Background: Lately, diabetes has become the main health concern for millions of people around
the world. Dipeptidyl peptidase-IV (DPP-IV) inhibitors have emerged as a new class of oral antidiabetic
agents. Formerly, acridines, N4-sulfonamido-succinamic, phthalamic, acrylic and benzoyl acetic acid derivatives,
and sulfamoyl-phenyl acid esters were designed and developed as new DPP-IV inhibitors.
Objective: This study aims to develop a pharmacophore model of DPP-IV inhibitors and to evaluate phenanthridines
as a novel scaffold for inhibiting DPP-IV enzyme. In addition, to assess their binding interactions
with the enzyme through docking in the binding site of 4A5S (PDB).
Methods: Herein, Quantum–Polarized Ligand Docking (QPLD) and ligand-based pharmacophore modeling
investigations were performed. Three novel 3,8-disubstituted-6-phenyl phenanthridine derivatives 3-5 have
been designed, synthesized and characterized. In vitro biological testing against DPP-IV was carried out using
fluorometric assay kit.
Results: QPLD study demonstrates that compounds 3-5 forms H-bond with Lys554, Trp629, and Tyr631,
besides charge transfer interaction between their aromatic rings and the aromatic rings of Tyr547 and
Tyr666. Moreover, they fit the three pharmacophoric point features of DPP-IV inhibitors and were proven
to have in vitro DPP-IV inhibitory activity where compound 5 displayed a % inhibition of 45.4 at 100 μM
Conclusion: Phenanthridines may serve as a potential lead compound for developing new DPP-IV inhibitors
as a promising antidiabetic agent. Computational results suggest future structural simplification.