, as well as the environmental contamination potential of diuron, hexazinone and sulfometuron-methyl herbicides in Brazilian soils. The sorption and desorption coefficients of the three herbicides were determined in laboratory tests for 15 soils from different Brazilian states. To predict the sorption and desorption of diuron, hexazinone and sulfometuron-methyl were used a multilayer perceptron ANNs (MLP). The inputs were the characteristics of the herbicides and the physical and chemical attributes of the soils, and the outputs of were the sorption and desorption coefficients (Kfs and Kfd). The risk of leaching of diuron, hexazinone, and sulfometuron-methyl herbicides were evaluated considering the sorption values observed and those estimated by the models. The Artificial Neural Network (ANN) models were efficient for the prediction of sorption and desorption of diuron, hexazinone, and sulfometuron-methyl herbicides. The physicochemical properties of the herbicides were more important for the modeling of multilayer perceptron ANNs than the soil attributes. The herbicides diuron, hexazinone, and sulfometuron-methyl have a high potential risk for contamination of groundwater in different Brazilian states.


Assuntos
Diurona/química , Herbicidas/química , Compostos de Sulfonilureia/química , Triazinas/química , Brasil
8.
J Microbiol Biotechnol ; 29(5): 713-720, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31030451

RESUMO

Acanthamoeba castellanii belonging to the T4 genotype may cause a fatal brain infection known as granulomatous amoebic encephalitis, and the vision-threatening eye infection Acanthamoeba keratitis. The aim of this study was to evaluate the antiamoebic effects of three clinically available antidiabetic drugs, Glimepiride, Vildagliptin and Repaglinide, against A. castellanii belonging to the T4 genotype. Furthermore, we attempted to conjugate these drugs with silver nanoparticles (AgNPs) to enhance their antiamoebic effects. Amoebicidal, encystation, excystation, and host cell cytotoxicity assays were performed to unravel any antiacanthamoebic effects. Vildagliptin conjugated silver nanoparticles (Vgt-AgNPs) characterized by spectroscopic techniques and atomic force microscopy were synthesized. All three drugs showed antiamoebic effects against A. castellanii and significantly blocked the encystation. These drugs also showed significant cysticidal effects and reduced host cell cytotoxicity caused by A. castellanii. Moreover, Vildagliptin-coated silver nanoparticles were successfully synthesized and are shown to enhance its antiacanthamoebic potency at significantly reduced concentration. The repurposed application of the tested antidiabetic drugs and their nanoparticles against free-living amoeba such as Acanthamoeba castellanii described here is a novel outcome that holds tremendous potential for future applications against devastating infection.


Assuntos
Acanthamoeba castellanii/efeitos dos fármacos , Amebicidas/farmacologia , Anti-Infecciosos/farmacologia , Hipoglicemiantes/farmacologia , Nanoconjugados/química , Amebicidas/química , Anti-Infecciosos/química , Carbamatos/química , Carbamatos/farmacologia , Células HeLa , Humanos , Hipoglicemiantes/química , Nanopartículas Metálicas/química , Piperidinas/química , Piperidinas/farmacologia , Prata/química , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacologia , Vildagliptina/química , Vildagliptina/farmacologia
9.
AAPS PharmSciTech ; 20(4): 144, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30887140

RESUMO

One-third of the population of the USA suffers from metabolic syndrome (MetS). Treatment of patients with MetS regularly includes drugs prescribed simultaneously to treat diabetes and cardiovascular diseases. Therefore, the development of novel multidrug formulations is recommended. However, the main problem with these drugs is their low solubility. The use of binary co-amorphous systems emerges as a promising strategy to increase drug solubility. In the present study, irbesartan (IBS) and glimepiride (GMP), class II active pharmaceutical ingredients (API), widely used in the treatment of arterial hypertension and diabetes, were selected to develop a novel binary co-amorphous system with remarkable enhancement in the dissolution of both APIs. The phase diagram of IBS-GMP was constructed and co-amorphous systems were prepared by melt-quench, in a wide range of compositions. Dissolution profile (studied at pH 1.2 and 37°C for mole fractions 0.01, 0.1, and 0.5) demonstrated that the xGMP = 0.01 formulation presents the highest enhancement in its dissolution. GMP went from being practically insoluble to reach 3.9 ± 0.9 µg/mL, and IBS showed a 12-fold increment with respect to the dissolution of its crystalline form. Infrared studies showed that the increase in the dissolution profile is related to the intermolecular interactions (hydrogen bonds), which were dependent of composition. Results of structural and thermal characterization performed by XRD and DSC showed that samples have remained in amorphous state for more than 10 months of storage. This work contributes to the development of a highly soluble co-amorphous drugs with potential used in the treatment of MetS.


