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1.
J Enzyme Inhib Med Chem ; 36(1): 1509-1520, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34238110

RESUMO

In the present study, a series of azo derivatives (TR-1 to TR-9) have been synthesised via the diazo-coupling approach between substituted aromatic amines with phenol or naphthol derivatives. The compounds were evaluated for their therapeutic applications against alpha-glucosidase (anti-diabetic) and pathogenic bacterial strains E. coli (gram-negative), S. aureus (gram-positive), S. aureus (gram-positive) drug-resistant strain, P. aeruginosa (gram-negative), P. aeruginosa (gram-negative) drug-resistant strain and P. vulgaris (gram-negative). The IC50 (µg/mL) of TR-1 was found to be most effective (15.70 ± 1.3 µg/mL) compared to the reference drug acarbose (21.59 ± 1.5 µg/mL), hence, it was further selected for the kinetic studies in order to illustrate the mechanism of inhibition. The enzyme inhibitory kinetics and mode of binding for the most active inhibitor (TR-1) was performed which showed that the compound is a non-competitive inhibitor and effectively inhibits the target enzyme by binding to its binuclear active site reversibly.


Assuntos
Antibacterianos/farmacologia , Compostos Azo/farmacologia , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Simulação de Acoplamento Molecular , alfa-Glucosidases/metabolismo , Antibacterianos/síntese química , Antibacterianos/química , Compostos Azo/síntese química , Compostos Azo/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Escherichia coli/efeitos dos fármacos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Cinética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Saccharomyces cerevisiae/enzimologia , Staphylococcus aureus/efeitos dos fármacos
2.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202801

RESUMO

In this research, the selected drugs commonly used in diabetes and its comorbidities (gliclazide, cilazapril, atorvastatin, and acetylsalicylic acid) were studied for their interactions with bovine serum albumin-native and glycated. Two different spectroscopic methods, fluorescence quenching and circular dichroism, were utilized to elucidate the binding interactions of the investigational drugs. The glycation process was induced in BSA by glucose and was confirmed by the presence of advanced glycosylation end products (AGEs). The interaction between albumin and gliclazide, with the presence of another drug, was confirmed by calculation of association constants (0.11-1.07 × 104 M-1). The nature of changes in the secondary structure of a protein depends on the drug used and the degree of glycation. Therefore, these interactions may have an influence on pharmacokinetic parameters.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/química , Soroalbumina Bovina/química , Animais , Bovinos , Humanos , Hipoglicemiantes/uso terapêutico , Ligação Proteica , Estrutura Secundária de Proteína
3.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206308

RESUMO

Horse chestnut (Aesculus hippocastanum L.)-derived drugs have shown their potential in biomedical applications. The seed of A. hippocastanum contains various kinds of chemical compounds including phenolics, flavonoids, coumarins, and triterpene saponins. Here, we investigated the chemical components in A. hippocastanum L. grown in Uzbekistan, which has not yet been studied in detail. We identified 30 kinds of triterpene saponins in an extract of A. hippocastanum L. Classifying extracted saponins into eight fractions, we next studied the hypoglycemic and the anti-inflammatory activities of escin and its derivatives through in vivo experiments. We came by data indicating the highest (SF-1 and SF-2) and the lowest (SF-5 and SF-8) antidiabetic and anti-inflammatory effects of those eight fractions. These results imply the prospective use of A. hippocastanum L. grown in Uzbekistan in the production of pharmaceutical drugs to treat diabetes and inflammation.


Assuntos
Aesculus/química , Anti-Inflamatórios , Glicosídeos , Hipoglicemiantes , Triterpenos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Feminino , Glicosídeos/química , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Masculino , Ratos , Ratos Wistar , Triterpenos/química , Triterpenos/isolamento & purificação , Triterpenos/farmacologia , Uzbequistão
4.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206320

RESUMO

Type 2 diabetes (T2D) is a chronic metabolic disease, which could affect the daily life of patients and increase their risk of developing other diseases. Synthetic anti-diabetic drugs usually show severe side effects. In the last few decades, plant-derived drugs have been intensively studied, particularly because of a rapid development of the instruments used in analytical chemistry. We tested the efficacy of Gundelia tournefortii L. (GT) in increasing the translocation of glucose transporter-4 (GLUT4) to the myocyte plasma membrane (PM), as a main strategy to manage T2D. In this study, GT methanol extract was sub-fractionated into 10 samples using flash chromatography. The toxicity of the fractions on L6 muscle cells, stably expressing GLUTmyc, was evaluated using the MTT assay. The efficacy with which GLUT4 was attached to the L6 PM was evaluated at non-toxic concentrations. Fraction 6 was the most effective, as it stimulated GLUT4 translocation in the absence and presence of insulin, 3.5 and 5.2 times (at 250 µg/mL), respectively. Fraction 1 and 3 showed no significant effects on GLUT4 translocation, while other fractions increased GLUT4 translocation up to 2.0 times. Gas chromatography-mass spectrometry of silylated fractions revealed 98 distinct compounds. Among those compounds, 25 were considered anti-diabetic and glucose disposal agents. These findings suggest that GT methanol sub-fractions exert an anti-diabetic effect by modulating GLUT4 translocation in L6 muscle cells, and indicate the potential of GT extracts as novel therapeutic agents for T2D.


Assuntos
Asteraceae/química , Diabetes Mellitus Tipo 2/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Hipoglicemiantes , Células Musculares/metabolismo , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Transportador de Glucose Tipo 4/genética , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Transporte Proteico/efeitos dos fármacos , Ratos
5.
Molecules ; 26(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199316

RESUMO

Herbs and spices have been used since antiquity for their nutritional and health properties, as well as in traditional remedies for the prevention and treatment of many diseases. Therefore, this study aims to perform a chemical analysis of both essential oils (EOs) from the seeds of Carum carvi (C. carvi) and Coriandrum sativum (C. sativum) and evaluate their antioxidant, antimicrobial, anti-acetylcholinesterase, and antidiabetic activities alone and in combination. Results showed that the EOs mainly constitute monoterpenes with γ-terpinene (31.03%), ß-pinene (18.77%), p-cymene (17.16%), and carvone (12.20%) being the major components present in C. carvi EO and linalool (76.41%), γ-terpinene (5.35%), and α-pinene (4.44%) in C. sativum EO. In comparison to standards, statistical analysis revealed that C. carvi EO showed high and significantly different (p < 0.05) antioxidant activity than C. sativum EO, but lower than the mixture. Moreover, the mixture exhibited two-times greater ferric ion reducing antioxidant power (FRAP) (IC50 = 11.33 ± 1.53 mg/mL) and equipotent chelating power (IC50 = 31.33 ± 0.47 mg/mL) than the corresponding references, and also potent activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) (IC50 = 19.00 ± 1.00 mg/mL), ß-carotene (IC50 = 11.16 ± 0.84 mg/mL), and superoxide anion (IC50 = 10.33 ± 0.58 mg/mL) assays. Antimicrobial data revealed that single and mixture EOs were active against a panel of pathogenic microorganisms, and the mixture had the ability to kill more bacterial strains than each EO alone. Additionally, the anti-acetylcholinesterase and α-glucosidase inhibitory effect have been studied for the first time, highlighting the high inhibition effect of AChE by C. carvi (IC50 = 0.82 ± 0.05 mg/mL), and especially by C. sativum (IC50 = 0.68 ± 0.03 mg/mL), as well as the mixture (IC50 = 0.63 ± 0.02 mg/mL) compared to the reference drug, which are insignificantly different (p > 0.05). A high and equipotent antidiabetic activity was observed for the mixture (IC50 = 0.75 ± 0.15 mg/mL) when compared to the standard drug, acarbose, which is about nine times higher than each EO alone. Furthermore, pharmacokinetic analysis provides some useful insights into designing new drugs with favorable drug likeness and safety profiles based on a C. carvi and C. sativum EO mixture. In summary, the results of this study revealed that the combination of these EOs may be recommended for further food, therapeutic, and pharmaceutical applications, and can be utilized as medicine to inhibit several diseases.


