Studies on Isolated or Fused 2-Pyranones and their Nucleophile-induced Products

Abstract

The choice of diabetes as a therapeutic area for research is very germane in both the national and international scenario. Diabetes is projected to increase, the world over, from 136 million in 1995 to 300 million in 2025. In India it may show a three-fold increase from 19.4 million to 57.2 million in the same period. This increasing trend is quite alarming and will pose a threat to public health and economic burden, if adequate measures are not taken in time. Type 2 Diabetes mellitus (T2DM) is the most important type of diabetes because more than 90% of diabetics are of this type. Further, 80 percent of T2DM patients are obese and most of them hyperinsulinaemic and insulin-resistant. T2DM is the result of impaired insulin stimulated glucose uptake and utilization in liver, skeletal muscle, adipose tissue and impaired suppression of hepatic glucose output. For the last few decades, treatment of T2DM has been focused on dietary management of obesity to improve insulin sensitivity, sulfonylureas to enhance insulin secretion, metformin to inhibit hepatic glucose output, and acarbose to inhibit or reduce the rate of glucose absorption from the gut. More recently alternative treatment modalities have been developed or are in development, which asks the question “can an increase in insulin receptor sensitivity by exogenous compounds without the stimulation of endogenous insulin secretion provide good benefit?” Such an approach is very appropriate as it can also address many of the accompanying metabolic syndromes of diabetes. Current therapies to combat diabetes have not kept pace with the epidemic’s progress. Although treatment with highly active thiazolidinedione (TZD) class of drugs has significantly improved the clinical treatment of type 2 diabetics, the current generation of drugs is associated with the risk of undesired side effects such as hepatotoxicity, weight gain and edema. Thus there is a resurgence of interest in the development of new antihyperglycemic agents for the treatment of Type 2 diabetes. Currently, numerous antidiabetic drug targets such as glucose-6-phosphatase, glycogen synthase, fructose-1,6-bisphosphatase, glucokinase, peroxisome proliferator activated receptors (PPARs), protein tyrosine phosphatase 1B (PTP1B) and dipeptidyl peptidase IV (DPP IV) etc are available for in vitro screening, and application of modern techniques such as high throughput screening (HTS) for in vitro evaluation of compounds has expedited the process of drug testing.Our interest in the development of potential antihyperglycemic agent prompted us to design and synthesis of suitably functionalized biaryl, teraryls and related compounds prepared through novel ring transformation strategy. Essentially, in this thesis an attempt is made to develop highly convenient synthetic route for chemically challenging and biologically interesting arenes and heteroarenes through ring transformation of 2H-pyran-2-ones in flexible or rigid conformations. The work incorporated in this thesis is divided into five chapters. The first chapter describes an overview on Diabetes Mellitus, pathogenesis and their treatment strategies. This review mainly deals with the current scenario of drug development in the management of type 2 Diabetes Mellitus. The second chapter describes novel synthesis and anti-hyperglycemic activity of biaryls, p-terphenyls, quaterphenyls, quinquephenyls and sexiphenyls. These compounds were prepared through easily accessible precursors utilizing the chemistry of flexible 2Hpyran- 2-ones. The third chapter is divided into two sections, first section deals with the development of novel route for polyisoprenylated benzenes and their antihyperglycemic activity, and the second section devoted to the synthesis of diterarylmethanes and diterarylethanes. Some of the synthesized diterarylmethanes and ethanes were evaluated for antimicrobial activity to uncover their therapeutic potential. The fourth chapter deals with the novel route for the synthesis of donor-acceptor fluorenes and fluorenones from α-pyranones through carbanion-induced ring transformation strategy. In this chapter, we addressed the origin of ‘Green Emission Defect’ (GED) associated with fluorene-based organic light emitting devices. We provided a novel concept of swapping donor-acceptor groups at appropriate positions onto fluorene-fluorenone backbone by synthesizing a library of fluorenes and fluorenones. Their photophysical and optical properties were examined and the performance of OLED devices is described. The chapter five of thesis describes the preparation of 2H-indenopyran-2-one, 2,4-dicyano-3-aminofluorenes, indeno[1,2-a]fluorenes, indeno[2,1-c]fluorenes and indenophenanthrenes prepared through novel ring transformation approach. Besides their synthesis and photophysical properties, antimalarial activity of indenofluorenes is discussed.