Assuntos
Hipoglicemiantes/química , Irbesartana/química , Compostos de Sulfonilureia/química , Varredura Diferencial de Calorimetria , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Quimioterapia Combinada , Humanos , Ligações de Hidrogênio , Hipoglicemiantes/administração & dosagem , Irbesartana/administração & dosagem , Difração de Pó , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Compostos de Sulfonilureia/administração & dosagem
10.
Artigo em Inglês | MEDLINE | ID: mdl-30691144

RESUMO

The widely used sulfonylurea herbicides have caused negative effects on the environment and human beings. Electrochemical degradation has attracted much attention in the treatment of refractory organic compounds due to its advantage of producing no secondary pollution. Three kinds of IrO2-based dimensionally stable anodes (DSAs) were used to degrade nicosulfuron by a batch electrochemical process. The results showed that a well-distributed crack network was formed on the Ti/Ta2O5-IrO2 electrode and Ti/Ta2O5-SnO2-IrO2 electrode due to the different coefficients of thermal expansion between the Ti substrate and oxide coatings. The oxygen evolution potential (OEP) increased according to the order of Ti/RuO2-IrO2 < Ti/Ta2O5-SnO2-IrO2 < Ti/Ta2O5-IrO2. Among the three electrodes, the Ti/Ta2O5-IrO2 electrode showed the highest efficiency and was chosen as the experimental electrode. Single factor experiments were carried out to obtain the optimum electrolysis condition, shown as follows: currency intensity 0.8 A; electrode spacing 3 cm, electrolyte pH 3. Under the optimum conditions, the degradation of nicosulfuron followed first-order kinetics and was mainly due to indirect electrochemical oxidation. It was a typical diffusion-controlled electrochemical process. On the basis of the intermediate identified by high performance liquid chromatograph-mass spectrometry (HPLC-MS), two possible degradation routes were proposed.


Assuntos
Técnicas Eletroquímicas , Herbicidas/química , Irídio/química , Piridinas/química , Compostos de Sulfonilureia/química , Eletrodos , Poluentes Ambientais/química , Cinética , Oxirredução , Óxidos/química , Titânio/química
11.
Bull Environ Contam Toxicol ; 102(2): 246-251, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30603767

RESUMO

A laboratory experiment was conducted to study the degradation dynamics of halosulfuron-methyl residues in sandy loam and clay loam soil. The herbicide formulation was applied at 0.034 and 0.068 mg kg- 1 equivalent to field application dose of 67.5 and 135 g a.i. ha- 1 as single and double dose respectively. Soil samples were collected on 0 (1 h), 1, 3, 7, 10, 15, 30 and 45 days after treatments. Extraction was done using modified QuEChERS method. Residues were estimated by UPLC coupled with quadrupole Dalton mass detector. Average recoveries ranged from 85.5% to 94.5% for both soils at different fortification levels of 0.005 to 0.1 mg kg- 1 with limit of detection (LOD) and limit of quantification (LOQ) as 0.001 and 0.005 mg kg- 1, respectively. Dissipation followed first order kinetics with half-life of 8.4 to 10.7 days in both soil at two doses. The residues reached below LOQ of 0.005 mg kg- 1 after 45 days of herbicide application.


Assuntos
Herbicidas/química , Resíduos de Praguicidas/química , Poluentes do Solo/química , Solo/química , Compostos de Sulfonilureia/química , Monitoramento Ambiental/métodos , Meia-Vida , Cinética , Limite de Detecção
12.
Eur J Med Chem ; 162: 348-363, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30448420

RESUMO

Accetohydroxyacid synthase (AHAS) is the first enzyme involved in the biosynthetic pathway of branched-chain amino acids. Earlier gene mutation of Candida albicans in a mouse model suggested that this enzyme is a promising target of antifungals. Recent studies have demonstrated that some commercial AHAS-inhibiting sulfonylurea herbicides exerted desirable antifungal activity. In this study, we have designed and synthesized 68 novel ethoxysulfulron (ES) derivatives and evaluated their inhibition constants (Ki) against C. albicans AHAS and cell based minimum inhibitory concentration (MIC) values. The target compounds 5-1, 5-10, 5-22, 5-31 and 5-37 displayed stronger AHAS inhibitions than ES did. Compound 5-1 had the best Ki of 6.7 nM against fungal AHAS and MIC values of 2.5 mg/L against Candida albicans and Candica parapsilosis after 72 h. A suitable nematode model was established here and the antifungal activity of 5-1 was further evaluated in vivo. A possible binding mode was simulated via molecular docking and a comparative field analysis (CoMFA) model was constructed to understand the structure-activity relationship. The current study has indicated that some ES derivatives should be considered as promising hits to develop antifungal drugs with novel biological target.


Assuntos
Acetolactato Sintase/antagonistas & inibidores , Antifúngicos/química , Relação Quantitativa Estrutura-Atividade , Compostos de Sulfonilureia/farmacologia , Animais , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Herbicidas , Camundongos , Simulação de Acoplamento Molecular , Nematoides/efeitos dos fármacos , Compostos de Sulfonilureia/química
13.
J Agric Food Chem ; 67(3): 836-843, 2019 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-30585487

RESUMO

Esterase SulE detoxicates a variety of sulfonylurea herbicides through de-esterification. SulE exhibits high activity against thifensulfuron-methyl but low activity against other sulfonylureas. In this study, two variants, m2311 (P80R) and m0569 (P80R and G176A), with improved activity were screened from a mutation library constructed by error-prone PCR. Variant m2311 showed a higher activity against sulfonylureas in comparison variant m0569 and was further investigated. The kcat/ Km value of variant m2311 for metsulfuron-methyl, sulfometuron-methyl, chlorimuron-ethyl, tribenuron-methyl, and ethametsulfuron-methyl increased by 3.20-, 1.72-, 2.94-, 2.26- and 2.96-fold, respectively, in comparison with the wild type. Molecular modeling suggested that the activity improvement of variant m2311 is due to the substitution of Pro80 by arginine, leading to the formation of new hydrogen bonds between the enzyme and substrate. This study facilitates further elucidation of the structure and function of SulE and provides an improved gene resource for the detoxification of sulfonylurea residues and the genetic engineering of sulfonylurea-resistant crops.


Assuntos
Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Esterases/genética , Esterases/metabolismo , Methylocystaceae/enzimologia , Compostos de Sulfonilureia/metabolismo , Proteínas de Bactérias/química , Evolução Molecular Direcionada , Esterases/química , Variação Genética , Herbicidas/química , Herbicidas/metabolismo , Cinética , Methylocystaceae/química , Methylocystaceae/genética , Pirimidinas/química , Pirimidinas/metabolismo , Compostos de Sulfonilureia/química , Tiofenos/química , Tiofenos/metabolismo
14.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1102-1103: 8-16, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30366211

RESUMO

Ultrafast affinity extraction was evaluated and used with microcolumns containing human serum albumin (HSA) to measure the global affinity constants and dissociation rate constants for several second- and third-generation sulfonylurea drugs with solution-phase normal HSA or glycated HSA. Glibenclamide, glimepiride and glipizide were used as model drugs for this work. Both single- and two-column systems were considered for the analysis of global affinities for the model drugs. These methods were optimized with respect to the flow rates, column sizes and sample residence times that were employed with each drug for ultrafast affinity extraction. Data acquired with single-column systems were further utilized to estimate the dissociation rate constants for normal HSA and glycated HSA with the given drugs. The binding constants obtained by the single- and two-column systems showed good agreement with each other and with values obtained from the literature. Use of a single-column system indicated that levels of glycation found in controlled or advanced diabetes resulted in a 18-44% decrease in the overall binding strength of the model drugs with HSA. Although the two-column system allowed work with smaller free drug fractions and clinically-relevant drug/protein concentrations, the single-column system required less protein, provided better precision, and was easier to use in binding studies.


