Design of New Α-Glucosidase Inhibitors Based on the Bis-4-Hydroxycoumarin Skeleton: Synthesis, Evaluation, and in Silico Studies Publisher Pubmed



Soleimani Z¹ ; Mohammadi M² ; Halimi M³ ; Safapoor S¹ ; Dastyafteh N¹ ; Safaie E¹ ; Mojtabavi S⁴ ; Faramarzi MA⁴ ; Bozorgikoushalshahi M¹ ; Larijani B¹ ; Mohammadikhanaposhtani M⁵ ; Mahdavi M¹ Show Affiliations
Source: Scientific Reports Published:2024

Abstract

In this work, we have reported the design, synthesis, in vitro, and in silico enzymatic evaluation of new bis-4-hydroxycoumarin-based phenoxy-1,2,3-triazole-N-phenylacetamide derivatives 5a-m as potent α-glucosidase inhibitors. All the synthesized analogues showed high inhibition effects against α-glucosidase (IC50 values ranging between 6.0 ± 0.2 and 85.4 ± 2.3 µM) as compared to the positive control acarbose (IC50 = 750.0 ± 0.6 µM). Among the newly synthesized compounds 5a-m, 2,4-dichloro-N-phenylacetamide derivative 5i with inhibition effect around 125-folds more than the acarbose was identified as the most potent entry. A structure–activity relationship (SAR) study about the title compounds 5a-m demonstrated that the inhibition effects of these compounds depend on the pattern of substitution on the N-phenylacetamide ring. The interaction modes and binding energies in the active site of enzyme of the important analogues (in term of SAR study) were evaluated through molecular docking study. Molecular dynamics and prediction of pharmacokinetic properties and toxicity of the most potent compound 5i also evaluated and the obtained data was compared with the acarbose. © The Author(s) 2024.