RESUMO
INTRODUCTION: The present study deals with the synthesis of pregnane-oximino-amino-alkyl-ethers and their evaluation for antidiabetic and anti-dyslipidemic activities in validated animal and cell culture models. METHODS: The effect on glucose tolerance was measured in sucrose-loaded rats; antidiabetic activity was evaluated in streptozotocin (STZ)-induced diabetic rats and genetically diabetic db/db mice; the anti-dyslipidemic effect was characterized in high-fructose, high-fat diet (HFD)-fed dyslipidemic hamsters. The effect on glucose production and glucose utilization was analyzed in HepG2 liver and L6 skeletal muscle cells, respectively. RESULTS: From the synthesized molecules, pregnane-oximino-amino-alkyl-ether (compound 14b) improved glucose clearance in sucrose-loaded rats and exerted antihyperglycemic activity on STZ-induced diabetic rats. Further evaluation in genetically diabetic db/db mice showed temporal decrease in blood glucose, and improvement in glucose tolerance and lipid parameters, associated with mild improvement in the serum insulin level. Moreover, compound 14b treatment displayed an anti-dyslipidemic effect characterized by significant improvement in altered lipid parameters of the high-fructose, HFD-fed dyslipidemic hamster model. In vitro analysis in the cellular system suggested that compound 14b decreased glucose production in liver cells and stimulated glucose utilization in skeletal muscle cells. These beneficial effects of compound 14b were associated with the activation of the G-protein-coupled bile acid receptor TGR5. CONCLUSION: Compound 14b exhibits antidiabetic and anti-dyslipidemic activities through activating the TGR5 receptor system and can be developed as a lead for the management of type II diabetes and related metabolic complications.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Pregnanos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Glicemia/efeitos dos fármacos , Linhagem Celular , Cricetinae , Diabetes Mellitus Experimental/metabolismo , Dislipidemias/metabolismo , Fenofibrato/farmacologia , Fenofibrato/uso terapêutico , Transportador de Glucose Tipo 4/metabolismo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Hipolipemiantes/uso terapêutico , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos , Pregnanos/química , Pregnanos/farmacocinética , Pregnanos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/metabolismoRESUMO
New 2,4-thiazolidinediones with aryl sulfonylurea moieties have been synthesized by condensing various substituted sulfonamides and 5-(isocyanatomethyl) thiazolidino-2,4-dione. The isocyanomethyl thiazolidinedione was obtained by using the Curtius rearrangement, starting from known 2,4-dioxo-5-thiazolidineacetic acid. The newly synthesized compounds have been evaluated for the antihyperglycemic activity in normal rats model and among these compounds showed significant antihyperglycemic activity in sucrose loaded rat model.
Assuntos
Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/farmacologia , Compostos de Sulfonilureia/química , Tiazolidinedionas/síntese química , Tiazolidinedionas/farmacologia , Animais , Glicemia/efeitos dos fármacos , Química Farmacêutica/métodos , Cromatografia em Camada Fina/métodos , Desenho de Fármacos , Masculino , Modelos Químicos , Ratos , Ratos Sprague-Dawley , Sacarose/química , Fatores de TempoRESUMO
A series of propiophenone derivatives (6-23) have been synthesized and evaluated for their in vivo antihyperglycemic activities in sucrose loaded model (SLM), sucrose challenged streptozotocin (STZ-S) induced diabetic rat model and C57BL/KsJ db/db diabetic mice model. Compound 15 and 16 were emerged as potent antihyperglycemics and lipid lowering agents. These compounds (15, 16) further validate the potency by reducing body weight and food intake in db/db mice model. Possible mechanism of action for the propiophenone derivatives was established by the evaluation in various in vitro models. Interestingly some of the compounds were efficiently inhibiting PTP-1B.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Propiofenonas/química , Propiofenonas/uso terapêutico , Redução de Peso/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Hipolipemiantes/síntese química , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Hipolipemiantes/uso terapêutico , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Propiofenonas/síntese química , Propiofenonas/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , EstreptozocinaRESUMO
Various phenolic C-glycosides were evaluated for their in vitro and in vivo antihyperglycemic activity employing glucose uptake by rat muscle cell lines (L-6) and low dosed-streptozotocin-induced diabetic rats, respectively. Some of phenolic C-glycosides were isolated from Pterocarpus marsupium and Ulmus wallichiana and other were synthesized by unprotected sugar and phloroacetophenone using Sc(OTf)(3) in aqueous ethanol. Eight among tested compounds showed significant lowering of blood glucose level on low dosed-streptozotocin-induced diabetic rats. The compound 24 lowered the blood glucose levels by 34.9% and 33.6% during 0-5h and 0-24h, respectively, at the dose of 25mg/kg body weight which is comparable to standard antidiabetic drug metformin.
