Antihyperglycemic activity of compounds isolated from Indian medicinal plants

Eleven antidiabetic Indian medicinal plants were investigated in streptozotocin induced diabetic rat model and provided scientific validation to prove their antihyperglycemic activity. Antidiabetic principles from five plants were isolated. All the compounds isolated were evaluated for antihyperglycemic activity in streptozotocin induced diabetic rat model and activities were compared with standard drug metformin. Some compounds were also screened in db/db mice. Two compounds (PP-1 and PP-2) inhibited significantly the activity of PTPase-1B in an in vitro system. This might be the underlying mechanism of antihyperglycemic activity of these compounds.     

Design and synthesis of 2,4-disubstituted polyhydroquinolines as prospective antihyperglycemic and lipid modulating agents

A series of 2,4-disubstituted polyhydroquinoline were synthesized and evaluated for their in vivo antihyperglycemic as well as antidyslipidemic activities. Several synthesized compounds have exhibited promising in vivo antihyperglycemic in SLM, STZ-S, and db/db mice model along with significant lipid and TG modulating activity. All these compounds were evaluated in various in vitro models of diabetes to know the possible mechanism of their antihyperglycemic action. Interestingly, compounds 3a–r (diaryl substitution) have exhibited promising protein-tyrosine phosphatase 1B (PTP1B) inhibitory activity whereas, compounds 5a–d (acid substituted) have shown significant glycogen phosphorylase activity.     

Synthesis and antihyperglycemic evaluation of new 2,4-thiazolidinediones having biodynamic aryl sulfonylurea moieties

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.     

Influence of chalcone analogues on serum glucose levels in hyperglycemic rats

A series of chalcone derivatives from 3,4-methylenedioxybenzaldehyde and substituted acetophenones have been synthesized and investigated as antihyperglycemic agents in a glucose loaded animal model. Chalcones with biological activity were compared with lispro, regular insulin and tolbutamide effects on serum glucose levels. Compound 01, without substituent in the A-ring was not able to change glycemic levels. On the other hand, compounds 03, 04, 05, 09 and 10 with substitutions at position 3' and/or 4' in the A-ring caused significant reduction in serum glucose levels. Concerning the antihyperglycemic effect, compounds 03 and 05 (methoxy substituent) inhibited the hyperglycemia induced by glucose around 96% similar to that demonstrated for lispro insulin and tolbutamide at 60 min. A rapid and lasting antihyperglycemic effect was found with compound 09 and 10 (nitro substituent). In conclusion, besides the nature of the functional groups electron-donor substituent, as methoxy and hydroxyl or electron-acceptor, as nitro groups, the position of the group may be mandatory for biological activity.     

Three-dimensional quantitative structure activity relationships (3-D-QSAR) of antihyperglycemic agents.

A three-dimensional quantitative structure activity relationship study (3-D-QSAR) was performed on a set of thiazolidinedione antihyperglycemic agents using the comparative molecular field analysis (CoMFA) method. The CoMFA models were derived from a training set of 53 compounds. Fifteen compounds, which were not used in model generation were used to validate the CoMFA models. All the compounds were superimposed to the template structure by atom-based and shape-based strategies. The SYBYL QSAR rigid body field fit was also used for aligning the ligands. A total of twelve different alignments were generated. The resulting models exhibited a good cross-validated r2cv values (0.624-0.764) and the conventional r2 values (0.689-0.921). A more robust cross-validation test using cross-validation by 2 groups (leave half out method) was performed 100 times to ascertain the predictiveness of the CoMFA models. The mean of r2cv values from 100 runs ranged from 0.611-0.690. Few models exhibited good external predictivity. These models were then used to define a hypothetical receptor model for antihyperglycemic agents.     

