Synthesis and antihyperglycemic activity of chalcone based aryloxypropanolamines § M. Satyanarayana, a Priti Tiwari, b Brajendra K. Tripathi, b A. K. Srivastava b and Ram Pratap a, * a Division of Medicinal Chemistry, Central Drug Research Institute, Lucknow 226001, India b Division of Biochemistry, Central Drug Research Institute, Lucknow 226001, India Received 23 October 2003; revised 23 December 2003; accepted 24 December 2003 Abstract—A series of aryloxypropanolamines (5a–r) of different chalcones (3a–e) were synthesized and evaluated for anti- hyperglycemic activity in sucrose loaded (SLM) and streptozotocin (STZ) induced diabetic animal models. Among them com- pounds 5a, g, m, o, p and r showed significant reduction in blood glucose levels in both SLM and STZ animal models. # 2004 Elsevier Ltd. All rights reserved. 1. Introduction Non-insulin dependent diabetes mellitus (NIDDM, type-II diabetes) is a chronic metabolic disease char- acterized by insulin resistance, hyperglycemia and hyperinsulinaemia. It represents 80–90% of the human population with diabetes and approximately 215 million will be afflicted worldwide by 2010. 1 The disease is often associated with obesity, dyslipidemia and hypertension leading to cardiovascular risks. 2 Primary therapy for type-II diabetes is caloric restriction and aerobic exercise 3 but only a small percentage of patients adopt them with sufficient rigor to achieve a significant improvement in hyperglycemic condition. Current therapies for type-II diabetes have inherent problems including non-compliance, ineffectiveness and hypogly- cemic episodes with insulin and sulphonyl ureas. 4 Gli- tazone type therapeutic agents are in the market but some of them have been reported to have hepatotoxi- city. 5 Therefore, here still remains a great need for more effective orally administered agents. b 3 -adrenergic receptors (b 3 -AR) are found on the cell surface of both white adipose (WAT) and brown adi- pose tissues (BAT) where their stimulation promotes lipolysis and thermogenesis respectively. 6 BAT also plays an important role in the maintenance of glucose homeostasis; hence b 3 -AR agonists are useful for treat- ing diabetes as well as obesity. 7 The aryloxy- propanolamines were first described as b 3 -AR agonists in the mid 1980s. 8 Later on several pharmaceutical industries are engaged in developing potent selective b 3 - AR agonists for treatment of type-II diabetes and obe- sity. CL-316243 9 has been reported for the treatment of type-II diabetes as well as obesity and recently L- 755507 10 as highly selective b 3 -AR agonist acting as metabolic rate enhancer in rodents. Chalcones either natural or synthetic are known to exhibit various biological activities. They have been reported as antioxidant, 11 14 antimalarial, 15 antil- eishmanial, 16 antiinflammatory 17 and antitumor 18 0968-0896/$ - see front matter # 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2003.12.026 Bioorganic & Medicinal Chemistry 12 (2004) 883–889 Keywords: Chalcones; Aryloxypropanolamines and antihyperglycemic activity. § C.D.R.I. Communication no. 6474. *Corresponding author. Tel.: +91-522-2212411x4347; fax: +91-522- 2223405; e-mail: rpcdri@yahoo.com