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Research Articles

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

, , , , , , , , , & show all
Pages 244-260 | Received 27 Jan 2023, Accepted 10 Mar 2023, Published online: 25 Apr 2023
 

Abstract

In the present study, a series of 2-amino-4,6-diarylpyrimidine derivatives was designed, synthesized, characterized and evaluated for their in vitro 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 4p and 6p 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 1p–15p structures and their inhibitory actions (IC50) with a correlation value (R2) 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 4p. 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

Acknowledgments

The authors extend heir appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through large group Research Project under grant number RGP2/167/44.

Disclosure statement

The authors declare that they have no conflicts of interest.

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