Design, Synthesis, and Biological Evaluation of 1,4-Dihydropyridine–Indole as a Potential Antidiabetic Agent via GLUT4 Translocation Stimulation

Abstract

In the quest for the discovery of antidiabetic compounds, a series of 27 1,4-dihydropyridine-indole derivatives were synthesized using a diversity approach. These compounds were systematically evaluated for their antidiabetic activity, starting with an in vitro assessment for GLUT4 translocation stimulation in L6-GLUT4<i>myc</i> myotubes, followed by in vivo antihyperglycemic activity evaluation in a streptozotocin (STZ)-induced diabetic rat model. Among the synthesized compounds, <b>12</b>, <b>14</b>, <b>15</b>, <b>16</b>, <b>19</b>, <b>27</b>, and <b>35</b> demonstrated significant potential to stimulate GLUT4 translocation in skeletal muscle cells. Compound <b>19</b> exhibited the highest potency and was selected for in vivo evaluation. A notable reduction of 21.6% (<i>p</i> < 0.01) in blood glucose levels was observed after 5 h of treatment with compound <b>19</b> in STZ-induced diabetic rats. Furthermore, pharmacokinetic studies affirmed that compound <b>19</b> was favorable to oral exposure with suitable pharmacological parameters. Overall, compound <b>19</b> emerged as a promising lead compound for further structural modification and optimization.