Assuntos
Acetilcolinesterase/química , Antibacterianos/farmacologia , Antioxidantes/farmacologia , Carum/química , Coriandrum/química , Hipoglicemiantes/farmacologia , Óleos Voláteis/farmacologia , Antibacterianos/química , Antibacterianos/farmacocinética , Antioxidantes/química , Antioxidantes/farmacocinética , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Óleos Voláteis/química , Óleos Voláteis/farmacocinética , Sementes/química
6.
Molecules ; 26(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201147

RESUMO

Many plants that are commonly used in folk medicine have multidirectional biological properties confirmed by scientific research. One of them is Aerva lanata (L.) Juss. (F. Amaranthaceae). It is widely used, but there are very few scientific data about its chemical composition and pharmacological activity. The aim of the present study was to investigate the chemical composition of phenolic acid (PA)-rich fractions isolated from methanolic extracts of A. lanata (L.) Juss. herb using the liquid/liquid extraction method and their potential antioxidant, anti-inflammatory, and anti-diabetic properties. The free PA fraction (FA), the PA fraction (FB) released after acid hydrolysis, and the PA fraction (FC) obtained after alkaline hydrolysis were analysed using liquid chromatography/electrospray ionization triple quadrupole mass spectrometry (LC-ESI-MS/MS). The phenolic profile of each sample showed a high concentration of PAs and their presence in A. lanata (L.) Juss. herb mainly in bound states. Thirteen compounds were detected and quantified in all samples, including some PAs that had not been previously detected in this plant species. Bioactivity assays of all fractions revealed high 2,2-diphenyl-1-picrylhydrazyl (DPPH•) (2.85 mM Trolox equivalents (TE)/g) and 2,2-azino-bis-3(ethylbenzthiazoline-6-sulphonic acid) (ABTS•+) (2.88 mM TE/g) scavenging activity. Fraction FB definitely exhibited not only the highest antiradical activity but also the strongest xanthine oxidase (XO) (EC50 = 1.77 mg/mL) and lipoxygenase (LOX)(EC50 = 1.88 mg/mL) inhibitory potential. The fraction had the best anti-diabetic properties, i.e., mild inhibition of α-amylase (EC50 = 7.46 mg/mL) and strong inhibition of α-glucosidase (EC50 = 0.30 mg/mL). The activities of all analysed samples were strongly related to the presence of PA compounds and the total PA content.


Assuntos
Amaranthaceae/química , Anti-Inflamatórios/química , Antioxidantes/química , Hidroxibenzoatos/química , Hipoglicemiantes/química , Extratos Vegetais/química , Flavonoides/química , Lipoxigenase/química , Medicina Tradicional/métodos , Metanol/química , Fenóis/química , Xantina Oxidase/química , alfa-Amilases/química , alfa-Glucosidases/química
7.
Molecules ; 26(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34208908

RESUMO

Diabetes mellitus is a multifactorial disease that affects both developing and developed countries and is a major public health concern. Many synthetic drugs are available in the market, which counteracts the associated pathologies. However, due to the propensity of side effects, there is an unmet need for the investigation of safe and effective drugs. This research aims to find a novel phytoconstituent having diminished action on blood glucose levels with the least side effects. Shikonin is a naturally occurring naphthoquinone dying pigment obtained by the roots of the Boraginaceae family. Besides its use as pigments, it can be used as an antimicrobial, anti-inflammatory, and anti-tumor agent. This research aimed to hypothesize the physicochemical and phytochemical properties of Shikonin's in silico interaction with protein tyrosine phosphate 1B, as well as it's in vitro studies, in order to determine its potential anti-diabetic impact. To do so, molecular docking experiments with target proteins were conducted to assess their anti-diabetic ability. Analyzing associations with corresponding amino acids revealed the significant molecular interactions between Shikonin and diabetes-related target proteins. In silico pharmacokinetics and toxicity profile of Shikonin using ADMET Descriptor, Toxicity Prediction, and Calculate Molecular Properties tools from Biovia Discovery Studio v4.5. Filter by Lipinski and Veber Rule's module from Biovia Discovery Studio v4.5 was applied to assess the drug-likeness of Shikonin. The in vitro studies exposed that Shikonin shows an inhibitory potential against the PTP1B with an IC50 value of 15.51 µM. The kinetics studies revealed that it has a competitive inhibitory effect (Ki = 7.5 M) on the enzyme system, which could be useful in the production of preventive and therapeutic agents. The findings of this research suggested that the Shikonin could be used as an anti-diabetic agent and can be used as a novel source for drug delivery.


