Development of Novel Phthalazinone-Triazole Hybrids as Potential Antidiabetic Agents Targeting GLUT4 Translocation in Skeletal Muscle

A series of 38 phthalazinone-triazole compounds were synthesized using Click chemistry to identify potential antidiabetic agents. These compounds were systematically tested for their ability to promote glucose transporter type 4 (GLUT4) translocation in skeletal muscle cells. Among the 38 derivatives, 11 compounds (i.e., <b>12k, 13a-13c, 13e-13i, 13s,</b> and <b>13v</b>) showed significant potential to stimulate GLUT4 translocation in skeletal muscle cells, with compound <b>13a</b> exhibiting most promising activity. Further, treatment with <b>13a</b> induced a concentration-dependent increase in GLUT4 translocation in L6 skeletal muscle cells through the activation of wortmannin-sensitive PI-3-K-dependent signaling and AMPK-dependent signaling pathways. The <i>in vivo</i> studies further demonstrated that compound <b>13a</b> effectively lowered blood glucose levels in STZ-induced diabetic rats and displayed favorable pharmacokinetic properties, making it a promising candidate for further development as an antidiabetic agent.