Design and synthesis of 2-amino-4,6-diarylpyrimidine derivatives as potent α-glucosidase and α-amylase inhibitors: structure–activity relationship, <i>in vitro</i> , QSAR, molecular docking, MD simulations and drug-likeness studies

Abstract

In the present study, a series of 2-amino-4,6-diarylpyrimidine derivatives was designed, synthesized, characterized and evaluated for their <i>in vitro</i> α-glucosidase and α-amylase enzyme inhibition assays. The outcomes proved that this class of compounds exhibit considerable inhibitory activity against both enzymes. Among the target compounds, compounds <b>4p</b> and <b>6p</b> demonstrated the most potent dual inhibition with IC₅₀ = 0.087 ± 0.01 μM for α-glucosidase; 0.189 ± 0.02 μM for α-amylase and IC₅₀ = 0.095 ± 0.03 μM for α-glucosidase; 0.214 ± 0.03 μM for α-amylase, respectively as compared to the standard rutin (IC₅₀ = 0.192 ± 0.02 μM for α-glucosidase and 0.224 ± 0.02 μM for α-amylase). Remarkably, the enzyme inhibition results indicate that test compounds have stronger inhibitory effect on the target enzymes than the positive control, with a significantly lower IC₅₀ value. Moreover, these series of compounds were found to inhibit α-glucosidase activity in a reversible mixed-type manner with IC₅₀ between 0.087 ± 0.01 μM to 1.952 ± 0.26 μM. Furthermore, molecular docking studies were performed to affirm the binding interactions of this scaffold to the active sites of α-glucosidase and α-amylase enzymes. The quantitative structure-activity relationship (QSAR) investigations showed a strong association between <b>1p-15p</b> structures and their inhibitory actions (IC₅₀) with a correlation value (<i>R</i>₂) of 0.999916. Finally, molecular dynamic (MD) simulations were carried out to assess the dynamic behavior, stability of the protein-ligand complex, and binding affinity of the most active inhibitor <b>4p</b>. The experimental and theoretical results therefore exposed a very good compatibility. Additionally, the drug-likeness assay revealed that some compounds exhibit a linear association with Lipinski's rule of five, indicating good drug-likeness and bioactivity scores for pharmacological targets.Communicated by Ramaswamy H. Sarma.