Assuntos
Chalconas/química , Glucosídeos/química , Hipoglicemiantes/síntese química , Fenóis/química , Animais , Glicemia/metabolismo , Linhagem Celular , Chalconas/isolamento & purificação , Chalconas/uso terapêutico , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Glucosídeos/síntese química , Glucosídeos/uso terapêutico , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Pterocarpus/química , Ratos , Relação Estrutura-Atividade , Ulmus/químicaRESUMO
A series of substituted phenoxy-3-piperazin-1-yl-propan-2-ols has been synthesized and evaluated for PTP1B inhibitory activity in vitro and for antidiabetic activity in vivo. Two molecules viz. 4a and 5b showed PTP1B inhibition of 31.58% and 35.90% at 100 µM concentration. The compound 4a also showed 40.3% normalization of plasma glucose levels at 100mg/kg in Sugar-loaded model (SLM) and 32% activity in Streptozodocin model (STZ). The docking studies of these molecules revealed that hydrogen bond formation with Arg221 is important for activity.
Assuntos
Inibidores Enzimáticos/síntese química , Hipoglicemiantes/síntese química , Piperazinas/síntese química , Propanóis/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Animais , Sítios de Ligação , Domínio Catalítico , Simulação por Computador , Diabetes Mellitus Experimental/tratamento farmacológico , Modelos Animais de Doenças , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Piperazina , Piperazinas/química , Piperazinas/uso terapêutico , Propanóis/síntese química , Propanóis/uso terapêutico , Estrutura Terciária de Proteína , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , RatosRESUMO
A simple synthesis of phenyl butenoyl C-glycosides has been achieved by Aldol condensation of peracetylated glycosyl acetones with aromatic aldehydes followed by deacetylation with methanolic NaOMe. The selected butenoyl C-glycosides on conjugate addition of diethyl malonate resulted in polyfunctional alkanonyl glycosides in good yields. The butenoyl C- and alkanoyl C-glycosides were evaluated for their alpha-glucosidase, glucose-6-phosphatse and glycogen phosphorylase enzyme inhibitory activities in vitro. Three of the synthesized (3, 5 and 9) showed potent enzyme inhibitory activities as compared to standard drugs. Compounds 3, 5 and 9 were evaluated in vivo too displaying significant activity as compared to standard drugs acarbose and metformin.
Assuntos
Inibidores Enzimáticos/síntese química , Glucose-6-Fosfatase/antagonistas & inibidores , Glicogênio Fosforilase/antagonistas & inibidores , Inibidores de Glicosídeo Hidrolases , Glicosídeos/síntese química , Animais , Glicemia/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glucose-6-Fosfatase/metabolismo , Glicogênio Fosforilase/metabolismo , Glicosídeos/química , Glicosídeos/farmacologia , Ratos , alfa-Glucosidases/metabolismoRESUMO
The present study was aimed to investigate antimicrobial potential of Glycyrrhiza glabra roots. Antimycobacterial activity of Glycyrrhiza glabra was found at 500 microg/mL concentration. Bioactivity guided phytochemical analysis identified glabridin as potentially active against both Mycobacterium tuberculosis H(37)Ra and H(37)Rv strains at 29.16 microg/mL concentration. It exhibited antimicrobial activity against both Gram-positive and Gram-negative bacteria. Our results indicate potential use of licorice as antitubercular agent through systemic experiments and sophisticated anti-TB assay.