Assuntos
Inibidores Enzimáticos/química , Hipoglicemiantes/química , Simulação de Acoplamento Molecular , Naftoquinonas/química , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Regulação Alostérica , Humanos , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/química , Relação Estrutura-Atividade
8.
Eur J Med Chem ; 222: 113542, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34118723

RESUMO

Peroxisome proliferator-activated receptor gamma (PPARγ) is a valuable drug target for diabetic treatment and ligands of PPARγ have shown potent anti-diabetic efficacy. However, to overcome the severe side effects of current PPARγ-targeted drugs, novel PPARγ ligands need to be developed. Sulindac, an identified ligand of PPARγ, is widely used in clinic as a non-steroidal anti-inflammatory drug. To explore its potential application for diabetes, we designed and synthesized a series of sulindac derivatives to investigate their structure-activity relationship as PPARγ ligand and potential anti-diabetic effect. We found that meta-substitution in sulindac's benzylidene moiety was beneficial to PPARγ binding and transactivation. Z rather than E configuration of the benzylidene double bond endowed derivatives with the selectivity of PPARγ activation. The indene fluorine is essential for binding and regulating PPARγ. Compared with rosiglitazone, compound 6b with benzyloxyl meta-substitution and Z benzylidene double bond weakly induced adipogenesis and PPARγ-targeted gene expression. However, 6b potently improved glucose tolerance in a diabetic mice model. Unlike rosiglitazone, 6b was devoid of apparent toxicity to osteoblastic formation. Thus, we provided some useful guidelines for PPARγ-based optimization of sulindac and an anti-diabetic lead compound with less side effects.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Desenho de Fármacos , Hipoglicemiantes/farmacologia , PPAR gama/agonistas , Sulindaco/farmacologia , Animais , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Relação Dose-Resposta a Droga , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulindaco/síntese química , Sulindaco/química
9.
Eur J Med Chem ; 222: 113602, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34139626

RESUMO

Clinical reports have highlighted the radical increase of antibiotic resistance. As a result, multidrug resistance has emerged as a serious threat to human health. Many organic compounds commonly used as drugs in the past, no longer have pure organic mode of action rather need bio-transformation or more activation. Bulk of research has shown that they need trace amount of metal ions incorporated within the chemistry of bioactive molecules for enhancement of their potentiality to fight aggressively against resistance. The deficiency of some metal ions can also be responsible for many diseases like growth retardation, pernicious anemia and heart diseases in infants. To overcome these problems, there is a need to introduce novel strategies which have new mechanism of action along with significant spectrum of biological activity, enhanced safety and efficacy. Bioinorganic compounds have played imperative role in developing the new strategy in the form of "Metal Based Drugs". In current years there have been momentous rise of interest in the application of metal based Schiff base compounds to treat various diseases which are difficult to be treated with conventional methodologies. The unique properties of metal chelates acting as an intermediate between conventional organic and inorganic compounds provided innovative opportunities in the field of pharmaceutical chemistry. In this review, we have exclusively focused on the search of metal based 1,2,4-triazole derived Schiff base compounds (synthesized, reported and reviewed in the past ten years) that possess various biological activities such as antifungal, antibacterial, antioxidant, antidiabetic, anthelmintic, anticancer, antiproliferative, cytotoxic and DNA-intercalation activity.


Assuntos
Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Complexos de Coordenação/farmacologia , Hipoglicemiantes/farmacologia , Triazóis/farmacologia , Anti-Infecciosos/química , Antineoplásicos/química , Antioxidantes/química , Complexos de Coordenação/química , Humanos , Hipoglicemiantes/química , Estrutura Molecular , Bases de Schiff/química , Bases de Schiff/farmacologia , Triazóis/química
10.
J Med Chem ; 64(13): 8939-8941, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34133152

RESUMO

Basal glucose control is commonly maintained by a single, once-daily administration of insulin through subcutaneous injection or a continuous pump-infusion. Insulin icodec, a novel ultralong-acting lipidated analog validates the concept of a once-weekly basal injection that is less burdensome, yet equally safe and efficacious as conventional once-daily treatment.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Glicemia , Diabetes Mellitus Tipo 2/metabolismo , Esquema de Medicação , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Infusões Subcutâneas , Insulina/administração & dosagem , Insulina/análogos & derivados
11.
Int J Biol Macromol ; 184: 289-296, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34119546

