Computational studies, synthesis, in-vitro binding and transcription analysis of novel imidazolidine-2,4‑dione and 2-thioxo thiazolidine-4-one based glitazones for central PPAR-γ agonism

Abstract

Herein, we describe the structure-based designing and synthesis of novel glitazones with imidazolidine 2, 4‑dione and 2-thioxo thiazolidine-4-one ring structures as the fundamental scaffold for central PPAR-γ binding and activation. The central activation of PPAR-γ/coactivator PGC-1α induces a beneficial effect in neurodegenerative disorders. The compounds were rationally designed with particular emphasis on toxicity parameters and subjected to computational screening. Totally, four compounds were selected from an in-house library of designed glitazones based on imidazolidine 2, 4‑dione and 2-thioxo thiazolidine-4-one ring structures for further investigation for PPAR-γ activation. Molecular docking of designed glitazones with PPAR-γ proteins revealed more binding affinity with hydrogen bond interaction of protein residue at Ser289, His323, Tyr327, and Tyr473 compared with standard Pioglitazone. The structural stability of protein-ligand complexes was confirmed by molecular dynamic (MD) simulation (100 ns), and results indicate significant interactions with PPAR-γ active sites. Additionally, the relationship between geometry and electronic properties of chemical compounds were investigated using HOMO-LUMO, MEP, and NBO analysis. The compounds were synthesized by established synthetic schemes and structurally analyzed using IR, 1H NMR, 13C NMR and mass spectral analysis. The binding affinity of the compounds with the target protein (PPAR-γ) was further confirmed by an in vitro competitive binding assay with values ranging from 0.951μM- 4.768 μM. TR-FRET binding assay also concluded the ability of the novel compounds G5 and G7 to bind specifically at the LBD of PPAR-γ. Among the developed glitazones, the compound G7 activates PPAR-γ in a dose-dependent manner in transcriptional assay. Our results also indicated that compounds G5 and G7 exhibit nontoxicity (IC50>120 μM) against the SH-SY5Y cell lines and both could be a most bioactive lead candidates for further investigations.