Molecular Docking Studies, Synthesis and Pharmacological Evaluation of 2-Aminothiophene Derivatives as Antidiabetic Agents

Abstract

India leads the world with largest number of diabetes subjects earning the dubious distinction of being termed the “diabetic capital of the world”. According to the Diabetes Atlas 2012 published by the International Diabetes Federation (IDF), the number of people with diabetes in India currently 63.0 million is expected to rise to 87 million by 2030 unless urgent preventive steps are taken. The most disturbing trend is the shift in age of onset of diabetes to a younger age in the recent years. This could have long lasting adverse effects on nation’s health and economy. The role of PTP1B in the disease pathology was studied and considered as a potential target to treat T2DM. Molecular structure of PTP1B consists of active as well as allosteric sites and WPD loop also involved in the catalytic mechanism of activation of the enzyme. Allosteric inhibitor opens new sites in the designing of potent molecules. In the current study, we designed a series of substituted 2- aminothiophene derivatives and performed Docking studies on the available PDB i.e, 1T49 with Surflex-Dock module. The designed molecules showed interactions with the amino acids that are matched with the known inhibitors of allosteric sites. The amino acids are Asn-193 and Lys-197. Some of the molecules also form hydrogen bond with HOH 494 which is also showed by known ligand. Synthesis was carried out for selected molecules with conventional methods and the yield are compromised in some cases. Structural elucidation was carried out with the help of IR, MASS and NMR spectroscopic methods. AGG-2, AGG-4, AGG-5, AGG-6 and AGG-8 were selected for in-vivo studies. OGTT test was performed on Non-diabetic male Wistar rats. Form the pharmacological studies AGG- 2 (ethyl 2-(methylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate) and AGG-8 (2-(2-hydroxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)- one) showed significant decrease in blood glucose levels at 120min when compared with standard Metformin.