RESUMO

Inhibiting the activity of the intestinal enzyme α-amylase that catalyzes the degradation of starch into glucose can control blood glucose and provide an essential way for the treatment of Type-II diabetes mellitus (T2DM). Here, we compared the structural information of chondroitin sulfate (CS) from different origins and the effects on activity of α-amylase and blood glucose have been investigated. The inhibitory effects of shark and porcine CSs against α-amylase activity is obvious with IC50 values of 11.97 and 14.42 mg/ml, respectively, but the bovine CS almost no effect. From the data of fluorescence spectroscopic analyses, CSs from shark and pig quench Try fluorescence intensity of the enzyme, whereas bovine CS induces an increase. In vivo, oral administration of shark and porcine CSs efficiently suppresses postprandial blood glucose levels in normal and diabetic mice. Our study found that CSs from different sources showed different biological functions even if both molecular weight and disaccharide subunit composition are almost the same, and demonstrated that the CSs from shark and pig as α-amylase inhibitors could be regarded as a novel functional food ingredient in T2DM management.


Assuntos
Sulfatos de Condroitina/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , alfa-Amilases/antagonistas & inibidores , Administração Oral , Animais , Glicemia/efeitos dos fármacos , Bovinos , Sulfatos de Condroitina/química , Sulfatos de Condroitina/farmacologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/enzimologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Concentração Inibidora 50 , Masculino , Camundongos , Tubarões , Especificidade da Espécie , Estreptozocina , Suínos , Resultado do Tratamento
12.
Int J Biol Macromol ; 184: 380-392, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34126149

RESUMO

Russula virescens is an edible wild mushroom that is widely distributed in south of China. This research aimed to analyze the structure characterization and evaluate the hypoglycemic, anticancer and immunological activities of two water soluble polysaccharides RVP-1 and RVP-2 from R. virescens. The results showed RVP-1 and RVP-2 were non-triple helix structured hetero-polysaccharides with different weight-average molecular weight 14,883 and 13,301 Da, respectively. Both RVP-1 and RVP-2 were composed of galactose, glucose, mannose and fructose, and the sugar residues were mainly linked by 1,6→, 1,2→, 1→ and 1,3,6→ glycosidic bonds. Moreover, the antidiabetic, anticancer and immune activities of RVP-1 and RVP-2 were explored in vitro methods. The two polysaccharides have potential for inhibiting α-glucosidase and α-amylase activities, suppressing HepG-2, A549 and MCF-7 cancer cells proliferation, and activating macrophage RAW 264.7 cells to secret immune cytokines for mediating cellular immune response. These findings provided a scientific basis for further utilization of polysaccharide from R. virescens.


Assuntos
Antineoplásicos/química , Antioxidantes/química , Basidiomycota/química , Citocinas/metabolismo , Polissacarídeos Fúngicos/química , Hipoglicemiantes/química , Células A549 , Animais , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Sequência de Carboidratos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Polissacarídeos Fúngicos/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Células Hep G2 , Humanos , Hipoglicemiantes/farmacologia , Células MCF-7 , Camundongos , Peso Molecular , Células RAW 264.7 , alfa-Amilases/antagonistas & inibidores
13.
Molecules ; 26(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065194

RESUMO

Diabetes mellitus (DM) is a chronic disorder and has affected a large number of people worldwide. Insufficient insulin production causes an increase in blood glucose level that results in DM. To lower the blood glucose level, various drugs are employed that block the activity of the α-glucosidase enzyme, which is considered responsible for the breakdown of polysaccharides into monosaccharides leading to an increase in the intestinal blood glucose level. We have synthesized novel 2-(3-(benzoyl/4-bromobenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-arylacetamides and have screened them for their in silico and in vitro α-glucosidase inhibition activity. The derivatives 11c, 12a, 12d, 12e, and 12g emerged as potent inhibitors of the α-glucosidase enzyme. These compounds exhibited good docking scores and excellent binding interactions with the selected residues (Asp203, Asp542, Asp327, His600, Arg526) during in silico screening. Similarly, these compounds also showed good in vitro α-glucosidase inhibitions with IC50 values of 30.65, 18.25, 20.76, 35.14, and 24.24 µM, respectively, which were better than the standard drug, acarbose (IC50 = 58.8 µM). Furthermore, a good agreement was observed between in silico and in vitro modes of study.


