Design, Synthesis and In-vivo Hypoglycemic Evaluation of Novel Non - TZD'S in a Type - 2 Diabetic Model

Abstract

With a view to develop novel non-TZD anti-diabetic compounds, series of isoxazolidinediones were designed to target the PPAR-γ receptors. Docking studies were performed on co-crystallized protein structure of rosiglitazone with PPAR-γ receptor obtained from Protein Data Bank (2PRG). Interactions similar to that of rosiglitazone were observed for three molecules; 3a, 3b and 3c which were further synthesized and subjected to in vivo hypoglycemic, total cholesterol (CHL) and triglyceride (TG) evaluation. 14 days treatment revealed significant reduction in blood glucose levels but did not portray desirable results in terms of total CHL and TG lowering effect. The blood glucose reduction observed for 3a, 3b and 3c at 20 mg/kg/day was 53.96 %, 61.35%, 61.32% respectively as against 59.95% of the standard pioglitazone at 10mg/kg/day.

Synthesis of 3,5-Isoxazolidinediones and 1H-2,3-Benzoxazine-1,4(3H)-diones from Aliphatic Oximes and Dicarboxylic Acid Chlorides

“…The flask was swept with N 2 , and the solution was chilled in an ice−water bath to 0 °C with stirring. To the cold solution was added dropwise over a 15 min period 20 mmol of the phthaloyl chloride (15) in 50 mL of anhydrous Et 2 O. The solution was stirred at rt under N 2 for 24 h. The white precipitate was filtered, and the filtrate was washed with HCl (10%, 3 × 50 mL) and then dried (MgSO 4 ).…”

“…8,9 They also act as antidiabetic agents. 10−15 Six-membered ring analogues of 1 include the 2 H -1,2-oxazine-3,6-diones ( 2 ) and the 1 H -2,3-benzoxazine-1,4(3 H )-diones ( 3 ). 16−25 While there has been one report each on the fungicidal properties 23 and the β-Lactamase pro-inhibitory activity 26 of 3 , the pharmacological properties of 2 and 3 have been largely unexplored.…”

“…The 3,5-isoxazolidinediones ( 1 ) are an important pharmacologically active class of compounds. We have shown that they are potent hypolipidemic − and cytotoxic agents, specific inhibitors of the type-2 isoform of IMPDH, and inhibitors of aldose reductase. , They also act as antidiabetic agents. − Six-membered ring analogues of 1 include the 2 H -1,2-oxazine-3,6-diones ( 2 ) and the 1 H -2,3-benzoxazine-1,4­(3 H )-diones ( 3 ). − While there has been one report each on the fungicidal properties and the β-Lactamase pro-inhibitory activity of 3 , the pharmacological properties of 2 and 3 have been largely unexplored. In contrast, the corresponding 2 H -1,3-benzoxazine-2,4­(3 H )-diones ( 4 ) have a wide range of pharmacologic activities including antimycobacterial, − antituberculotic, − analgesic, , cardiovascular, antimitotic, antifungal, , cytotoxic, and antifungal, and the 2 H -1,4-benzoxazine-2,3­(4 H )­diones ( 5 ) are active as antimiotic, antimicrobial, antiallergic, , and renin inhibitory agents.…”

Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists

“…However, despite of the potent activity, glitazones were discontinued in clinic due to the serious side effects such as weight gain, edema, hepatotoxicity and cardiovascular toxicity [9, 13, 14]. The primary reason may attribute to the single full or partial PPARs activation.…”