Syntheses of some potential antihyperglycemic and antihyperlipidemic agents

Abstract

The prevalence of diabetes is rapidly rising all over the globe at an alarming rate and even afflicting children. Though there is an increase in the prevalence of type 1diabetes, the major driver of the epidemic is the more common form of diabetes, viz. type 2 diabetes which accounts for more than 90% of all the cases of diabetes. India leads the world with largest number of diabetic subjects earning the dubious distinction of being termed the “diabetes capital of the world”. The International Diabetes Federation (IDF) estimates the total number of diabetic subjects to be ~ 40.9 million in India and this is further set to rise to 69.9 million by the year 2025. The treatment targets for patients with type 2 diabetes include a glycaemic goal of pre-prandial capillary plasma glucose 90-130 mg/dl; peak post-prandial plasma glucose <180 mg/dl; LDL <100 mg/dl (<70 mg/dl in the presence of diagnosed CVD); triglycerides <150 mg/ dl; HDL >40 mg/dl (>50 mg/dl in women) and blood pressure <130/80 mmHg (<125/75 mmHg with proteinuria). In order to achieve the above glycaemic goals, we have several anti-hyperglycemic agents, including the insulin secretagogues: sulphonylureas and meglitinides (nateglinide and repaglinide); α-glucosidase inhibitors: acarabose and miglitol; biguanides: metformin; thiazolidinediones (TZDs): rosiglitazone and pioglitazone. However, with continuous use of these drugs several patients who responded initially become refractory to the treatment over the time which therefore necessitates search of drugs with newer mechanisms. The present thesis describes our efforts in this direction. In the present work, the chapter 1 discusses the fundamental causes of type 2 diabetes and its micro-vascular complications due to the oxidative stress. Chapter 2 discusses the synthesis and biological activities of flavone which has been selected as base molecule to synthesize molecules included in the present work. Chapter 3 describes the synthesis of hybrid molecules with flavones and chalcones and their anti-diabetic activities. Chapter 4 describes the synthesis and biological activities of flavone based anti-hyperlipidemic agents. Chapter 5 describes the total synthesis of natural flavones through a common intermediate. Chapter 6 describes the deuterium labeling of CDRI compound 80/574 and isolation of a fungal metabolite to study its pharmaco-dynamic behavior.