Assuntos
Cromatografia de Afinidade/métodos , Hipoglicemiantes/metabolismo , Albumina Sérica Humana/metabolismo , Compostos de Sulfonilureia/metabolismo , Diabetes Mellitus , Glicosilação , Humanos , Hipoglicemiantes/química , Ligação Proteica , Albumina Sérica Humana/química , Compostos de Sulfonilureia/química
15.
Int J Pharm ; 553(1-2): 272-280, 2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30359686

RESUMO

Glimepiride (GLIM) is used as an oral antihyperglycemic agent for treatment of type 2 diabetes. The drug presents two polymorphic forms (GLIM form I and GLIM form II) described in the literature, and according to in vitro data, GLIM form II is about 3.5 times more soluble and releases 2 times the drug amount than GLIM form I in the physiological pH range. Considering the literature in vitro data and that the diabetes treatment demands glycemic control, avoiding abrupt fluctuations in the blood glucose levels, this work aimed to study the impact of GLIM polymorphism in the in vivo performance of GLIM solid oral dosages. For this, hard gelatin capsules with GLIM form I or II were prepared and orally administered in rats. After that, pharmacokinetic studies were performed by sampling animal blood at different times, and biochemical parameters (pharmacodynamic), such as glucose and insulin, were also evaluated. Our results showed that the in vitro data corroborate with our in vivo assays. GLIM form II provided higher plasma concentration of drug than form I (at baseline up to approximately 200 min after oral administration) and, consequently, increased insulin release and reduced levels of glucose, showing good correlation between pharmacokinetic and pharmacodynamics assays. Thus, this study demonstrated that GLIM polymorphs in oral dosages might alter the drug efficacy, which may expose the patients to risks, such as hypoglycemia.


Assuntos
Glicemia/efeitos dos fármacos , Hipoglicemiantes/química , Insulina/sangue , Compostos de Sulfonilureia/química , Administração Oral , Animais , Cápsulas , Cristalização , Gelatina , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Masculino , Ratos , Ratos Wistar , Solubilidade , Compostos de Sulfonilureia/farmacocinética , Compostos de Sulfonilureia/farmacologia
16.
Bioorg Chem ; 81: 1-20, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30081353

RESUMO

To evaluate the role of COX-2 and 5-LOX as dual inhibitors in controlling the cancer cell proliferation, a set of two series having 42 compounds of 1, 2, 3-Tethered Indole-3-glyoxamide derivatives were synthesized by employing click chemistry approach and were also evaluated for their in vitro cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) inhibitory activities with in vivo anti-inflammatory and in vitro anti-proliferative potencies. Among the compounds tested, compounds 11q and 13s displayed excellent inhibition of COX-2 (IC50 0.12 µM) with good COX-2 selectivity index (COX-2/COX-1) of 0.058 and 0.046 respectively. Compounds 11q and 13s also demonstrated comparable 5-LOX inhibitory activity with IC50 7.73 and 7.43 µM respectively to that of standard Norhihydroguaiaretic acid (NDGA: IC50 7.31 µM). Among all the selected cell lines, prostate cancer cell line DU145 was found to be susceptible to this class of compounds. Among all the tested compounds, compounds 11g, 11i, 11k, 11q, 13r, 13s and 13u demonstrated excellent to moderate anti-proliferative activity with IC50s ranging between 6.29 and 18.53 µM. Compounds 11q and 11g demonstrated better anti-proliferative activities against DU145 cancer cell line with IC50 values 8.17 and 8.69 µM respectively when compared to the standard drug etoposide (VP16; IC50 9.80 µM). Compounds 11g, 11k, 11q, 13s and 13u showed good dual COX-2/5-LOX inhibitory potentials with excellent anti-proliferative activity. Results from carrageenan-induced hind paw edema demonstrated that compounds 11b, 11l, 11q and 13q exhibited significant anti-inflammatory activity with 69-77% inhibition at 3 h, 75-82% inhibition at 5 h when compared to the standard drug indomethacin (66.6% at 3 h and 77.94% at 5 h). Ulcerogenic study revealed that compounds 11q and 13q did not cause any gastric ulceration. In vitro tubulin assay resuted that compound 11q interfered with microtubulin dynamic and act as tubulin polymerization inhibitor. In silico molecular docking studies demonstrated that compounds 11q and 13s are occupying the colchicines binding site of tubulin polymer and 11q illustrated very good binding affinities towards COX-2 and 5-LOX.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Compostos de Sulfonilureia/farmacologia , Triazóis/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Araquidonato 5-Lipoxigenase/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Indóis/síntese química , Indóis/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Compostos de Sulfonilureia/síntese química , Compostos de Sulfonilureia/química , Triazóis/química , Tubulina (Proteína)/metabolismo
17.
Pharm Res ; 35(9): 181, 2018 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-30054741