Design and synthesis of novel imidazoline derivatives with potent antihyperglycemic activity in a rat model of type 2 diabetes

Imidazoline derivatives have been reported to show antihyperglycemic activity in vivo. In the present study, we first showed that there was no correlation between the in vivo antidiabetic activity and the in vitro affinities for the I1/I2 binding sites for several substituted aryl imidazolines. Among these compounds, 2-(alpha-cyclohexyl-benzyl)-4,5-dihydro-1H-imidazole 2 exhibited potent antihyperglycemic properties. It was then chosen as lead compound. Thirty-six new derivatives were synthesized by replacing the cyclohexyl/benzyl group by various cyclic systems or the imidazoline ring by isosteric heterocycles. These compounds were evaluated in vivo for their antihyperglycemic activity using an oral glucose tolerance test (OGTT) in a rat model of type-2 diabetes obtained by giving a single intravenous (iv) injection of a low dose of streptozotocin to rats (STZ rats) and in normal rats. Nine compounds with an imidazoline moiety, possibly substituted by a methyl group, had a potent effect on the glucose tolerance in normal or STZ-diabetic rats, after an oral (po) administration of the test compound at a dose of 30 or 10 mg kg(-1), without any hypoglycemia. Replacement of the imidazoline ring by isosteric heterocycles resulted in a total loss of activity.     

Synthesis and in vivo antihyperglycemic activity of nature-mimicking furanyl-2-pyranones in STZ-S model

Various nature-mimicking pyranones such as 6-(2,5-dimethylfuran-3-yl)-pyran-2-one and 6-(furan-2-yl)-pyran-2-one derivatives were synthesized and evaluated for their in vivo antihyperglycemic activity in sucrose-loaded streptozotocin-induced diabetic rat model. Five of the test compounds showed significant lowering of plasma glucose level in STZ-S model.     

Antioxidant potential of n-butanol fraction from extract of Jasminum mesnyi Hance leaves

Methanolic extract of Jasminum mesnyi Hance leaves having antidiabetic activity was subjected to fractionation to obtain antioxidant and antihyperglycemic rich fraction. Different concentrations of ethyl acetate and n-butanol fractions were subjected to antioxidant assay by DPPH method, nitric oxide scavenging activity and reducing power assay. The fractions showed dose dependent free radical scavenging property in all the models. IC50 values for ethyl acetate and n-butanol fractions were 153.45 +/- 6.65 and 6.22 +/- 0.25 microg/ml, respectively, as compared to L-ascorbic acid and rutin (as standards; IC50 values 6.54 +/- 0.24 and 5.43 +/- 0.21 microg/ml, respectively) in DPPH model. In nitric oxide scavenging activity, IC50 values were 141.54 +/- 9.95 microg/ml, 35.12 +/- 1.58 microg/ml, 21.06 +/- 0.95 microg/ml and 29.93 +/- 0.32 microg/ml for ethyl acetate, n-butanol fractions, L-ascorbic acid and rutin, respectively. n-Butanol fraction showed a good reducing potential and better free radical scavenging activity as compared to ethyl acetate fraction. Potent antioxidant n-butanol fraction showed better oral glucose tolerance test (antihyperglycemic) at par with metformin (standard drug), n-Butanol fraction contained secoiridoid glycosides which might be responsible for both antioxidant and antihyperglycemic activity.     

Novel glitazones: Design,synthesis, glucose uptake and structure–activity relationships

Glitazones are known to exhibit antihyperglycemic activity by decreasing peripheral insulin resistance. In the present study, we have designed some novel glitazones based on the structure–activity relationships as possible PPAR-γ agonists. The manually designed glitazones were synthesized by using the appropriate synthetic schemes and screened for their in vitro antihyperglycemic activity by estimating glucose uptake by rat hemi-diaphragm, both in the absence and in the presence of external insulin. Some of the glitazones exhibited good antihyperglycemic activity in presence of insulin. Illustration about their design, synthesis, evaluation, and structure–activity relationships is described.     

