Synthesis and antihyperglycemic activity of novel N-acyl-2-arylethylamines and N-acyl-3-coumarylamines q Atma P. Dwivedi, a Shailesh Kumar, a Vandana Varshney, a Amar B. Singh, b Arvind K. Srivastava b and Devi P. Sahu a, * a Medicinal and Process Chemistry Division, Central Drug Research Institute, M.G. Marg, P B No. 173, Lucknow 226001, India b Biochemistry Division, Central Drug Research Institute, Lucknow 226001, India Received 2 January 2008; revised 27 February 2008; accepted 1 March 2008 Available online 6 March 2008 Abstract—A series of novel N-acyl-2-arylethylamines and N-acyl-3-coumarylamines were synthesized and evaluated for their anti- hyperglycemic activity. Compounds 3g and 6d exhibited lowering of postprandial plasma glucose by 30.7%, 23.3% in SLM and 25.6%, 25.4% in STZ models respectively which is significant compared to metformin and glybenclamide. Other compounds exhib- ited moderate to good activity ranging from 19.5% to 32.8% in SLM and 3.26% to 25.4% in STZ models. Ó 2008 Elsevier Ltd. All rights reserved. Diabetes mellitus (type-II diabetes, T2D) is an acquired syndrome of elevated blood glucose and develops due to the effect of sedentary lifestyle, dietary changes and ge- netic factors. T2D is closely associated with obesity and other metabolic syndromes, and is characterized by initial phase progressive insulin resistance and subse- quent phase exhaustion of b cells in the pancreas. It is estimated that over 330 million people worldwide would be affected by T2D by 2030. 1 The current treatment of T2D includes efficient oral antidiabetic agents such as Metformin, sulfonyl ureas, glinides, and glitazones. Metformin though safe and well tolerated poses a risk of inducing lactic acidolysis and is contraindicated in the setting of renal failure. Both sulfonyl ureas and gli- nides induce weight gain and have adverse effect in obese patients. The glitazones pose a risk of oedema, weight gain, and is contraindicated in the setting of congestive heart failure. A number of candidates based upon action on different molecular targets such as DPP4 inhibitors, GLP1 analogues, SGL2 inhibitors are at various stages of clinical trials and soon may replace existing drugs. 2 Despite the remarkable progress in the management of diabetes mellitus there has been a resurgence of phyto- therapeutical approach for the generation of new leads from active principle of medicinal plants traditionally used worldwide for the treatment of T2D and related metabolic disorders. 3 The active compounds isolated from some of the plants such as Scoparone from Artemesia Capillaris, 4 3-hydroxyumbelliferone deriva- tives from Bahia ambrosioides, 5 Glycyrin from Glycyr- rhiza uralensis 6 and Marmesin and Umbelliferone ether isolated from Aegle marmelos 7 used traditionally for the management of diabetes and related metabolic disor- ders contain 7-hydoxycoumarin motif. An alkaloid, Aegeline (N-cinnamoyl-4-methoxyphenylethanolamine) isolated from the same plant Aegle marmelos reported to exhibit both antihyperglycemic and antidyslipidemic activities. 8 The active constituent isolated from the plants Actaea dahurica, Cinnamomum aromaticum Nees, Ipomoea batatas, Scrophularia buergeriana are derivative of either mono or polyhydroxylated cinnamic acids. 3 Based upon these phytochemical leads it was envisaged that a library of N-acyl 2-arylethylamines and N-acyl- 3-coumarylamines of type A (Chart 1) should possess antihyperglycemic activity. The synthesis and our preliminary study on antihyperglycemic activity of N- acyl-2-arylethylamines and N-acyl-3-coumarylamines are presented in this letter. N-Cinnamoyl-3,4-dimethoxyphenylethylamines 3 were synthesized by the acylation of 2 with substituted cin- namic acid 1 (Scheme 1). Thus, the acid chloride ob- tained on treatment of cinnamic acid 1 with either 0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2008.03.003 Keywords: N-Acyl 2-arylethylammines; N-Acyl-3-coumarylamines; SLM; STZ. q CDRI Communication No.7440. * Corresponding author. Tel.: +91 522 2612415x4378; fax: +91 522 2623405; e-mail addresses: dpsahuin@yahoo.com; dp_sahu@cdri. res.in Available online at www.sciencedirect.com Bioorganic & Medicinal Chemistry Letters 18 (2008) 2301–2305