RESUMO

PURPOSE: To use valvejet technology for printing a fixed dose combination of ramipril and glimepiride, and to investigate the stability profile of ramipril, which is susceptible to a range of processing and storage conditions. METHODS: Inks of ramipril and glimepiride were formulated and printed on to HPMC film and the films were evaluated for the chemical and solid-state integrity of the APIs using HPLC and XRPD. The stability of the APIs in the inks and in the printed samples was investigated using Raman and NMR techniques. RESULTS: The printed samples demonstrated excellent precision and accuracy in the doses of APIs deposited. Both drugs were chemically intact in the freshly printed samples and ramipril was found to be in its amorphous form. Ramipril in the printed samples has transformed into ramipril diketopiperazine when stored at 40°C with 75% RH, but remained stable when stored in a desiccator. Results from the stability study of ramipril ink show that the API has undergone degradation when stored both at room temperature and at 40°C but remained stable when stored in a refrigerator. CONCLUSION: An FDC of ramipril and glimepiride was successfully printed using valvejet technology. The significance of inkjet printing in producing amorphous dosage forms from solution based inks and personalised dosage forms of drugs susceptible to processing conditions was demonstrated using ramipril. This study illustrates the significance of examining the stability of the APIs in the inks and the importance of appropriate storing of both the inks and printed samples.


Assuntos
Anti-Hipertensivos/química , Composição de Medicamentos/instrumentação , Hipoglicemiantes/química , Impressão/instrumentação , Ramipril/química , Compostos de Sulfonilureia/química , Cristalização , Combinação de Medicamentos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Excipientes/química , Derivados da Hipromelose/química , Viscosidade
18.
J Mol Recognit ; 31(7): e2706, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29630758

RESUMO

The study considers the Suppressor of cytokine signaling 1 (SOCS1) protein as a novel Type 2 diabetes mellitus (T2DM) drug target. T2DM in human beings is also triggered by the over expression of SOCS proteins. The SOCS1 acts as a ubiquitin ligase (E3), degrades Insulin Receptor Substrate 1 and 2 (IRS1 and IRS2) proteins, and causes insulin resistance. Therefore, the structure of the SOCS1 protein was evaluated using homology-modeling and molecular dynamics methods and validated using standard computational protocols. The Protein-Protein docking study of SOCS1 with its natural substrates, IRS1 and IRS2, and subsequent solvent accessible surface area analysis gave insight into the binding region of the SOCS1 protein. The in silico active site prediction tools highlight the residues Val155 to Ile211 in SOCS1 being implicated in the ubiquitin mediated protein degradation of the proteins IRS1 and IRS2. Virtual screening in the active site region, using large structural databases, results in selective lead structures with 3-Pyridinol, Xanthine, and Alanine moieties as Pharmacophore. The virtual screening study shows that the residues Glu149, Gly187, Arg188, Leu191, and Ser205 of the SOCS1 are important for binding. The docking study with current anti-diabetic therapeutics shows that the drugs Glibenclamide and Glyclopyramide have a partial affinity towards SOCS1. The predicted ADMET and IC50 properties for the identified ligands are within the acceptable range with drug-like properties. The structural data of SOCS1, its active site, and the identified lead structures are expedient in the development of new T2DM therapeutics.


