Design and Synthesis of Barbiturates and Hydantoins with Multitarget Antidiabetic Effect

Abstract

In current work, we prepared a series of ten 4-aryloxy-5-benzylidenebarbiturates and hydantoins as 1,3-thiazolidine-2,4-dione bioisosteres. An in silico pharmacological consensus analysis (PHACA) was conducted to assess the pharmacokinetic, pharmacodynamics, biopharmaceutical, and toxicological properties of compounds 1-10. The goal was to identify computationally safe hits using a color-coded system resembling a traffic light. The compounds identified as safe computational hits through PHACA were 1, 2, and 4 from the barbiturate series, which were then selected by in vitro assays targeting PPAR-γ, GPR40, and GLUT-4 gene expression. Additionally, these three compounds underwent in vivo evaluation through a glucose tolerance curve assay conducted on normoglycemic mice. Compounds 1 and 4 exhibited antihyperglycemic effects within the first thirty minutes post-administration. Molecular docking studies were conducted to clarify the dual effect and binding mode of compounds 1, 2 and 4 on PPAR-γ and GPR40. Compounds 1 and 4 exhibited robust in vitro and in vivo efficacy and could be considered as multitarget modulators with antidiabetic effect.