Design, synthesis, and biological evaluation of quinazolinone-dihydropyrimidinone as a potential anti-diabetic agent via GLUT4 translocation stimulation.

A library of 30 novel quinazolinone-dihydropyrimidinone derivatives was synthesized employing a diversity-oriented approach for the identification of potential anti-diabetic therapeutic lead. In vitro evaluation revealed that seven compounds (5d, 5e, 5i, 5j, 5l, 5m and 5s) significantly enhanced the rate of GLUT4 translocation to the cell surface in L6-GLUT4myc myotubes. Out of these, compound, 5m exhibited promising potency to stimulate GLUT4 translocation in skeletal muscle cells via activating AMPK-dependent pathway, but independent to PI-3-K/AKT signaling. Under in vivo conditions, treatment with 5m demonstrated a marked 39.5 % (p < 0.001) reduction in blood glucose levels in a streptozotocin-induced diabetic rat model after 5 h of treatment. Pharmacokinetic analysis indicated compound 5m shows favourable pharmacokinetic properties. Overall, the compound 5m emerged as a promising lead compound for subsequent structural modification and optimization to develop a novel and potent anti-hyperglycemic agent.