Assuntos
Antibacterianos/farmacologia , Glycyrrhiza/química , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade MicrobianaRESUMO
Based on high throughput screening of our chemical library, we identified two 4,5-dihydro-2H-benzo[e]indazole derivatives (5d and 5g), which displayed a significant effect on glucose uptake in L6 skeletal muscle cells. Based on these lead molecules, a series of benzo[e]indazole derivatives were prepared. Among all the synthesized dihydro-2H-benzo[e]indazoles, 8-(methylthio)-2-phenyl-6-p-tolyl-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate (5e) showed significant glucose uptake stimulation in L6 skeletal muscle cells, even better than lead compounds. Additionally, 5e decreased glucagon-induced glucose release in HepG2 hepatoma cells. The 2H-benzo[e]indazole 5e exerted an antihyperglycemic effect in normal, sucrose challenged streptozotocin-induced diabetic rats and type 2 diabetic db/db mice. Treatment with 5e at a dose of 30 mg kg-1 in db/db mice caused a significant decrease in triglyceride and total cholesterol levels and increased the HDL-C level in a significant manner. The mechanistic studies revealed that the 2H-benzo[e]indazole 5e significantly stimulated insulin-induced signaling at the level of IRS-1, Akt and GSK-3ß in L6 skeletal muscle cells, possibly by inhibiting protein tyrosine phosphatase-1B. This new 2H-benzo[e]indazole derivative has potential for the treatment of diabetes with improved lipid profile.
RESUMO
In this work, we demonstrated insulin signaling and the anti-inflammatory effects by the chloroform fraction of ethanolic extract of Nymphaea rubra flowers in TNF-α-induced insulin resistance in the rat skeletal muscle cell line (L6 myotubes) to dissect out its anti-hyperglycemic mechanism. N. rubra enhances the GLUT4-mediated glucose transport in a dose dependent manner and also increases the tyrosine phosphorylation of both IR-ß and IRS-1, and the IRS-1 associated PI-3 kinase activity in TNF-α-treated L6 myotubes. Moreover, N. rubra decreases Ser(307) phosphorylation of IRS-1 by the suppression of JNK and NF-κB activation. In conclusion, N. rubra reverses the insulin resistance by the inhibition of c-Jun NH2-Terminal Kinase and Nuclear-κB.
Assuntos
Anti-Inflamatórios/farmacologia , Flores/química , Hipoglicemiantes/farmacologia , Resistência à Insulina , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fibras Musculares Esqueléticas/metabolismo , NF-kappa B/metabolismo , Nymphaea/química , Extratos Vegetais/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Anti-Inflamatórios/química , Linhagem Celular , Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Hipoglicemiantes/química , Insulina/metabolismo , Fibras Musculares Esqueléticas/citologia , Extratos Vegetais/química , RatosRESUMO
A series of functionalized biaryl-4-carbonitriles was synthesized in three steps and evaluated for PTP-1B inhibitory activity. Among the synthesized compounds, four biaryls 6a-d showed inhibition (IC50 58-75 µM) against in vitro PTP-1B assay possibly due to interaction with amino acid residues Lys120, Tyr46 through hydrogen bonding and aromatic-aromatic interactions, respectively. Two biaryl-4-carbonitriles 6b and 6c showed improved glucose tolerance, fasting as well as postprandial blood glucose, serum total triglycerides, and increased high-density lipoprotein-cholesterol in SLM, STZ, STZ-S and C57BL/KsJ-db/db animal models. The bioanalysis of 4'-bromo-2,3-dimethyl-5-(piperidin-1-yl)biphenyl-4-carbonitrile (6b) revealed that like insulin, it increased 2-deoxyglucose uptake in skeletal muscle cells (L6 and C2C12 myotubes). The compound 6b significantly up-regulated the genes related to the insulin signaling pathways like AMPK, MAPK including glucose transporter-4 (GLUT-4) gene in muscle tissue of C57BL/KsJ-db/db mice. Furthermore, it was observed that the compound 6b up-regulated PPARα, UCP2 and HNF4α, which are key regulator of glucose, lipid, and fatty acid metabolism. Western blot analysis of the compound 6b showed that it significantly increased the phosphorylation of AMPK and p38 MAPK and ameliorated glucose uptake in C57BL/KsJ-db/db mice through the AMPK-p38 MAPK pathway.