2-O-carboxymethylpyrogallol derivatives as PTP1B inhibitors with antihyperglycemic activity

2-O-carboxymethylpyrogallol derivatives (4-17) were synthesized, with their in vitro inhibitory activities against PTP1B and in vivo antihyperglycemic effects examined. Compound 14, the most potent among the series, showed a K(i) value of 1.1 microM against PTP1B, 7-fold lower than that against TC-PTP. When compound 14 was fed to a high-fat diet-induced diabetic mouse model, significant improvements were observed in both the fasting glucose level and glucose tolerance.     

Synthesis and antihyperglycemic evaluation of new 2-hydrazolyl-4-thiazolidinone-5-carboxylic acids having pyrazolyl pharmacophores

In the search of new antihyperglycemic agents and following rational approach of drug designing here new 2-hydrazolyl-4-thiazolidinone-5-carboxylic acids (4a–g) with pyrazolyl pharmacophore have been synthesized via thia Michael addition reaction of 1-((3-(4-substituted phenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)thiosemicarbazides (3a–g) with maleic anhydride. The required precursors, (3a–g) were obtained by condensing known 3-(4-substituted phenyl)-1-phenyl-1H-pyrazole-4-carbaldehydes (1a–g) with thiosemicarbazide in ethanol. The newly synthesized compounds (4a–g) have been evaluated for the antihyperglycemic activity in sucrose loaded rat model and among these compounds 4d, 4f and 4g have displayed significant antihyperglycemic activity.     

Antihyperglycemic activity of 2-methyl-3,4,5-triaryl-1H-pyrroles in SLM and STZ models

Various 3,4,5-triarylpyrroles were synthesized and evaluated for their in vivo antihyperglycemic activity in sucrose-loaded (SLM) and/or streptozotocin-induced (STZ) diabetic rat models. Three of the test compounds, 2-methyl-4,5-diphenyl-3-substituted-phenyl-1H-pyrroles (3c, d and h) showed significant inhibition on postprandial hyperglycemia in normal rats post sucrose loaded. These compounds also showed lowering of plasma glucose level in STZ-induced diabetic rat model.     

Synthesis of propiophenone derivatives as new class of antidiabetic agents reducing body weight in db/db mice

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.     

Synthesis and in vivo antihyperglycemic activity of 5-(1H-pyrazol-3-yl)methyl-1H-tetrazoles

A series of 5-[(5-aryl-1H-pyrazol-3-yl)methyl]-1H-tetrazoles 3a-h have been synthesized and evaluated for their in vivo antihyperglycemic activity. Some of the synthesized compounds have shown significant glucose lowering activity in male Sprague-Dawley rats in sucrose loaded model. These compounds were also evaluated for their peroxisome proliferator activated receptor gamma agonistic property, but none of them displayed any significant activity.     

Dimerization of piceatannol by Momordica charantia peroxidase and α-glucosidase inhibitory activity of the biotransformation products

Stilbenes, especially those oligomers, have great potential to be antihyperglycemic agents. In this study, eight stilbene dimers, including five new ones, were obtained by biotransformation of piceatannol using Momordica charantia peroxidase (MCP) for the first time. Their structures were established on the basis of spectroscopic evidences. These piceatannol dimers displayed potential α-glucosidase inhibitory activities, and trans double bond, tetrahydrofuran ring, and free adjacent phenolic dihydroxyls were found to be important for their activities. Enzymatic biotransformation of stilbenes by M.charantia peroxidase (MCP) was showed to be a prominent way to produce oligomeric stilbenes for antihyperglycemic development.     

Hypoglycemic and antihyperglycemic activity of Syzygium alternifolium (Wt.) Walp. seed extracts in normal and diabetic rats

Aqueous, ethanolic and hexane fractions of Syzygium alternifolium seeds were prepared and given different doses of these extracts individually to different batches of rats (both normal and alloxan diabetic rats) after an overnight fast. The blood glucose levels were measured at 0, 1, 3, 5 and 7 hours after the treatment. The aqueous extract of Syzygium alternifolium at a dosage of 0.75 g/kg b.w. is showing maximum blood glucose lowering effect in both normal and alloxan diabetic rats. The ethanol and hexane fractions are also showing hypoglycemic and antihyperglycemic activity, but the effect is significantly less than that of aqueous extract. The antihyperglycemic activity of Syzygium alternifolium seed was compared with the treatment of Glibenclamide.     

