Synthesis, <i>in silico</i> studies and biological evaluation of novel thiazolidinone[5,4-d] isoxazole derivatives as antidiabetic agents

A new class of dihydrothiazolo-isoxazole-5-one derivatives were synthesized by a sequence of reactions starting from Knoevenagel condensation of different aromatic aldehydes with thiazolidinediones (TZD), amino alkylation by Mannich reaction and then cyclization to isoxazole with reaction with hydroxylamine. The titled compounds <b>4a–4j</b> and <b>5a–5e</b> were evaluated for <i>in vivo</i> antidiabetic evaluation as well as their effects on weight gain and results showed significant activity compared to pioglitazone. Compound <b>4j</b> and <b>5c</b> showed significant glucose lowering effect against streptozotocin–nicotinamide induced diabetic mice with no weight gains and the antidiabetic activity were comparable to the standard. The docking studies were performed against PPAR-γ receptor showed strong interactions and favorable binding energies. The present study suggests that dihydrothiazolo-isoxazole-5-one derivatives act as a promising new approach for the treatment of type-II diabetes.