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Nitrilas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Glicemia/metabolismo , Linhagem Celular , HDL-Colesterol/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Regulação da Expressão Gênica , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Hiperglicemia , Hipoglicemiantes/síntese química , Insulina/metabolismo , Canais Iônicos/genética , Canais Iônicos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Modelos Moleculares , Fibras Musculares Esqueléticas , Nitrilas/síntese química , PPAR alfa/genética , PPAR alfa/metabolismo , Ratos , Estreptozocina , Triglicerídeos/sangue , Proteína Desacopladora 2 , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
Design and synthesis of protein tyrosine phosphatases-1B (PTP1B) inhibitors are important for the drugs targeted to treat diabetes and obesity. The pharmacophore modeling, docking and scaffold hopping techniques have been applied to discover the novel PTP1B inhibitors. The ten prioritized compounds (115-119, 120-121, 127, 130-131) from the library of 86 compounds were synthesized and found positive in the micro molar range for PTP1B in-vitro inhibitory assays as compared to Suramin (IC50 9.5 µM). Among these five active compounds (115-119) were tested in STZ-s induced diabetic rat model and the most active compound 115 in this test, was further tested in C57BL/KsJ-db/db mice where it significantly improved OGTT along with the fasting and random blood glucose level. The treatment by the compound 115 significantly improved the insulin resistance and insulin signaling by restoring the insulin level and normalizing the serum lipid profile. Compound 115 also augmented the insulin action by modulating the expression of genes involved in insulin signaling like IRS 1-2, PI3K, PTPN1, Akt2, AMPK and PPAR-α. Western blot analysis of both skeletal muscle and liver demonstrated that proteins and intermediate enzymes of insulin signaling were also increased as compared to control group. The compound 115 was also investigated for anti-adipogenic effect on 3T3L-1 cells. The compound 115 inhibited MDI induced lipid accumulation in a dose-dependent manner. The oral bioavailability of compound 115 was â¼10.29% after 30 mg/kg oral dosing assessed in rat.
Assuntos
Inibidores Enzimáticos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Animais , Domínio Catalítico , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Relação Quantitativa Estrutura-Atividade , RatosRESUMO
Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia. α-Glucosidase (EC 3.2.1.20) inhibitors interfere with enzymatic action to slow down the liberation of d-glucose from oligosaccharides and disaccharides, resulting in delayed glucose absorption and decreased postprandial plasma glucose levels. In continuation of our drug discovery program on antidiabetic agents, we synthesized novel N-allylated/N-alkylated niacin and α-amyrin (4-9) and lupeol (12-16) hybrids and tested for their α-glucosidase inhibiting activity. Compounds 4-9 showed better activity profile than the marketed α-glucosidase inhibitor i.e. acarbose. Compound 4 possess the highest inhibitory action with IC50 of 5 µM. Kinetic and CD studies revealed that 4 inhibited the α-glucosidase in a noncompetitive manner and caused conformational changes in secondary structure of the enzyme protein.