Antihyperglycemic activity of phenylpropanoyl esters of catechol glycoside and its dimers from Dodecadenia grandiflora

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.     

A novel 3D liver organoid system for elucidation of hepatic glucose metabolism

Hepatic glucose metabolism is a key player in diseases such as obesity and diabetes as well as in antihyperglycemic drugs screening. Hepatocytes culture in two-dimensional configurations is limited in vitro model for hepatocytes to function properly, while truly practical platforms to perform three-dimensional (3D) culture are unavailable. In this work, we present a practical organoid culture method of hepatocytes for elucidation of glucose metabolism under nominal and stress conditions. Employing this new method of culturing cells within a hollow fiber reactor, hepatocytes were observed to self-assemble into 3D spherical organoids with preservation of tight junctions and display increased liver-specific functions. Compared to both monolayer culture and sandwich culture, the hepatocyte organoids displayed higher intracellular glycogen content, glucose consumption, and gluconeogenesis and approached the in vivo values, as also confirmed by gene expression of key enzymes. Moreover, hepatocyte organoids demonstrated more realistic sensitivity to hormonal challenges with insulin, glucagon, and dexamethasone. Finally, the exposure to high glucose demonstrated toxicities including alteration of mitochondrial membrane potential, lipid accumulation, and reactive oxygen species formation, similar to the in vivo responses, which was not captured by monolayer cultures. Collectively, hepatocyte organoids mimicked the in vivo functions better than hepatocyte monolayer and sandwich cultures, suggesting suitability for applications such as antihyperglycemic drugs screening.     

The new clinical trials with thiazolidinediones--DREAM, ADOPT, and CHICAGO: promises fulfilled?

PURPOSE OF REVIEW: Despite extensive documentation of their insulin-sensitizing and antihyperglycemic effects, the importance and place of the thiazolidinediones in diabetes management remain unclear. Three new controlled clinical trials of thiazolidinediones offer new information on the clinical utility of these agents. RECENT FINDINGS: During the past year, three new trials of thiazolidinediones were reported. In Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication, rosiglitazone reduced progression to diabetes in prediabetic patients by 60%. A Diabetes Outcome Progression Trial found rosiglitazone to have greater antihyperglycemic durability than metformin and glyburide in patients with recently diagnosed type 2 diabetes. Finally, in the Carotid Intima-media Thickness in Atherosclerosis using Pioglitazone, treatment with pioglitazone in patients with type 2 diabetes slowed progression of carotid wall thickness compared with the sulfonylurea glimepiride. SUMMARY: These trials support the contention that thiazolidinediones have superior efficacy in improving and stabilizing glycemic control than older antihyperglycemic agents, especially early in the course of type 2 diabetes. Findings from the Carotid Intima-media Thickness in Atherosclerosis using Pioglitazone add to the evidence that these agents have clinically meaningful vasculoprotective effects. Although generally well tolerated, they promote weight gain, limiting their acceptability to some extent, and occasionally lead to a diagnosis of heart failure, mostly in susceptible individuals.     

Reduction in post-prandial hyperglycemic excursion through alpha-glucosidase inhibition by beta-acetamido carbonyl compounds

A series of β-acetamido carbonyl compounds (S₁–S₇) were prepared using Dakin-West reaction from different substituted aldehyde and acetophenone in the presence of lanthanum triflate as a solid catalyst. All the compounds were tested for their α-glucosidase inhibitory potential against rat intestinal α-glucosidase. The most potent rat intestinal α-glucosidase inhibitors S₅ and S₇ were tested for their antihyperglycemic activity following carbohydrate tolerance test. Both the compounds displayed antihyperglycemic activity equivalent to the standard drug acarbose.