Assuntos
Acetamidas/síntese química , Acetamidas/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Tiazinas/química , Tiazinas/farmacologia , Acetamidas/química , Acetamidas/uso terapêutico , Simulação por Computador , Diabetes Mellitus/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Tiazinas/síntese química
14.
Molecules ; 26(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073973

RESUMO

The present work is a concrete example of how physico-chemical studies, if performed in depth, are crucial to understand the behavior of pharmaceutical solids and constitute a solid basis for the control of the reproducibility of the industrial batches. In particular, a deep study of the thermal behavior of glipizide, a hypoglycemic drug, was carried out with the aim of clarifying whether the recognition of its polymorphic forms can really be done on the basis of the endothermic peak that the literature studies attribute to the melting of the compound. A number of analytical techniques were used: thermal techniques (DSC, TGA), X-ray powder diffraction (XRPD), FT-IR spectroscopy and scanning electron microscopy (SEM). Great attention was paid to the experimental design and to the interpretation of the combined results obtained by all these techniques. We proved that the attribution of the endothermic peak shown by glipizide to its melting was actually wrong. The DSC peak is no doubt triggered by a decomposition process that involves gas evolution (cyclohexanamine and carbon dioxide) and formation of 5-methyl-N-[2-(4-sulphamoylphenyl) ethyl] pyrazine-2-carboxamide, which remains as decomposition residue. Thermal treatments properly designed and the combined use of DSC with FT-IR and XRPD led to identifying a new polymorphic form of 5-methyl-N-[2-(4-sulphamoylphenyl) ethyl] pyrazine-2-carboxamide, which is obtained by crystallization from the melt. Hence, our results put into evidence that the check of the polymorphic form of glipizide cannot be based on the temperature values of the DSC peak, since such a peak is due to a decomposition process whose Tonset value is strongly affected by the particle size. Kinetic studies of the decomposition process show the high stability of solid glipizide at room temperature.


Assuntos
Glipizida/química , Hipoglicemiantes/química , Varredura Diferencial de Calorimetria , Microscopia Eletrônica de Varredura , Difração de Pó , Espectroscopia de Infravermelho com Transformada de Fourier , Termogravimetria
15.
Int J Mol Sci ; 22(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072216

RESUMO

Cheonggukjang (CGJ, fermented soybean paste), a traditional Korean fermented dish, has recently emerged as a functional food that improves blood circulation and intestinal regulation. Considering that excessive consumption of refined salt is associated with increased incidence of gastric cancer, high blood pressure, and stroke in Koreans, consuming CGJ may be desirable, as it can be made without salt, unlike other pastes. Soybeans in CGJ are fermented by Bacillus strains (B. subtilis or B. licheniformis), Lactobacillus spp., Leuconostoc spp., and Enterococcus faecium, which weaken the activity of putrefactive bacteria in the intestines, act as antibacterial agents against pathogens, and facilitate the excretion of harmful substances. Studies on CGJ have either focused on improving product quality or evaluating the bioactive substances contained in CGJ. The fermentation process of CGJ results in the production of enzymes and various physiologically active substances that are not found in raw soybeans, including dietary fiber, phospholipids, isoflavones (e.g., genistein and daidzein), phenolic acids, saponins, trypsin inhibitors, and phytic acids. These components prevent atherosclerosis, oxidative stress-mediated heart disease and inflammation, obesity, diabetes, senile dementia, cancer (e.g., breast and lung), and osteoporosis. They have also been shown to have thrombolytic, blood pressure-lowering, lipid-lowering, antimutagenic, immunostimulatory, anti-allergic, antibacterial, anti-atopic dermatitis, anti-androgenetic alopecia, and anti-asthmatic activities, as well as skin improvement properties. In this review, we examined the physiological activities of CGJ and confirmed its potential as a functional food.