Assuntos
Hipoglicemiantes/química , Proteínas Substratos do Receptor de Insulina/química , Proteína 1 Supressora da Sinalização de Citocina/química , Sequência de Aminoácidos , Domínio Catalítico , Diabetes Mellitus Tipo 2 , Glibureto/química , Glibureto/metabolismo , Humanos , Hipoglicemiantes/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Cinética , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Proteólise , Piridonas/química , Piridonas/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Especificidade por Substrato , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/metabolismo , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Termodinâmica
19.
Int J Biol Macromol ; 115: 961-969, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29704602

RESUMO

Selective carbonic anhydrase (CA) inhibitors have gained a lot of importance owing to the implication of specific isoforms of CA in certain diseases like glaucoma, leukemia, cystic fibrosis, and epilepsy. A novel class of sulfonylurea derivatives was synthesized from corresponding sulfonyl chlorides and amines. Compounds with different pendant moieties in the sulfonylurea derivatives show significant interactions with human carbonic anhydrase II (CAII). In vitro evaluation of the sulfonylurea derivatives revealed that three compounds possess admirable inhibitory activity against CAII. Compounds containing methyl (G2), isopropyl (G4) and o-tosyl (G5) groups displayed IC50 (109-137 µm) for CAII. Fluorescence binding and cytotoxicity studies revealed that these compounds are showing good binding affinity (18-34 µM) to CAII and non- toxic to human cells. Further, molecular docking studies of G2, G4 and G5 with CAII showed that these compounds fit nicely in the active site of CAII. Molecular dynamics simulation studies of these compounds complexed with CAII showed that essential interactions were maintained up to 50 ns of simulation. These results indicate the promising nature of the sulfonylurea scaffold towards CAII inhibition and opens scope of hit to-lead optimization for discovery of effective drugs against CAII-associated disorders.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacologia , Anidrase Carbônica II/química , Anidrase Carbônica II/metabolismo , Domínio Catalítico , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Compostos de Sulfonilureia/metabolismo
20.
Eur J Pharm Sci ; 120: 40-52, 2018 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-29678613

RESUMO

Fused Deposition Modelling (a.k.a. FDM-3D printing) has been previously employed in the development of personalized medicines with unique properties and release behavior. In the present work, a bilayer dosage form containing two anti-diabetic drugs with different daily dosage regimens; i.e. metformin and glimepiride, was manufactured via FDM 3D printing, studied using a variety of techniques and characterized in vitro. Metformin and glimepiride were embedded in Eudragit® RL sustained release layer and polyvinyl alcohol (PVA) layer respectively. Incorporation of more than one API's into the formulation is desirable, as it increases patient compliance and reduces cost of treatment, especially when distinct dosages of API's can be adjusted individually in situ, in order to meet each patient's specific needs, a capability provided by 3D printing. A number of different preparation methods, which involved different plasticizers and extruders, were tested on manufacturing Eudragit® RL drug-loaded filaments for printing the sustained release layer. The properties of the produced filaments were assessed by means of mechanical and physicochemical characterization techniques and the filaments with the optimum properties were used for printing. Microfocus computed tomography (µCT) imaging-based actual/nominal comparison analysis showed a printing accuracy ranging between -100, +200 µm, while X-ray (XRD) diffractograms revealed the incorporation of the (initially crystalline) API's as amorphous dispersions into polymer matrices. Dissolution tests showed sufficient drug release for both drugs in desired time frames (75 min for glimepiride and 480 min for metformin). The results from the current study emphasize the potentiality of 3D printing technology for tailor-made solid dosage forms for combined pharmacotherapy, even at the cases when API's with different desirable release profiles are employed.


Assuntos
Hipoglicemiantes/química , Metformina/química , Impressão Tridimensional , Compostos de Sulfonilureia/química , Tecnologia Farmacêutica/métodos , Administração Oral , Cristalização , Cristalografia por Raios X , Preparações de Ação Retardada , Formas de Dosagem , Portadores de Fármacos , Combinação de Medicamentos , Composição de Medicamentos , Liberação Controlada de Fármacos , Hipoglicemiantes/administração & dosagem , Cinética , Metformina/administração & dosagem , Polímeros/química , Álcool de Polivinil/química , Solubilidade , Compostos de Sulfonilureia/administração & dosagem , Microtomografia por Raio-X
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