ABSTRACT
In current work, we prepared a series of nine 4-benzyloxy-5-benzylidene-1,3-thiazolidine-2,4-diones using a two-step pathway. Compounds 1-9 were tested in vitro using a set of three proteins recognized as important targets in diabetes and related diseases: PPARα, PPARγ, and GLUT-4. Compounds 1-3, 5, and 7 showed significant increases in the mRNA expression of PPARγ and GLUT-4, whereas compounds 1-3 did it over PPARα. Compounds 1-3 were identified as a dual PPAR α/γ modulators and were selected for evaluating the in vivo antidiabetic action at 100 mg/kg dose, being orally actives and decreasing blood glucose concentration in a hyperglycemic mice model, as well as reducing the triacylglycerides levels in normolipidemic rats. Docking and molecular dynamics studies were conducted to clarify the dual effect and binding mode of compounds 1-3 on both PPARs. Compounds 2 and 3 exhibited robust in vitro and in vivo efficacy and could be considered dual PPAR modulators with antidiabetic and antidyslipidemic effects.
Subject(s)
Hypoglycemic Agents , PPAR gamma , Animals , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Lipids , Mice , PPAR alpha/metabolism , PPAR gamma/metabolism , Rats , Thiazolidines/pharmacologyABSTRACT
This work presents the synthesis of two hybrid compounds (1 and 2) with thiazolidine-2,4-dione structure as a central scaffold which were further screened in combo (in vitro as PTP-1B inhibitors, in vivo antihyperglycemic activity, in silico toxicological profile and molecular docking). Compound 1 was tested in the enzymatic assay showing an IC50 = 9.6 ± 0.5 µM and compound 2 showed about a 50% of inhibition of PTP-1B at 20 µM. Therefore, compound 1 was chosen to test its antihyperglycemic effect in a rat model for non-insulin-dependent diabetes mellitus (NIDDM), which was determined at 50 mg/kg in a single dose. The results indicated that compound showed a significant decrease of plasma glucose levels that reached 34%, after a 7 h post-administration. Molecular docking was employed to study the inhibitory properties of thiazolidine-2,4-dione derivatives against Protein Tyrosine Phosphatase 1B (PDB ID: 1c83). Concerning to the two binding sites in this enzyme (sites A and B), compound 1 has shown the best docking score, which indicates the highest affinity. Finally, compounds 1 and 2 have demonstrated an in silico satisfactory pharmacokinetic profile. This shows that it could be a very good candidate or leader for new series of compounds with this central scaffold.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/therapeutic use , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Thiazolidinediones/chemical synthesis , Thiazolidinediones/therapeutic use , Animals , Computer Simulation , Dose-Response Relationship, Drug , Escherichia coli/enzymology , Hypoglycemic Agents/chemistry , Male , Molecular Docking Simulation , Rats, Wistar , Streptozocin , Thiazolidinediones/chemistryABSTRACT
Hit, Lead & Candidate Discovery Protein tyrosine phosphatase 1B (PTP-1B) has attracted interest as a novel target for the treatment of type 2 diabetes, this because its role in the insulin-signaling pathway as a negative regulator. Thus, the aim of current work was to obtain seven ursolic acid derivatives as potential antidiabetic agents with PTP-1B inhibition as main mechanism of action. Furthermore, derivatives 1-7 were submitted in vitro to enzymatic PTP-1B inhibition being 3, 5, and 7 the most active compounds (IC50 = 5.6, 4.7, and 4.6 µM, respectively). In addition, results were corroborated with in silico docking studies with PTP-1B orthosteric site A and extended binding site B, showed that 3 had polar and Van der Waals interactions in both sites with Lys120, Tyr46, Ser216, Ala217, Ile219, Asp181, Phe182, Gln262, Val49, Met258, and Gly259, showing a docking score value of -7.48 Kcal/mol, being more specific for site A. Moreover, compound 7 showed polar interaction with Gln262 and Van der Waals interactions with Ala217, Phe182, Ile219, Arg45, Tyr46, Arg47, Asp48, and Val49 with a predictive docking score of -6.43 kcal/mol, suggesting that the potential binding site could be localized in the site B adjacent to the catalytic site A. Finally, derivatives 2 and 7 (50 mg/kg) were selected to establish their in vivo antidiabetic effect using a noninsulin-dependent diabetes mice model, showing significant blood glucose lowering compared with control group (p < .05).
