A series of novel thiazolidinedione derivatives as peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonists bearing stearic acid esters and amides as substituent’s in the positions 3 and 4 of the benzylidene moiety have been designed, synthesized and tested as potential antihyperglycemic agents. The compounds containing stearic acid (A1TU, A2TU, A3TU, A2TS and A3TS) exhibited the maximum activity (64.7-70.3 % BG reduction) among all the synthesized compounds. The compound A3TU has been found to exhibit the maximum activity. The docking simulation of the most active compound A3TU towards PPAR-γ receptor showed that the ligand-receptor complex was stabilized by hydrophobic interactions occurring between the lipophilic and aromatic moieties of the ligand and hydrophobic residues of the binding site. Its lipophilic and aromatic moieties were oriented towards the hydrophobic region lined by ARG-280, ILE-281, GLN-283, GLY-284, CYS-285, GLN-286, PHE-287, ARG-288, SER-289, ALA-292, VAL-293, VAL-322, HIS-323, ILE-326, TYR-327, LEU-330, LEU-333, VAL-339, LEU-340, ILE-341, SER-342, MET-348, PHE-363, MET-364, LYS-367, HIS-449, LEU-453, LEU-465, LEU-469, ILE-472 and TYR-473. The binding conformation of A3TU exhibited hydrogen bonding with ARG-288, TYR-473, HIS-323 and HIS-449. The stearic acid derivatives except A2TU showed better activity profile than rosiglitazone. Docking simulations performed on PPAR-γ receptor indicated that hydrophobic and hydrophilic key interactions may govern the drug receptor binding.
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