Discovery of novel chalcone-benzenesulfonamide conjugates as PPARγ agonists: Design, synthesis, and biological evaluation.

In the present study, a series of novel chalcone-benzenesulfonamides 7a-w was designed and synthesized. Compounds 7a-w were evaluated for their PPARγ ligand binding compared to pioglitazone, and their IC50 (μM) values were determined. The 4-methoxybenzyloxy (unsubstituted)benzenesulfonamide 7o revealed as the most potent PPARγ ligand (IC50 = 1.752 ± 0.04 μM), and high binding affinity (Ki = 54.81 nM). Eleven compounds 7a, 7f, 7g, 7i-l, 7n, 7o, 7t, and 7w were further selected, and evaluated for their PPARγ agonistic activity compared to pioglitazone, and their EC50 (μM) values were reported. Compound 7o displayed PPARγ agonistic activity comparable to pioglitazone with EC50 values of 0.273 ± 0.01, and 0.197 ± 0.007 μM, respectively. Selected compounds 7g, 7l, and 7o were further examined to determine their PPARα/δ agonistic activities compared to fenofibrate, and bezafibrate, respectively. Compounds 7l, and 7o demonstrated a higher selectivity towards PPARγ than PPARα by 24.8-fold, and 12.1-fold, respectively, while 7g showed a realtively equipotent dual PPARγ/α agonistic activity, however, the three tested compounds displayed a weak PPARδ agonistic activity. Moreover, compounds 7g, 7l, and 7o enhanced PPARγ protein expression in HepG-2 cells in a dose-dependent manner, whereas, 7g increased the PPARα expression level. In vivo studies revealed that compound 7o at a dose 72 mg/kg possessed antidiabetic activity better than that of pioglitazone. Furthermore, molecular docking studies and molecular dynamic simulations were carried out for the newly synthesized compounds to study their predicted binding modes and energies in the PPARγ/α binding sites.