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Triterpenes , Animals , Blood Glucose/drug effects , Computer Simulation , Diabetes Mellitus, Experimental/blood , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Male , Mice , Molecular Conformation , Molecular Docking Simulation , Molecular Structure , Protein Tyrosine Phosphatase, Non-Receptor Type 1/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Recombinant Fusion Proteins/metabolism , Triterpenes/chemistry , Triterpenes/pharmacology , Triterpenes/therapeutic use , Ursolic AcidABSTRACT
Extensive knowledge of diabetes and its complications is helpful to find new drugs for proper treatment to stop degenerative changes derived from this disease. In this context, chrysin (5,7-dihydroxyflavone) is a natural product that occurs in a variety of flowers and fruits with anti-inflammatory and antidiabetic effects, among others. Thus, a diabetic model in athymic nude mice was developed and used to establish the ability of chrysin to decrease the secretion of pro-inflammatory cytokines. Also, it was determined the acute (50 mg/kg) and sub-acute (50 mg/kg/day/10 days) antidiabetic and antihyperlipidemic activities after the period of time treatment. Results indicate that chrysin has significant acute antihyperglycemic and antidiabetic effects in nude diabetic mice (p < 0.05). Moreover, triglyceride blood levels were reduced and IL-1ß and TNF-α were diminished after 10 days' treatment compared with control group (p < 0.05). In conclusion, it was found that chrysin could produce similar effects as metformin, a drug used for the treatment of diabetes, since both test samples decreased glucose and triglycerides levels, they impaired the generation of pro-inflammatory cytokines involved in the development of diabetes and its consequences, such as atherosclerosis and other cardiovascular diseases.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Diabetes Mellitus, Experimental/drug therapy , Flavonoids/therapeutic use , Hypoglycemic Agents/therapeutic use , Hypolipidemic Agents/therapeutic use , Animals , Blood Glucose , Cytokines/metabolism , Flavonoids/administration & dosage , Interleukin-1beta/metabolism , Male , Metformin/therapeutic use , Mice, Nude , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Herein, the design and synthesis of 10 novel N'-arylidene pyrazole-3-carbohydrazides are described. Compounds were pretended to act as dual agents against diabetes and oxidative stress, two correlated pathologies involved in metabolic syndrome development and progression. The antioxidant capacity was evaluated by means of DPPH and FRAP in vitro assays. It was found that compounds bearing a hydroxyl group at 4-position of the hydrazone moiety are potent antioxidant entities, being compound 3g (a syringaldehyde derivative) the most active compound. In addition, the in vivo hypoglycemic effect of the analogues was determined. With regard to the above, the cinnamaldehyde derivatives showed a scarce biological activity, while the 4-hydroxy analogues showed the higher glycemia reduction at 7h after administration. Interestingly, the most potent antioxidants 3b and 3g also were of the most active compounds in reducing the plasma glucose, reaching 80% of reduction in the case of 3g. Molecular docking binding poses conducted to a plausible interpretation of the biological outcomes and a possible interaction between a hydroxy group and Asn287 of CB1R was proposed as an important feature for enhancing the observed activity.
Subject(s)
Antioxidants/chemistry , Antioxidants/therapeutic use , Diabetes Mellitus, Experimental/drug therapy , Hydrazines/chemistry , Hydrazines/therapeutic use , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Animals , Antioxidants/pharmacology , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/metabolism , Halogenation , Hydrazines/pharmacology , Hypoglycemic Agents/pharmacology , Male , Molecular Docking Simulation , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Rats, Wistar , Receptor, Cannabinoid, CB1/metabolismABSTRACT
Herein, we report the design and synthesis of 13 diarylpyrazole hybrids with vanillin constructed as dual compounds against oxidative stress and diabetes. Compounds were tested in two different antioxidant assays. It was found that all compounds showed an important antioxidant activity in both DPPH and ORAC models and the activity was even more remarkable than vanillin. In addition, the hypoglycemic effect of compounds 1, 2, 4 and 12 was evaluated. Interestingly, compound 1 had the most potent hypoglycemic effect with a glycemia reduction of 71%, which was higher than rimonabant. Finally, a DFT study to propose a reasonable antioxidant mechanism is detailed. Both thermodynamic and kinetic studies indicated that the most feasible mechanism consists in the HAT abstraction of the phenolic hydrogen due to the formation of an stable transition state through the most rapid and exergonic path, while the SPLET mechanism is the most significant at higher pH values.
