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

[Display omitted] •New 4,5-diphenyl-imidazol-α-aminophosphonate hybrids 4a-m were synthesized as potent α-glucosidase and α-amylase inhibitors.•These compounds were synthesized by simple chemical reactions and evaluated in vitro.•Compounds 4l and 4j showed excellent α-glucosidase and α-amylase inhibitory activities.•The most potent compound 4l was 18-fold more potent than standard inhibitor against α-glucosidase.•The most potent compound 4l was 27-fold more potent than standard inhibitor against α-amylase.•Molecular docking results of the most potent compounds were in agreement to in vitro results. Herein, a novel series of 4,5-diphenyl-imidazol-α-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: α-glucosidase and α-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 α-glucosidase. Moreover, compound 4l with IC50 = 1.62 nM was 27-times more potent than acarbose (IC50 = 44.16 nM) against α-amylase. Molecular docking analysis revealed that this compound well accommodated in the binding site of α-glucosidase and α-amylase enzymes with notably more favorable binding energy as compared to acarbose.