Assuntos
Produtos Biológicos , Fermentação , Alimento Funcional , Soja , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Ingredientes de Alimentos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Estrutura Molecular , Avaliação Nutricional , Osteogênese/efeitos dos fármacos , Probióticos , Soja/química , Soja/metabolismo , Soja/microbiologia
16.
J Food Sci ; 86(7): 2962-2977, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34076269

RESUMO

Alcalase hydrolyzates were prepared from the albumin (AH) and globulin (GH) fractions of eight chickpea (Cicer arietinum L.) genotypes from Mexico and 10 from other countries. Protein content, antioxidant activity (AA) (ABTS, DPPH), and degree of hydrolysis were evaluated and the best genotype was selected by principal component analysis. The hydrolyzates of the chosen genotype were analyzed for its antidiabetic potential measured as inhibition of α-amylase, α-glucosidase, and dipeptidyl peptidase-4 (DPP4). Peptide profiles were obtained by liquid chromatography-mass spectrometry (UPLC-DAD-MS), and the most active peptides were analyzed by molecular docking. The average antioxidant activity of albumin hydrolyzates was higher than that of globulin hydrolyzates. ICC3761 was the selected genotype and peptides purified from the albumin hydrolyzate showed the best antioxidant activity and antidiabetic potential (FEI, FEL, FIE, FKN, FGKG, and MEE). FEI, FEL, and FIE were in the same chromatographic peak and this mixture showed the best ABTS scavenging (78.25%) and DPP4 inhibition (IC50  = 4.20 µg/ml). MEE showed the best DPPH scavenging (47%). FGKG showed the best inhibition of α-amylase (54%) and α-glucosidase (56%) and may be a competitive inhibitor based on in silico-predicted interactions with catalytic amino acids in the active site of both enzymes. These peptides could be used as nutraceutical supplements against diseases related to oxidative stress and diabetes. PRACTICAL APPLICATION: This study showed that chickpea protein hydrolyzates are good sources of peptides with antidiabetic potential, showing high antioxidant activity and inhibition of enzymes related to carbohydrate metabolism and type 2 diabetes. These hydrolyzates could be formulated in functional foods for diabetes.


Assuntos
Antioxidantes/química , Cicer/química , Hipoglicemiantes/química , Peptídeos/química , Proteínas de Plantas/química , Cromatografia Líquida , Cicer/genética , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/química , Genótipo , Humanos , Espectrometria de Massas , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Hidrolisados de Proteína/química , Sementes/química , Sementes/genética , alfa-Amilases/química , alfa-Glucosidases/química
17.
J Food Sci ; 86(7): 3046-3060, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34146413

RESUMO

This study aimed to assess the biological properties of peptide fractions isolated from dried fermented dairy products (jameed) as influenced by processing. Peptide fractions were separated by reversed-phase high-performance liquid chromatography (RP-HPLC) from salted (Sa) and unsalted (Us) cow milk jameed after drying the fermented curd by sun drying (Sd) or freeze-drying (Fd) and were characterized for their antioxidant capacity and inhibitory activity toward angiotensin I-converting enzyme (ACE) and α-amylase. Sd samples showed more numerous peptide peaks in RP-HPLC chromatograms than Fd samples, regardless of the salt content. High antioxidant activity was evidenced in several peptide fractions from FdUs jameed (including fractions 1, 2, 4, 7, 8, 9, and 10), SdUs jameed (1, 2, 5, 7, and 9), and FdSa jameed (2, 5, 6, and 9). By contrast, peptide fractions from SdSa (1, 2, 3, 5, 8, and 9), SdUs (4, 5, and 10), and FdUs (5, 6, and 8) jameed displayed the highest ACE inhibitory activity. Similarly, the highest inhibition of α-amylase was obtained with fractions from SdSa (1, 2, 3, 4, 5, 6, 8, and 9), SdUs (2 and 6), and FdUs (1, 7 and 9) jameed. A significant negative correlation was evidenced between antioxidant activity and anti-α-amylase activity of peptide fractions from SdSa jameed. These findings demonstrate that cow milk jameed is a source of bioactive peptides with antioxidant, anti-ACE, and anti-α-amylase properties in vitro, which can be tailored by adjusting the salt content and the drying conditions. PRACTICAL APPLICATION: This study shows that cow milk jameed, a staple fermented food in several Mediterranean countries, can serve as a useful source of multifunctional bioactive peptides with potential antioxidant, hypotensive, and hypoglycemic effects, which may help prevent and manage chronic health conditions such as hypertension, type 2 diabetes, and the metabolic syndrome. The bioactivities of certain peptide fractions were enhanced by lowering the salt content of jameed or by the drying method. The relatively simple RP-HPLC method described in this study can be used to isolate the peptide fractions of interest for further characterization and use as functional ingredients.


