Discovery of novel 4,5-diphenyl-imidazol-α-aminophosphonate hybrids as promising anti-diabetic agents: Design, synthesis, in vitro, and in silico enzymatic studies

Herein, a novel series of 4,5-diphenyl-imidazol-alpha-aminophosphonate hybrids 4a-m was designed, synthesized, and evaluated as new anti-diabetic agents. These compounds were evaluated against two important target enzymes in the diabetes treatment: alpha-glucosidase and alpha-amylase. These new compounds were synthesized in three steps and characterized by different spectroscopic techniques. The in vitro evaluations demonstrated that all the synthesized compounds 4a-m were more potent that standard inhibitor acarbose against studied enzymes. Among these compound, the most potent compound against both studied enzymes was 3-bromo derivative 4l. The latter compound with IC50 = 5.96 nM was 18-times more potent than acarbose (IC50 = 106.63 nM) against alpha-glucosidase. Moreover, compound 4l with IC50 = 1.62 nM was 27-times more potent than acarbose (IC50 = 44.16 nM) against alpha-amylase. Molecular docking analysis revealed that this compound well accommodated in the binding site of alpha-glucosidase and alpha-amylase enzymes with notably more favorable binding energy as compared to acarbose.

Automated summary

A series of novel anti-diabetic compounds were designed, synthesized, and evaluated in vitro. The results showed that these compounds exhibited higher inhibitory activity against the target enzymes compared to the standard inhibitor acarbose. Molecular docking analysis provided insights into the improved activity of the most potent compound.