Pharmacological Evaluation of Some Novel Glitazones as Antidiabetic Agents

Abstract

Glitazones used to be the one of the most widely prescribed agents in the management of T2DM. These drugs score over other class of agents in this category because of their ability to reverse insulin resistance without stimulating the release of insulin from and#946;-cells. They achieve this effect by reducing the hepatic glucose production and increasing the peripheral glucose utilization through their actions on PPAR receptors. Unfortunately, the clinically used TZDs, (troglitazone, pioglitazone and rosiglitazone) suffered with serious side effects. Several new approaches have, therefore, been made to address the problems associate with current TZDs. One of these is the development of molecules which have got both PPAR-and#945;/and#947; dual agonistic activities. These molecules have been claimed to achieve a broad spectrum of metabolic effects by improving insulin resistance, hyperglycemia and atherosclerotic dyslipidemia. They are most beneficial in those T2DM patients with coexisting dyslipidemia, which is most common in patients with T2DM. newlineIn the present study eleven novel TZDs were synthesized and evaluated for their dual agonistic activities. A total of 257 molecules, including 5-(4-(3-phenoxypropoxy)benzyl) thiazolidine-2,4-dione, 5-(4-(3-phenoxypropoxy) benzylidene) thiazolidine-2, 4-dione, 5-(4-(2-phenoxyethoxy) benzylidene) thiazolidine-2,4-dione, 5-(4-(2-phenoxyethoxy)benzyl) thiazolidine-2,4-dione derivatives and standard TZDs were subjected to docking studies against PPAR-and#945; and and#947; LBD. The results of the study showed a good glide scores for most of the designed molecules which in many instances was better than the standard molecules for both the receptors, indicating a good amount of interactions with these receptors. In conclusion, in the present study, the eleven compounds synthesized and being reported for the first time after filing a patent (Annexure-I) show moderate to good dual agonistic activities in the in silico and in vitro studies. Among these compounds, 10b shows a better PPAR-and#945; and and#947; activity.