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Phenanthridine Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Design, Synthesis and Biological Evaluation

Author(s):

Reema Abu Khalaf*, Shorooq Alqazaqi, Maram Aburezeq, Dima Sabbah, Ghadeer Albadawi and Ghassan Abu Sheikha   Pages 1 - 17 ( 17 )

Abstract:


Background: Diabetes mellitus is a chronic metabolic disorder, characterized by hyperglycemia over a prolonged period, disturbance of fat, protein and carbohydrate metabolism, resulting from defective insulin secretion, insulin action or both. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are relatively a new class of oral hypoglycemic agents that reduces the deterioration of gut-derived endogenous incretin hormones that are secreted in response to food ingestion to stimulate the secretion of insulin from beta cells of pancreas.

Objective: In this study, synthesis, characterization, and biological assessment of twelve novel phenanthridine sulfonamide derivatives 3a-3l as potential DPP-IV inhibitors was carried out. The target compounds were docked to study the molecular interactions and binding affinities against DPP-IV enzyme.

Methods: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and MS. Quantum-polarized ligand docking (QPLD) was also performed.

Results: In vitro biological evaluation of compounds 3a-3l reveals comparable DPP-IV inhibitory activities ranging from 10%-46% at 100 ┬ÁM concentration, where compound 3d harboring ortho-fluoro moiety exhibited the highest inhibitory activity. QPLD study shows that compounds 3a-3l accommodate DPP-IV binding site and form H-bonding with the R125, E205, E206, S209, F357, R358, K554, W629, S630, Y631, Y662, R669 and Y752 backbones.

Conclusion: In conclusion, phenanthridine sulfonamides could serve as potential DPP-IV inhibitors that require further structural optimization in order to enhance their inhibitory activity.

Keywords:

Diabetes, dipeptidyl peptidase-IV, inhibitors, phenanthridine, sulfonamide, QPLD.

Affiliation:

Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman



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