Synthesis and Biological Activity of Piperine Derivatives as Potential PPARγ Agonists (original) (raw)

Novel Piperine Derivatives with Antidiabetic Effect as PPAR-γ Agonists

Chemical Biology & Drug Design, 2016

Piperine is an alkaloid responsible for the pungency of black pepper. In this study, piperine isolated from Piper nigrum L. was hydrolyzed under basic condition to obtain piperic acid and was used as precursor to carry out the synthesis of twenty piperine derivatives containing benzothiazole moiety. All the benzothiazole derivatives were evaluated for their antidiabetic potential by OGT test followed by assessment of active derivatives on STZ-induced diabetic model. It was observed that nine of twenty novel piperine analogues (5b, 6a-h), showed significantly higher antidiabetic activity in comparison with rosiglitazone (standard). Furthermore, these active derivatives were evaluated for their action as PPAR-c agonists demonstrating their mechanism of action. The effects on body weight, lipid peroxidation, and hepatotoxicity after administration with active derivatives were also studied to further establish these derivatives as lead molecules for treatment of diabetes with lesser side-effects.

Synthesis and Biological Evaluation of Some Novel PPAR-γ agonists for the Management of Type II Diabetes

2013

Diabetes mellitus (DM) is a progressive disease cha racterized by hyperglycemia due to insulin deficien cy and insulin resistance or both. The fasting and postpra ndial blood glucose gets elevated, exposing the pat ient to acute and chronic complications (micro- and macro-vascular) leads to blindness, kidney failure, heart diseas e, stroke and amputations. Diabetes mellitus is one of the most c ommon endocrine disorders affecting almost 6% of the world's population. The number of diabetic patients will re ach 300 million in 2025. More than 97% of these pat ients will have type II diabetes. "Glitazones," bind to ppar-γ, a type of nuclear regulatory proteins involved in transcription of genes regulating glucose and fat metabolism. These PPAR-γ acts on Peroxisome Proliferator Responsive Element s (PPRE). In the present article, Rhodanine analogs w ere screened for their anti diabetic activity. Rosi glitazone is used as a reference standard. The compounds R2, R5 and R7 sho...

Design, synthesis, molecular docking, and in vitro antidiabetic activity of novel PPARγ agonist

Monatshefte für Chemie - Chemical Monthly, 2018

The present work describes the design, synthesis, molecular docking, biological evaluation, and assessment of structure-activity relationship of new derivatives based upon the molecular skeleton of the drug pioglitazone, a compound which is currently used for the management of type 2 diabetes mellitus. Pioglitazone has several side effects such as weight gain, edema, congestive heart failure, and bladder cancer. Therefore, there is a strong demand for identification of new lead candidates in the treatment of type 2 diabetes mellitus. A series of 24 compounds were prepared and evaluated for their peroxisome proliferator-activated receptor-c (PPARc) binding affinity assay and the IC 50 values were determined. Among these compounds, six compounds exhibited promising IC 50 values as compared to standard drugs pioglitazone and rosiglitazone. Furthermore, in order to confirm the target of these molecules, molecular docking study was carried out with peroxisome proliferator-activated receptor-c (PPARc) protein. Molecular modeling studies suggested that these compounds appropriately interact in the active sites of receptor.

Design and synthesis of non-TZD peroxisome proliferator-activated receptor γ (PPARγ) modulator

Medicinal Chemistry Research, 2014

Thiazolidinediones (TZDs) are an important class of compound used for the treatment of type 2 diabetes, targeting the peroxisome proliferator-activated receptor c (PPARc). Drug-induced hepatotoxicity, edema, and weight gain are the main concerns associated with TZDs. It was unclear whether the side effects observed are target mediated or compound mediated, but most of the TZDs activate PPARc. This obliged developing of a new diverse class of ligands as antihyperglycemic agents including non-TZD PPAR ligands that could be highly effective, safe, and devoid of side effects. Here, we report the design and synthesis of N-(5-chloro-6-((1-phenylpiperidin-4-yl)oxy)pyridin-3-yl)benzenesulfonamide derivatives as non-TZD PPARc modulators.

