Bis(benzimidazol-2-yl)amine-Based DPP-4 Inhibitors Potentially Suitable for Combating Diabetes and Associated Nervous...

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Neuropharmacology

Background:

• Dipeptidyl peptidase-4 (DPP-4) inhibitors are crucial for diabetes treatment.
• The bis(benzimidazol-2-yl)amine scaffold has not been previously explored for DPP-4 inhibition.
• Understanding DPP-4's role in neuronal homeostasis is essential.

Purpose of the Study:

• To evaluate the dipeptidyl peptidase-4 (DPP-4) inhibitory potential of novel bis(benzimidazol-2-yl)amine derivatives.
• To assess the safety profile and potential off-target effects of these compounds.
• To explore the therapeutic implications for diabetes and neurological disorders.

Main Methods:

• Synthesis and in vitro evaluation of bis(benzimidazol-2-yl)amine derivatives for DPP-4 inhibition.
• Determination of inhibition mode and IC50 values.
• Assessment of cytotoxicity in SH-SY5Y cells and binding affinity to dopamine and histamine receptors.

Main Results:

• Three derivatives (5, 6, 7) exhibited noncompetitive DPP-4 inhibition with IC50 values under 50 μM.
• Compounds bind to the S2 extensive subsite of DPP-4, involving Phe357 and Arg358.
• No significant cytotoxicity or off-target binding to dopamine D2, D3, and histamine H1, H3 receptors was observed at relevant concentrations.

Conclusions:

• Bis(benzimidazol-2-yl)amine derivatives are effective noncompetitive DPP-4 inhibitors.
• These compounds demonstrate a favorable safety profile, lacking cytotoxicity and significant off-target receptor binding.
• The findings suggest potential therapeutic applications for diabetes and associated neuronal homeostasis disruptions.