Subject(s)
Antioxidants/pharmacology , Diabetes Mellitus, Experimental/drug therapy , Hypoglycemia/drug therapy , Hypoglycemic Agents/pharmacology , Pyrazoles/pharmacology , Quantum Theory , Animals , Antioxidants/chemical synthesis , Antioxidants/chemistry , Benzaldehydes/chemistry , Benzaldehydes/pharmacology , Dose-Response Relationship, Drug , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Molecular Structure , Oxidative Stress/drug effects , Pyrazoles/chemistry , Rats , Structure-Activity RelationshipABSTRACT
Non-insulin dependent diabetes mellitus is a multifactorial disease that links different metabolic routes; a point of convergence is the enzyme PTP-1B which turns off insulin and leptin receptors involved in glucose and lipid metabolism, respectively. Pentacyclic acid triterpenes such as oleanolic acid (OA) have proved to be excellent PTP-1B inhibitors, thus, the purpose of current work was to generate a series of derivatives that improve the pharmacological effect of OA. Our findings suggest that the presence of the carboxylic acid and/or its corresponding reduction product carbinol derivative (H-bond donor) in C-28 is required to maintain the inhibitory activity; moreover, this is further enhanced by ester or ether formation on C-3. The most active derivatives were cinnamoyl ester (6) and ethyl ether (10). Compound 6 showed potent in vitro inhibitory activity and significantly decrease of blood glucose levels on in vivo experiments. Meanwhile, 10 showed contrasting outcomes, since it was the compound with higher inhibitory activity and selectivity over PTP-1B and has improved interaction with site B, according with docking studies, the in vivo antidiabetic effect was similar to oleanolic acid. In conclusion, oleanolic acid derivatives have revealed an enhanced inhibitory effect over PTP-1B activity by increasing molecular interactions with either catalytic or allosteric sites and producing a hypoglycaemic effect on non insulin dependent diabetes mellitus rat model.
Subject(s)
Computer Simulation , Oleanolic Acid/chemical synthesis , Oleanolic Acid/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Animals , Binding Sites , Chemistry Techniques, Synthetic , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/metabolism , Hypoglycemic Agents/pharmacology , Male , Molecular Docking Simulation , Oleanolic Acid/chemistry , Oleanolic Acid/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 1/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , RatsABSTRACT
Compound {4-[({4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}acetyl)amino]phenoxy}acetic acid (1) was prepared and the in vitro relative expression of PPARγ, GLUT-4 and PPARα, was estimated. Compound 1 showed an increase of 2-fold in the mRNA expression of PPARγ isoform, as well as the GLUT-4 levels. The antidiabetic activity of compound 1 was determined at 50 mg/Kg single dose using a non insulin dependent diabetes mellitus (NIDDM) rat model. The in vivo results indicated a significant decrease of plasma glucose levels, during the 7 h post-administration. Also, we performed a molecular docking of compound 1 into the ligand binding pocket of PPARγ, showing important short contacts with residues Ser289, His323 and His449 in the active site.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Glucose Transporter Type 4/metabolism , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , PPAR gamma/metabolism , Thiazolidines/pharmacology , Thiazolidines/therapeutic use , Animals , Diabetes Mellitus, Experimental/metabolism , Disease Models, Animal , Glucose Transporter Type 4/genetics , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Ligands , Mice , Molecular Docking Simulation , Molecular Structure , PPAR gamma/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Thiazolidines/chemistryABSTRACT
