Design, synthesis, and antidiabetic evaluation of Hantzsch's 1,4-dihydropyridine-pyrazole scaffolds as stimulator of skeletal-muscle GLUT4 translocation.

In the quest for new antidiabetic agents, a library of twenty-three 1,4-dihydropyridine-pyrazole derivatives was synthesized via an efficient green multicomponent Hantzsch reaction. The compounds were screened in vitro for GLUT4 translocation stimulatory activity in L6-GLUT4myc myotubes, and subsequently evaluated in vivo for anti-hyperglycemic effects in a streptozotocin-induced diabetic rat model. Several compounds, particularly 6c, 6 h, 6j, 6 l, and 6 m, significantly enhanced GLUT4 translocation to cell surface in L6-GLUT4myc myotubes, suggesting improved glucose uptake potential. Among them, compound 6c exhibited the highest activity and produced a significant reduction in blood glucose levels (23.9%, p < 0.01) in diabetic rats. The observed biological activity highlights the therapeutic relevance of the 1,4-dihydropyridine-pyrazole scaffold and identifies compound 6c as a promising lead for further structure-activity relationship studies aimed at the development of novel antidiabetic agents.