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., 12k, 13a-13c,
13e-13i, 13s, and 13v) showed significant potential
to stimulate GLUT4 translocation in skeletal muscle cells, with compound 13a exhibiting most promising activity. Further, treatment
with 13a 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 in vivo studies further demonstrated
that compound 13a 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.