Synthesis and Bioactivity Investigation of Novel 2-({2-[(Dialkylamino) Methyl] Quinazolin-4-one-3-yl} Methyl) Benzonitrile Derivatives as Dipeptidyl Peptidase-4 Inhibitory Agent.

Abstract

Background: Quinazolinone derivatives have been documented to exhibit antidiabetic properties via the mechanism of dipeptidyl peptidase-4 (DPP-4) inhibition.

Objectives: To prepare and investigate the DPP-4 inhibitory activity in vitro and in silico of a series of novel 2-({2-[(dialkylamino)methyl]quinazolin-4-one-3-yl}methyl)benzonitrile derivatives.

Methods: The compounds were synthesized, and the chemical structures were confirmed through spectroscopic techniques. The in vitro DPP-4 inhibitory activity was assessed using an assay kit. Additionally, an in silico study was conducted using molecular docking methods to analyze the occurring binding interactions.

Results: The title compounds exhibited good inhibition against DPP-4 enzyme activity (IC₅₀: 1.4621 to 6.7805 µM). Among the compounds studied, the compound having morpholino-methyl substituted at C-2 (5d) exhibited the highest potency in DPP-4 inhibitory activity. Their activities were lower than sitagliptin as the reference standard with IC₅₀: 0.0236 µM and lead compound. In the in silico study, the compounds bound against the DPP-4 enzyme, with affinity values similar to those of sitagliptin. However, only compound 5f showed an interaction orientation and amino acid residues that were somewhat similar to those observed in the interaction between the DPP-4 enzyme and sitagliptin, as well as in the interaction between the DPP-4 enzyme and the lead compound.

Conclusions: A series of novel 2-({2-[(dialkylamino)methyl]quinazolin-4-one-3-yl}methyl)benzonitrile derivatives have been synthesized successfully. All the synthesized compounds had lower DPP-4 inhibitory activity than sitagliptin and the lead compound. The lower bioactivity was predicted due to the differences in the interaction between the synthesized and lead compounds against the DPP-4 enzyme.