Assuntos
Inibidores Enzimáticos/síntese química , Hipoglicemiantes/síntese química , Niacina/química , Triterpenos/química , Animais , Glicemia/metabolismo , Dicroísmo Circular , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/prevenção & controle , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores de Glicosídeo Hidrolases , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Cinética , Modelos Químicos , Estrutura Molecular , Ratos , Resultado do Tratamento , alfa-Glucosidases/química , alfa-Glucosidases/metabolismoRESUMO
A series of pyranosyl homo-C-nucleosides have been synthesized by reaction of butenonyl C-glycosides (5a-5j, and 8) and cyanoacetamide in presence of t-BuOK followed by further modifications. The reaction proceeds by Michael addition of cyanoacetamide to the butenonyl C-glycosides and subsequent dehydrative cyclization and oxidative aromatization to give glycosylmethyl pyridones (6a-6j, 7a-7j, 9, and 10). The glycosylmethyl pyridones (6a-6e) on reaction with POCl(3) under reflux gave respective glycosylmethyl pyridines (11a-11e and 12a-12e) in good yields. The synthesized compounds were screened for their in vitro α-glucosidase, glucose-6-phosphatase and glycogen phosphorylase inhibitory activities. One of the pyridylmethyl homo-C-nucleoside, compound 11d, displayed 52% inhibition of glucose-6-phosphatase as compared to the standard drug sodium orthovanadate while compound 12a showed a significant antihyperglycemic effect of 17.1% in the diabetic rats as compared to the standard drug metformin.
Assuntos
Inibidores Enzimáticos/uso terapêutico , Hipoglicemiantes/síntese química , Nucleosídeos/síntese química , Piranos/síntese química , Animais , Ciclização , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glucose-6-Fosfatase/antagonistas & inibidores , Glucose-6-Fosfatase/metabolismo , Glicogênio Fosforilase/antagonistas & inibidores , Glicogênio Fosforilase/metabolismo , Inibidores de Glicosídeo Hidrolases , Glicosilação , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Modelos Químicos , Nucleosídeos/química , Nucleosídeos/uso terapêutico , Piranos/química , Piranos/uso terapêutico , Piridinas/metabolismo , Piridonas/metabolismo , Ratos , alfa-Glucosidases/metabolismoRESUMO
A new anthraquinone (3,8-dihydroxy-2-methyl anthraquinone), named tectone (1), along with fourteen known compounds (2-15) comprised of five terpenoids (2-5, 15), four flavonoids (6-9), three flavone glycosides (10-12), and two phenolic glycosides (13-14) were isolated from the chloroform and n-butanol fractions of the ethanol extract of Tectona grandis leaves. Attempts were made to synthesize compound 1. This resulted in the synthesis of three additional anthraquinones (16-18), out of which compound 16 is new. The structures of all compounds were established by spectral analysis. The isolated and synthesized compounds were evaluated for their antihyperglycemic activity. Compounds 1, 2, 4 and 14 showed significant antihyperglycemic activity in streptozotocin-induced diabetic rats at a dose of 100 mg/kg body weight, which is comparable to the standard drug metformin.
Assuntos
Antraquinonas/química , Antraquinonas/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Verbenaceae/química , Animais , Antraquinonas/síntese química , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/síntese química , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Metformina/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Ratos , Ratos Sprague-DawleyRESUMO
Bioactivity-guided separation of an antihyperglycemic extract from the leaves of Dodecadenia grandiflora afforded two phenylpropanoyl esters of catechol glycosides (1 and 4) and two lignane bis(catecol glycoside)esters (2 and 3). Their structures were established on the basis of extensive spectroscopic analysis (1D and 2D-NMR, MS). Compounds 2 and 3 are believed to be derived from dimerization via the two phenylpropanoid units of 1. Compounds 1-4 showed significant antihyperglycemic activity in streptozotocin-induced (STZ) diabetic rats, which is comparable to the standard drug metformin. Our results provide support to explain the use of D. grandiflora as antihyperglycemic agent by the traditional medical practitioners.