Synthesis, In Vitro, In Vivo and In Silico Antidiabetic Bioassays of 4-Nitro(thio)phenoxyisobutyric Acids Acting as Unexpected PPARγ Modulators: An In Combo Study

Four isobutyric acids (two nitro and two acetamido derivatives) were prepared in two steps and characterized using spectral analysis. The mRNA concentrations of PPAR gamma and GLUT-4 (two proteins documented as key diabetes targets) were increased by 3T3-L1 adipocytes treated with compounds 1-4, but an absence of in vitro expression of PPAR alpha was observed. Docking and molecular dynamics studies revealed the plausible interaction between the synthesized compounds and PPAR gamma. In vivo studies established that compounds 1-4 have antihyperglycemic modes of action associated with insulin sensitization. Nitrocompound 2 was the most promising of the series, being orally active, and one of multiple modes of action could be selective PPAR gamma modulation due to its extra anchoring with Gln-286. In conclusion, we demonstrated that nitrocompound 2 showed strong in vitro and in vivo effects and can be considered as an experimental antidiabetic candidate.

Automated summary

This study synthesized and characterized four isobutyric acid derivatives. The results showed that these compounds increased the mRNA concentration of PPAR gamma and GLUT-4, and had antihyperglycemic effects. Nitrocompound 2 was identified as the most promising candidate.