Compounds 1-10 were designed using a bioisosteric approach and were prepared using a short synthetic route. The in vitro inhibitory activity of the compounds against 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) was evaluated. Compounds 5 (α-series) and 10 (ß-series) had a moderate inhibitory enzyme activity (55.26% and 67.03% inhibition at 10 µM, respectively) and were as active as BVT.14225 (positive control). Both compounds have a piperidine ring in their structure, but the most active (10) was selected to establish its in vivo antidiabetic effect using a non insulin-dependent diabetes mellitus rat model. The antidiabetic activity of compound 10 was determined at 50 mg/kg single dose in an acute model, and also by short term sub-chronic administration for 5 days. The results indicated a significant decrease of plasma glucose levels, similar than BVT.14225. Additionally, a molecular docking of the most active compounds of each series into the ligand binding pocket of one subunit of human 11ß-HSD1 was performed. In this model the oxygen atom of the sulfonamide make hydrogen bond interactions with the catalytic residues Ser170 and Ala172. We also observed important π-π interactions between the naphthyl group and Tyr177.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , Acetamides/chemical synthesis , Diabetes Mellitus, Experimental/drug therapy , Enzyme Inhibitors/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Acetamides/pharmacology , Acetamides/therapeutic use , Animals , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Molecular Docking Simulation , RatsABSTRACT
Diabetes and obesity are two universal health problems that constitute a research objective of several groups due to the lack of efficient and safe drug treatment. In this sense, cannabinoid receptor 1 (CB1) has attracted interest because of its role in food intake and metabolic balance, two targets in the control of metabolic syndrome. In this work, novel 1,5-diaryl pyrazole derivatives were synthesized in accordance with the pKi prediction of a previously reported CoMFA model by our group. To further investigate the biological activity of these compounds in metabolic disorders, their hypoglycemic activity in an in vivo model was tested. Interestingly, a high degree of correlation was observed between the predicted pKi and hypoglycemic effect 7 h after administration. Compounds 4, 9 and 13 showed the most significant plasma glucose reduction with decreases of 60%, 64% and 60% respectively. This result not only surpasses the activity of the lead rimonabant, but also that of the reference drug glibenclamide. Moreover, PASS prediction and molecular docking in an excellent validated homology model of CB1 suggest that these compounds would probably act as CB1 antagonists/inverse agonists and therefore, anti-obesity agents. The ligand-receptor complexes demonstrate that 1,5-diaryl pyrazole derivatives bind to the proposed binding site where a hydrophobic moiety interacts with the phenyl rings in the pyrazole nucleus and Lys192 forms a hydrogen bond with the oxygen of the carbonyl group. Dynamics simulations were also carried out to study the stability of the ligand-receptor complexes where the most active compounds showed smaller ΔG values and more hydrogen bonds throughout the simulation. These compounds are considered useful leads for further optimization in the treatment of such metabolic illnesses.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Drug Design , Hydrazines/chemical synthesis , Hydrazines/pharmacology , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Quantitative Structure-Activity Relationship , Animals , Humans , Hydrazines/chemistry , Hypoglycemic Agents/chemistry , Male , Models, Molecular , Molecular Dynamics Simulation , Pyrazoles/chemistry , Rats , Rats, Wistar , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/antagonists & inhibitors , ThermodynamicsABSTRACT
Morolic (1) and moronic (2) acids are the main constituents of acetonic extract from Phoradendron reichenbachianum (Loranthaceae), a medicinal plant used in Mexico for the treatment of diabetes. The aim of the current study was to establish the sub-acute antidiabetic and antihyperlipidemic effects of compounds 1 and 2 over non insulin-dependent diabetic rat model. Also, to determine the antihyperglycemic action on normoglycemic rats by oral glucose tolerance test. Daily-administered morolic (1) and moronic (2) acids (50 mg/kg) significantly lowered the blood glucose levels at 60% since first day until tenth day after treatment than untreated group (p<0.05). Moreover, analyzed blood samples obtained from diabetic rats indicated that both compounds diminished plasmatic concentration of cholesterol (CHO) and triglycerides (TG), returning them to normal levels (p<0.05). Also, pretreatment with 50 mg/kg of each compound induced significant antihyperglycemic effect after glucose and sucrose loading (2 g/kg) compared with control group (p<0.05). In vitro studies showed that compounds 1 and 2 induced inhibition of 11ß-HSD 1 activity at 10 µM. However, in silico analysis of the pentaclyclic triterpenic acids on 11ß-HSD 1 revealed that all compounds had high docking scores and important interactions with the catalytic site allowing them to inhibit 11ß-HSD 1 enzyme. In conclusion, morolic and moronic acids have shown sustained antidiabetic and antihyperglycemic action possibly mediated by an insulin sensitization with consequent changes of glucose, cholesterol and triglycerides, in part mediated by inhibition of 11ß-HSD 1 as indicated by in vitro and in silico studies.