Design, Biological Evaluation, and PPARγ Modulation of Nitro- and Acetamidophenoxyisobutyric Acids as Antidiabetic Agents

Four isobutyric acid derivatives, including two nitro- and two acetamido-substituted analogues, were synthesized through a two-step procedure and fully characterized by spectroscopic techniques. Treatment of 3T3-L1 adipocytes with compounds 1–4 resulted in elevated mRNA expression levels of PPARγ and GLUT-4, two well-established molecular targets in diabetes therapy, whereas no detectable induction of PPARα expression was observed in vitro. Computational docking and molecular dynamics simulations supported favorable binding interactions between the synthesized molecules and PPARγ. In vivo evaluations demonstrated that all tested compounds exerted antihyperglycemic effects linked to enhanced insulin sensitivity. Among the series, nitrocompound 2 exhibited the most pronounced activity and oral bioavailability. Its mechanism of action may involve selective modulation of PPARγ, potentially facilitated by an additional stabilizing interaction with the Gln-286 residue. Overall, these findings identify nitrocompound 2 as a promising experimental candidate for antidiabetic drug development.