Synthesis and glucose-6-phosphatase inhibitory activity of (thiouriedo)alkanoic acid esters q Farhanullah, a Diptesh Sil, a Brajendra K. Tripathi, b Arvind K. Srivastava b and Vishnu Ji Ram 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 24 December 2003; accepted 23 February 2004 Abstract—A series of (3-pyridin-2-yl-thiouriedo)alkanoic acid esters (5a–j) have been synthesized by the reaction of pyridin-2-yl- dithiocarbamic acid methyl ester (2) and amino acid esters (4). Most of the synthesized compounds have been evaluated against glucose-6-phosphatase enzyme but only four compounds (5g–j) displayed significant inhibitory activity of the enzyme. Ó 2004 Elsevier Ltd. All rights reserved. 1. Introduction Diabetes mellitus type 2 is a metabolic disorder, char- acterized by resistance of the peripheral target tissues to the binding of insulin. 1;2 Nearly 90% of the diabetic population is suffering from type-2 diabetes. The etiol- ogy of type-2 diabetes is quite complex and in most of the cases insulin resistance is developed that leads to hyperinsulinemia. In such a situation b-cells of the pancreas do not maintain the hyperinsulinemic state for longer period resulting insulin deficiency leading to hyperglycemia. Recently, it has been reported that 3-guanidinoprop- ionic acid (I), 3-(pyridin-2-yl-amino)-propionic acid (II), and 3-carbamimidoylsulfanyl-propionic acid (III) pos- sess both antihyperglycemic and antiobesity activities in KKA y mouse. 3–5 The mode of action of these com- pounds is obscure but it is believed that probably they increased the disposal of glucose without affecting glu- coneogenesis, hepatic glycogen content or intestinal glucose absorption. 5 The antihyperglycemic potential of lipophilic guanidine derivatives is known since a decade 6 but significance of zwitterionic guanidine derivatives in diabetes was realized from the work of Horlicks et al. 7 The high intolerance of these compounds necessitated to modify the structures to obtain efficacious compounds. The structural modification of I–III led to design and synthesize (3-pyridin-2-yl-thiouriedo)alkanoic acid ester IV, which were equipotent and less toxic. In search of more effective and least toxic antihyper- glycemic agents, compounds with in built amidine, thiourea, and amino acid ester pharmacophores were synthesized as potential inhibitors of glucose-6-phos- phatase (G-6-pase), an enzyme responsible for main- taining normal blood glucose level. 8 2. Chemistry Various (3-pyridin-2-yl-thiouriedo)alkanoic acid esters have been synthesized in two steps. The first step is the formation of pyridin-2-yl-dithiocarbamic acid methyl esters 9 (2) from the reaction of 2-aminopyridine (1) and carbon disulfide in presence of alkali in DMSO followed Keywords: Thiouriedoalkanoic acid; Glucose-6-phosphatase; Hyper- insulinemic; Hyperglycemic. q CDRI Communication no. 6475. * Corresponding author. Tel.: +91-522-22124116; fax: +91-522-222- 3405; e-mail: vjiram@yahoo.com 0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2004.02.079 Bioorganic & Medicinal Chemistry Letters 14 (2004) 2571–2574