Synthesis, in vitro and in silico studies of a PPARγ and GLUT-4 modulator with hypoglycemic effect

Bioorganic & Medicinal Chemistry Letters, 2014

Compound {4-[({4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}acetyl)amino]phen-oxy}acetic acid (1) was prepared and the in vitro relative expression of PPARc, GLUT-4 and PPARa, was estimated. Compound 1 showed an increase of 2-fold in the mRNA expression of PPARc 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 PPARc, showing important short contacts with residues Ser289, His323 and His449 in the active site.

Design and synthesis of 6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid derivatives as PPARγ activators

Bioorganic & Medicinal Chemistry Letters, 2007

The design and synthesis of novel series of 6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid (pyrimidone) derivatives that are high affinity ligands for peroxisome proliferators activated receptor c have been reported as a potential substitute of 2,4-thiazolidinedione head group. The FlexX docking and radioligand binding affinity of some promising compounds of this series is comparable to that of thiazolidinedione based antidiabetic drugs currently in clinical use.

Medicinal Chemistry and Actions of Dual and Pan PPAR Modulators 2011

Peroxisome proliferator-activated receptor (PPAR) agonists are used as adjunct therapy in the treatment of diabetes mellitus. Fibrates, including fenofibrate, gemfibrozil, benzafibrate, ciprofibrate, and clofibrate act on PPAR alpha to reduce the level of hypertriglyceridemia. However, agonists (ligands) of PPAR-beta/delta receptors, such as tesaglitazar, muraglitazar, ragaglitazar, imiglitazar, aleglitazar, alter the body's energy substrate preference from glucose to lipids and hence contribute to the reduction of blood glucose level. Glitazones or thiazolidinediones on the other hand, bind to PPAR-gamma receptors located in the nuclei of cells. Activation of PPAR-gamma receptors leads to a decrease in insulin resistance and modification of adipocyte metabolism. They reduce hyperlipidaemia by increasing the level of ATPbinding cassette A1, which modifies extra-hepatic cholesterol into HDL. Dual or pan PPAR ligands stimulate two or more isoforms of PPAR and thereby reduce insulin resistance and prevent short-and long-term complications of diabetes including micro-and macroangiopathy and atherosclerosis, which are caused by deposition of cholesterol. This review examines the chemical structure, actions, side effects and future prospects of dual and pan PPAR agonists.

Selective peroxisome proliferator-activated receptor γ (PPARγ) modulation as a strategy for safer therapeutic PPARγ activation

The American Journal of Clinical Nutrition, 2009

Peroxisome proliferator-activated receptor c (PPARc) is a clinically validated target for treatment of insulin resistance. PPARc activation by full agonists such as thiazolidinediones has shown potent and durable glucose-lowering activity in patients with type 2 diabetes without the concern for hypoglycemia or gastrointestinal toxicities associated with some other medications used to treat this disease. However, thiazolidinediones are linked to safety and tolerability issues such as weight gain, fluid retention, edema, congestive heart failure, and bone fracture. Distinctive properties of PPARc provide the opportunity for selective modulation of the receptor such that desirable therapeutic effects may be attained without the unwanted effects of full activation. PPARc is a nuclear receptor that forms a complex with coreceptor RXR and a cell type-and cell statespecific array of coregulators to control gene transcription. PPARc affinity for these components, and hence transcriptional response, is determined by the conformational changes induced by ligand binding within a complex pocket with multiple interaction points. This molecular mechanism thereby offers the opportunity for selective modulation. A desirable selective PPARc modulator profile would include high-affinity interaction with the PPARc-binding pocket in a manner that leads to retention of the insulin-sensitizing activity that is characteristic of full agonists as well as mitigation of the effects leading to increased adiposity, fluid retention, congestive heart failure, and bone fracture. Examples of endogenous and synthetic selective PPARc modulator (SPPARM) ligands have been identified. SPPARM drug candidates are being tested clinically and provide support for this strategy.