Assuntos
Aminoácidos/análise , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/farmacocinética , Antioxidantes/farmacologia , Produtos Fermentados do Leite , Hipoglicemiantes/farmacologia , Leite/química , Fragmentos de Peptídeos/farmacologia , Inibidores da Enzima Conversora de Angiotensina/química , Animais , Anti-Hipertensivos/química , Antioxidantes/química , Bovinos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipertensão/tratamento farmacológico , Hipoglicemiantes/química , Fragmentos de Peptídeos/química , Peptidil Dipeptidase A/metabolismo
18.
Eur J Med Chem ; 221: 113546, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34023737

RESUMO

Hydroxypyranone and hydroxypyridinone are important oxygen-containing or nitrogen-containing heterocyclic nucleus and attracted increasing attention in medicinal chemistry and drug discovery over the past decade. Previous literature reports revealed that hydroxypyranone and hydroxypyridinone derivatives exhibit a wide range of pharmacological activities such as antibacterial, antifungal, antiviral, anticancer, anti-inflammatory, antioxidant, anticonvulsant, and anti-diabetic activities. In this review, we systematically summarized the literature reported biological activities of hydroxypyranone and hydroxypyridinone derivatives. In particular, we focus on their biological activity, structure-activity relationship (SAR), mechanism of action, and interaction mechanisms with the target. The collected information is expected to provide rational guidance for the development of clinically useful agents from these pharmacophores.


Assuntos
Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Hipoglicemiantes/farmacologia , Anti-Infecciosos/química , Anti-Inflamatórios/química , Antineoplásicos/química , Antioxidantes/química , Descoberta de Drogas , Humanos , Hipoglicemiantes/química , Piranos/química , Piranos/farmacologia , Piridonas/química , Piridonas/farmacologia
19.
J Med Chem ; 64(13): 8942-8950, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-33944562

RESUMO

Here, we describe the molecular engineering of insulin icodec to achieve a plasma half-life of 196 h in humans, suitable for once-weekly subcutaneously administration. Insulin icodec is based on re-engineering of the ultra-long oral basal insulin OI338 with a plasma half-life of 70 h in humans. This systematic re-engineering was accomplished by (1) further increasing the albumin binding by changing the fatty diacid from a 1,18-octadecanedioic acid (C18) to a 1,20-icosanedioic acid (C20) and (2) further reducing the insulin receptor affinity by the B16Tyr → His substitution. Insulin icodec was selected by screening for long intravenous plasma half-life in dogs while ensuring glucose-lowering potency following subcutaneous administration in rats. The ensuing structure-activity relationship resulted in insulin icodec. In phase-2 clinical trial, once-weekly insulin icodec provided safe and efficacious glycemic control comparable to once-daily insulin glargine in type 2 diabetes patients. The structure-activity relationship study leading to insulin icodec is presented here.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Animais , Cães , Esquema de Medicação , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Injeções Intravenosas , Injeções Subcutâneas , Insulina/administração & dosagem , Insulina/análogos & derivados , Masculino , Ratos , Ratos Sprague-Dawley
20.
Int J Biol Macromol ; 181: 1224-1230, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-33989689

RESUMO

Proteins and peptides are widely used in various areas including pharmaceutical, health, food, textile and biofuel industries. At present, pharmaceutical proteins and peptides have attracted the attention of many researchers. These types of drugs are superior to chemical drugs in many ways so that every year the number of drugs with a protein or peptide moiety is increasing. Due to high performance and low side effects, the demand for these drugs has increased year by year. The beginning of the protein and peptide drug industry dates back to 1982 with the introduction of the protein hormone insulin into the field of treatment. From this year onwards, a new number of protein and peptide drugs have entered the field of treatment every year. In this article, we focus on human therapeutic insulin. First, the history of the hormone will be introduced, then-current methods for insulin therapy will be discussed and finally, the treatments by this hormone in the future will be pointed. Reading this article would be very helpful for nano researchers, biochemists, organic chemists, material scientists and other people who are interested in soft and hard matters interfaces.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Administração Oral , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Indústria Farmacêutica , Humanos , Hipoglicemiantes/química , Insulina/metabolismo , Peptídeos/química , Peptídeos/uso terapêutico , Proteínas/genética , Proteínas/uso terapêutico
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