Pyranocoumarins: A new class of anti-hyperglycemic and anti-dyslipidemic agents Atul Kumar a, * , Ram Awatar Maurya a , Siddharth Sharma a , Pervez Ahmad a , A. B. Singh b , Gitika Bhatia b , Arvind K. Srivastava b a Medicinal and Process Chemistry Division, Central Drug Research Institute, Council of Scientific & Industrial Research, Lucknow 226 001, India b Biochemistry Division, Central Drug Research Institute, Council of Scientific & Industrial Research, Lucknow 226 001, India article info Article history: Received 23 April 2009 Revised 7 September 2009 Accepted 9 September 2009 Available online 12 September 2009 Keywords: Pyranocoumarins Anti-hyperglycemic Anti-dyslipidemic PTP 1B abstract A series of pyranocoumarin derivatives were synthesized and evaluated in vivo for their anti-hypergly- cemic as well as anti-dyslipidemic activities. Compounds 7a, 7c, 8a, 8b, 8c, 8e and 8f have shown prom- ising anti-hyperglycemic activities in sucrose loaded model (SLM) as well as sucrose challenged streptozotocin induced diabetic rat model (STZ). Compounds 8a and 8b were showing 38.0% and 42.0% blood glucose lowering activity in db/db mice model. In vitro anti-hyperglycemic activity evaluation exhibited that compounds 8a (IC 50 = 24.5 lM) and 8b (IC 50 = 36.2 lM) are potential PTP-1B inhibitors thereby revealing their possible mechanism of anti-diabetic action. Compounds 7a, 7b, 8a, 8b, 8d, 8e and 8f have shown significant anti-dyslipidemic activity in triton induced dyslipidemia in rats. Ó 2009 Elsevier Ltd. All rights reserved. Diabetes mellitus is multifactorial disease characterized by high level of blood glucose and impaired insulin action. 1 It is an inde- pendent risk factor for the development of coronary artery dis- eases, myocardial infarction, hypertension, and dyslipidemia. Non-insulin dependent diabetes mellitus (NIDDM) accounts for approximately 80–90% of all diabetes cases. 2 The number of dia- betic complains are continuously growing with a currently esti- mated worldwide incidence of about 194 million people and expected to increase to 330 million by 2025. 3 When the carbohy- drates are not present in sufficient amount or their metabolism is impaired, fats become the principle source of energy. Fatty acids are mobilized into the general circulation leading to secondary tri- glyceridemia in which total serum lipids in particular triglycerides as well as the levels of cholesterol and phospholipids increases. This rise is proportional to the severity of the diabetes. Uncon- trolled diabetes is manifested by a very high rise in triglycerides and fatty acid levels. 4 An increase in plasma lipids, particularly cholesterol, is a common feature of atherosclerosis, a condition involving arterial damage, which may lead to ischemic heart dis- ease, myocardial infarction, and cerebro-vascular accidents. These conditions are responsible for one-third of deaths in industrialized nations. 5 Therefore, an anti-hyperglycemic drug, having lipids (tri- glycerides and cholesterol) lowering activity is of great demand. Several research groups have focused their attention to develop such dual-acting agents. 6 Herein, we describe design, synthesis, anti-hyperglycemic and anti-dyslipidemic activity of pyranocoum- arin derivatives. The design of pyaranocoumarin is based on natu- ral products exhibiting promising antidiabetic activity such as Sanggenone C, 7 Luvangetin, 8 and Rutamarin. 9 These natural prod- ucts have coumarin as central nucleus along with pyran or furan scaffolds present in linear arrangements. Based on this we have designed and synthesized pyranocoumarin having angular arrangements for their anti-hyperglycemic and lipid lowering activity (Fig. 1). The key intermediate 8-acetyl-7-hydroxy-4-methyl-2H-chro- men-2-one 5 was synthesized from resorcinol 1 in four steps. Resor- cinol 1 was treated with ethyl acetoacetate 2 and concentrated H 2 SO 4 to yield 7-hydroxy-4-methyl-2H-chromen-2-one 3. 7-Hydro- xy-4-methyl-2H-chromen-2-one 3 on reaction with acetic anhy- dride in pyridine gave 4-methyl-2-oxo-2H-chromen-7-yl acetate 4. Fries migration of the acetyl group of compound 4 by AlCl 3 at 170 °C resulted to the formation of 8-acetyl-7-hydroxy-4-methyl- 2H-chromen-2-one 5. Compound 5 was treated with paraformalde- hyde and amine in different optimized reaction conditions resulting to the formation of a range of pyranocoumarins. 8-Acetyl-7-hydro- xy-4-methyl-2H-chromen-2-one 5, when refluxed with 2 equiv of paraformaldehyde in ethanol afforded 9-ethoxymethyl-4-methyl- 8, 9-dihydro-pyrano[2,3-f]chromene-2,10-dione 6 in 62% yield. Refluxing 8-acetyl-7-hydroxy-4-methyl-2H-chromen-2-one 5 with 3 equiv of paraformaldehyde and 1 equiv of amine in ethanol affor- ded compounds 7a–c and 8a–h. 8-Acetyl-7-hydroxy-4-methyl-2H- chromen-2-one 5, when refluxed with 3 equiv of paraformaldehyde and 2 equiv of amine in ethanol afforded compounds 9a–h in 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.09.031 * Corresponding author. E-mail address: dratulsax@gmail.com (A. Kumar). Bioorganic & Medicinal Chemistry Letters 19 (2009) 6447–6451 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl