Anti-glycemic potential of benzophenone thio/semicarbazone derivatives: synthesis, enzyme inhibition and ligand docking studies

Inhibition of dipeptidyl peptidase-IV (DPP-IV) has been identified as a promising approach for the treatment of type 2 diabetes mellitus (T2DM). Therefore, development of DPP-IV inhibitors with new chemical scaffold is of utmost importance to medicinal chemistry. In the present study, we identified benzophenone thio- and semicarbazone scaffolds as novel DPP-IV inhibitors. For that purpose, benzophenone thio- and semicarbazone were synthesized through a 2-step reaction. These newly synthetic derivatives were characterized by different spectroscopic techniques, including HREI-MS and NMR. whereas stereochemistry of the iminic bond was predicted by NOESY experiments. Thio- and semicarbazones derivatives were evaluated for their DPP-IV inhibitory potential and found to exhibit a good to moderate enzyme inhibitory activity. Most active and non-cytotoxic derivatives were further evaluated for their DPP-IV inhibitory potential in in cellulo model. The binding sites as well as affinity of active compounds for DPP- IV enzyme were predicted by in silico studies, and compared to a standard drug, sitagliptin. Pharmacophore studies of thio- and semicarbazones derivatives 1-29 suggest that substitution of aryl group, particularly a lipophilic substituents at C-4 '' of benzene ring, and a hydroxyl at C-4 ' strongly influenced the DPP-IV inhibitory activity. Compound 9 showed the highest inhibitory activity (IC50 = 15.0 +/- 0.6 mu M), whereas compounds 10, 17, 12, 14 and 23 showed a moderate activity with IC50 values in the range of 28.9-39.2 mu M. This study identifies thio- and semicarbazones as new classes of DPP-IV inhibitors which may translate into safe and effective therapeutics for a better management of type 2 diabetes. Communicated by Ramaswamy H. Sarma

Automated summary

The study identified benzophenone thio- and semicarbazone as novel DPP-IV inhibitors with moderate to good enzyme inhibitory activity. Pharmacophore studies indicated that substitution of aryl group at C-4'' of benzene ring with a lipophilic substituent and addition of a hydroxyl at C-4' strongly influenced the inhibitory activity.