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 activity of suitably functionalized 3H-quinazolin-4-ones

A series of 2-sec-amino-3H-quinazolin-4-ones (4a-p) and 4-sec-amino-2-chloroquinazolines (5a-b) have been synthesized by nucleophilic substitution reaction of 2-chloro-4(3H)-quinazolones (3) and 2,4-dichloroquinazolines (2) with amines, respectively. Most of the synthesized compounds were evaluated for antihyperglycemic activity but only 4a,b,d,j,o displayed significant reduction in blood glucose level in streptozotocin and sucrose loaded rat models.     

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.     

Synthesis and antihyperglycemic evaluation of various protoberberine derivatives

Various berberine derivatives (2-17) were synthesized and their antihyperglycemic activities were evaluated in a model of beta-cell-membrane chromatography and a model of alloxan-induced diabetes mice. The results indicated that compounds 5 and 14 exhibited antihyperglycemic activity. Their structure-activity relationships were discussed.     

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.     

Synthesis,characterization and biological evaluation of some novel 2,4-thiazolidinediones as potential cytotoxic,antimicrobial and antihyperglycemic agents

A series of some novel 2,4-thiazolidinediones (TZDs) (2a–x) have been synthesized and characterized by FTIR, ¹H NMR, ¹³C NMR and LC mass spectral analysis. All the synthesized compounds were evaluated for their cytotoxicity, antimicrobial and in vivo antihyperglycemic activities. Among the tested compounds for cytotoxicity using Brine Shrimp Lethality assay, compound 2t ((Z)-5-(4-((E)-3-oxo-3-(thiophen-2-yl)prop-1-enyl)benzylidene)-1,3-thiazolidine-2,4-dione) exhibited significant inhibitory activity at ED₅₀ value 4.00 ± 0.25 μg/mL and this level of activity was comparable to that of the reference drug podophyllotoxin with ED₅₀ value 3.61 ± 0.17 μg/mL. Antimicrobial activity was screened using agar well diffusion assay method against selected Gram-positive, Gram-negative and fungal strains and the activity expressed as the minimum inhibitory concentration (MIC) in μg/mL. From the results of antimicrobial activity compound 2s ((Z)-5-(4-((E)-3-(3,5-bis(benzyloxy)phenyl)-3-oxoprop-1-enyl)benzylidene)-1,3-thiazolidine-2,4-dione) was found to be the most active against all the tested strains of microorganisms with MIC value 16 μg/mL. In vivo antihyperglycemic effect of twenty four TZDs (2a–x) at different doses 10, 30 and 50 mg/kg b.w (oral) were assessed using percentage reduction of plasma glucose (PG) levels in streptozotocin-induced type II diabetic rat models. From the results, the novel compound 2x ((Z)-5-(4-((E)-3-(9H-fluoren-2-yl)-3-oxoprop-1-enyl)benzylidene)-1,3-thiazolidine-2,4-dione) exhibited considerably potent blood glucose lowering activity than that of the standard drug rosiglitazone and it could be a remarkable starting point to evaluate structure–activity relationships and to develop new lead molecules with potential cytotoxicity, antimicrobial and antihyperglycemic activities. In addition molecular docking studies were carried out against PPARγ molecular target using Molegro Virtual Docker v 4.0 to accomplish preliminary confirmation of the observed in vivo antihyperglycemic activity.     

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.     

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.     

Photoaffinity-labeled Auxins: Synthesis and Biological Activity

Two light-sensitive analogs of 2,4-dichlorophenoxyacetic acid, namely 4-azido-2-chlorophenoxyacetic acid and 3-azido-5-chlorophenoxyacetic acid, have been synthesized for use as auxin photoaffinity labels. The preparation and biological activity of the compounds are described. Both contain the photolabile azido group; the 2,4-substituted compound shows auxin activity and the 3,5-substituted compound does not. These photoaffinity analogs of 2,4-dichlorophenoxyacetic acid may be useful in the identification of the auxin receptor molecules in plant cells and eventually of the receptor sites within these molecules.     

Synthesis and antihyperglycemic activity profiles of novel thiazolidinedione derivatives

A number of thiazolidine-2,4-diones derivatives having carboxylic ester appendage at N-3 were synthesized and their antihyperglycemic activity was evaluated. Many of these derivatives as well as their corresponding carboxylic acid showed significant improvement on post-prandial hyperglycemia in normal rats, in contrast to their poor agonist activity at PPARgamma.     

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.     

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.     

Synthesis and antihyperglycemic activity of chalcone based aryloxypropanolamines

A series of aryloxypropanolamines (5a-r) of different chalcones (3a-e) were synthesized and evaluated for antihyperglycemic activity in sucrose loaded (SLM) and streptozotocin (STZ) induced diabetic animal models. Among them compounds 5a, g, m, o, p and r showed significant reduction in blood glucose levels in both SLM and STZ animal models.     

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.     

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.     

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.     

Chalcone based aryloxypropanolamines as potential antihyperglycemic agents

A series of chalcone based aryloxypropanolamines were synthesized and evaluated for their antihyperglycemic activity in SLM and STZ rat models. Most of the compounds exhibited moderate to good activity ranging from 6.5% to 31.1% in SLM and 8.3% to 22.6% in STZ models, respectively. The most potent compound 5 g exhibited glucose lowering of 26.7% in SLM and 22.6% in STZ models. A definite structure-activity relationship was observed while varying the nature as well as the position of the amine in ring B.     

Synthesis, biological active molecular design, and molecular docking study of novel deazaflavin-cholestane hybrid compounds

Novel deazaflavin-cholestane hybrid compounds, 3',8'-disubstituted-5'-deazacholest-2,4-dieno[2,3-g]pteridine-2',4'(3'H,8'H)-diones, have been synthesized by condensation reaction between 6-(monosubstituted amino)-pyrimidin-2,4(1H,3H)-diones and 2-hydroxymethylenecholest-4-en-3-one in presence of p-toluenesulfonic acid monohydrate and diphenyl ether. The antitumor activities against human tumor cell lines (CCRF-HSB-2 and KB cells) have been investigated in vitro, and many of these compounds showed promising antitumor activities. Furthermore, molecular docking study using LigandFit within the software package Discovery Studio 1.7 was done for lead optimization of these compounds as potential PTK inhibitors. In general, all of the synthesized steroid-hybrid compounds showed good binding affinities into PTK (PDB code: 1t46).     

Dual action spirobicycloimidazolidine-2,4-diones: Antidiabetic agents and inhibitors of aldose reductase-an enzyme involved in diabetic complications

The desired 3-(arylsulfonyl)spiroimidazolidine-2,4-diones were synthesized by reacting spiroiminoimidazolidine-2,4-dione with arylsulfonyl chlorides. Spiroimidazolidine-2,4-dione was in turn synthesized from norcamphor. Structures of the synthesized molecules were established by modern spectroscopic techniques. The synthesized compounds were screened for in vivo antidiabetic activity and aldose reductase inhibition. Compounds 2a, 2b and 2g exhibited excellent dual activity, compound 2a being most prominent. These results reveal that the synthesized compounds may serve as the molecule of choice to treat diabetes and diabetic complications using a single medication.     

Synthesis and biological activity of novel alpha-substituted beta-phenylpropionic acids having pyridin-2-ylphenyl moiety as antihyperglycemic agents

We previously reported the identification of novel oximes having 5-benzyl-2,4-thiazolidinedione with antihyperglycemic activity. We now report the synthesis and biological activity of a novel series of oximes and amides having alpha-substituted-beta-phenylpropionic acids. In this series, we obtained potent PPAR alpha/gamma dual agonist (S)-9d, with which activation of PPAR alpha and PPAR gamma was considerably more potent than that of the reference compounds GW9578 22 and rosiglitazone 3, respectively. This means (S)-9d is of the strongest class of PPAR alpha/gamma dual agonists. In the course of this study, we also obtained 8h, which indicated potent plasma glucose lowering effect in spite of weak PPAR alpha/gamma agonistic activity.