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Hypoglycemic Agents/pharmacology , Oleanolic Acid/analogs & derivatives , Triterpenes/pharmacology , 11-beta-Hydroxysteroid Dehydrogenase Type 1/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Animals , Blood Glucose/analysis , Cholesterol/blood , Computer Simulation , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 1/drug therapy , Enzyme Inhibitors/pharmacology , Glucose Tolerance Test , HEK293 Cells/drug effects , Humans , Molecular Docking Simulation , Oleanolic Acid/chemistry , Oleanolic Acid/pharmacology , Rats , Rats, Wistar , Triglycerides/blood , Triterpenes/chemistryABSTRACT
The aim of the current study was to investigate the oral antidiabetic activity of four structurally-related triterpenic acids: ursolic (RE-01), oleanolic (RE-02), moronic (RE-03) and morolic (RE-04) acids. STZ-nicotinamide diabetic rats were treated with these triterpenes (50 mg/kg) and the antidiabetic effects in acute experiment were determined. All compounds showed significant antidiabetic activity in comparison with control group (p<0.05). The in vitro inhibitory activity of compounds against protein tyrosine phosphatase 1B (PTP-1B) was also evaluated. At 50 µM, the enzymatic activity was almost completely inhibited. All compounds were docked with a crystal structure of PTP-1B. Docking results suggested the potential binding of the triterpenic acids in a binding pocket next to the catalytic site. An extensive hydrogen bond network with the carboxyl group and Van der Waals interactions stabilize the protein-ligand complexes.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Enzyme Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Triterpenes/pharmacology , Animals , Diabetes Mellitus, Experimental/enzymology , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Humans , Hypoglycemic Agents/chemistry , Male , Models, Molecular , Molecular Conformation , Protein Tyrosine Phosphatase, Non-Receptor Type 1/isolation & purification , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Rats , Rats, Wistar , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/isolation & purification , Recombinant Proteins/metabolism , Stereoisomerism , Structure-Activity Relationship , Triterpenes/chemistryABSTRACT
OBJECTIVES: The aim was to evaluate the relaxant effect of extracts from Valeriana edulis and determine the possible mechanism of action of the hexanic extract as vasorelaxant agent. METHODS: Extracts from rhizomes obtained by maceration (hexanic (HEVe), dichloromethanic (DEVe), methanolic (MEVe) and hydroalcoholic (HAEVe) (3.03-500 microg/ml)) were evaluated on aortic rat rings with and without endothelium. KEY FINDINGS: Extracts induced a significant concentration-dependent and endothelium-independent relaxation on isolated rat aorta pre-contracted with noradrenaline (0.1 microM). HEVe, the most potent extract (0.15-50 microg/ml), induced relaxation in aortic rings pre-contracted with KCl (80 mM), with an IC50 value of 34.61 +/- 1.41 microg/ml and E(max) value of 85.0 +/- 4.38%. Pretreatment with HEVe (30 microg/ml) also inhibited contractile responses to noradrenaline and CaCl(2). HEVe (9.98 +/- 2.0 microg/ml) reduced noradrenaline-induced transient contraction in Ca(2+)-free solution, and inhibited contraction induced by KCl (80 mM). In endothelium-denuded rings, the vasorelaxant effect of HEVe was not modified by 1-H-[1,2,4]-oxadiazolo-[4,3a]-quinoxalin-1-one (1 microM), tetraethylammonium (5 mM), glibenclamide (10 microM) or 2-aminopyridine (100 microM). CONCLUSIONS: Our results suggest that HEVe induces relaxation through an endothelium-independent pathway, involving blockade of Ca(2+) channels, and this effect could be related to the presence of valepotriates.