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

Abstract

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 µM), whereas compounds 10, 17, 12, 14 and 23 showed a moderate activity with IC₅₀ values in the range of 28.9–39.2 µM. 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

Keywords:

• Type 2 diabetes mellitus
• dipeptidyl peptidase-IV (DPP-IV)
• thiosemicarbazone
• benzophenone
• Caco-2 cell line

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Authors are grateful to the Higher Education Commission (HEC), Pakistan, for providing financial support under the Indigenous Ph.D. Fellowship for 5000 Scholars Phase-II program and Pakistan Academy of Sciences for financial support to Project No. 5-9/PAS/440.