Roriz_2025_Pharmaceuticals.(Basel)_18_

Background/Objectives: Dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents that regulate blood glucose by preventing the degradation of active incretin hormones. Although clinically effective, this drug class is associated with adverse effects, creating the need for new molecular scaffolds with improved safety and efficacy. Methods: We evaluated the antihyperglycemic activity of beta-aminohydrazine and beta-amino-N-acylhydrazone derivatives (LASSBio-2123, 2125, 2129, and 2130) using a combined in vivo and in silico approach. Male C57BL/6 mice underwent glucose tolerance tests (GTT) and dexamethasone-induced insulin resistance protocols. Hepatic and skeletal muscle glycogen levels, as well as GLUT4 mRNA expression, were quantified. In silico studies included ADMET predictions and molecular docking analyses against aldose reductase and glucokinase enzymes. MTT was performed on the pancreatic cell line MIN6 (Mus musculus). Results: Among the compounds tested, LASSBio-2129 demonstrated the most promising profile, with favorable ADMET parameters, metabolic stability, and high docking affinity for aldose reductase and glucokinase. In vivo, LASSBio-2129 (10 mg/kg, i.p.) reduced blood glucose, increased hepatic and muscle glycogen storage, and upregulated GLUT4 mRNA expression in skeletal muscle. Additionally, LASSBio-2129 improved insulin sensitivity in the dexamethasone-induced insulin resistance model, with effects comparable to sitagliptin. Conclusions: The combined pharmacological, docking, and ADMET analyses identified LASSBio-2129 as aldose reductase inhibitor candidate and glucokinase activator. Its ability to improve glucose tolerance, enhance glycogen storage, and increase GLUT4 expression highlights its potential as a promising molecule for the treatment of type 2 diabetes mellitus.