Discovery of Phthalimide-1,2,3-triazole-N-phenylacetamide Hybrids as Potent a-Glucosidase Inhibitors: Design, Synthesis, ADMET Prediction, and in vitro and in silico Enzymatic Evaluations

Thirteen new derivatives of the phthalimide-1,2,3-triazole-N-phenylacetamide hybrids were synthesized via simple chemical reactions. These hybrids were evaluated for their inhibitory potential against a-glucosidase in vitro and in silico. Among these thirteen derivatives, seven compounds showed excellent inhibition against studied enzyme (IC50 values = 1.30-31.7 mu M) as compared to positive control acarbose (IC50 value = 750.1 mu M) and among them, compound with 2,4-dichloro substituent on the phenyl ring of N-phenylacetamide moiety was identified as the most potent inhibitor against a-glucosidase. This compound was almost 577-fold more active than acarbose. Kinetic study on the most potent compound demonstrated that this compound is a competitive a-glucosidase inhibitor. To understand the interaction mode, stability, and flexibility of the most potent compounds, molecular docking and molecular dynamics studies were conducted. Furthermore, the drug-likeness, pharmacokinetic, and toxicity properties of the title compounds were predicted by in silico studies.

Automated summary

Thirteen new derivatives of phthalimide-1,2,3-triazole-N-phenylacetamide hybrids were synthesized and evaluated for their inhibitory potential against a-glucosidase. Seven compounds showed excellent inhibition (IC50 values = 1.30-31.7 μM) compared to the positive control acarbose (IC50 value = 750.1 μM), with the compound containing a 2,4-dichloro substituent on the phenyl ring being the most potent inhibitor. Molecular docking and dynamics studies were conducted to understand the interaction mode, stability, and flexibility of the most potent compounds, and in silico studies predicted their drug-likeness, pharmacokinetic, and toxicity properties.