Pyrrolidine derivatives as α-amylase and α-glucosidase inhibitors: Design, synthesis, structure-activity relationship (SAR), docking studies and HSA binding

Abstract

In our pursuit of developing effective inhibitors for the enzymes α-amylase and α-glucosidase, which play a crucial role in carbohydrate metabolism related to type-2 diabetes, we synthesized compounds featuring a pyrrolidine ring. The synthesis involved coupling N-Boc-proline with various aromatic amines, resulting in the formation of distinct N-Boc proline amides. To investigate the influence of the Boc group on enzyme inhibition, the Boc group was subsequently removed. In vitro, testing against α-amylase and α-glucosidase, with metformin and acarbose as reference standards, revealed that the 4-methoxy analogue 3g showed noteworthy inhibitory activity, with IC50 values of 26.24 and 18.04 μg/mL, respectively. Compounds 3a with an IC50 value of 36.32 μg/mL and 3f with an IC50 value of 27.51 μg/mL displayed significant inhibitory activity against α-amylase and α-glucosidase, respectively. The results of molecular docking studies of the most potent pyrrolidine derivatives 3a and 3g with α-amylase and 3f and 3g with α-glucosidase showed good agreement with experimental data. Moreover, compound 3g showed strong binding interactions with HSA having binding constant values of 7.08 × 105 M−1 and 4.77 × 105 M−1 using UV–visible and fluorescence spectrophotometry, respectively.

Keywords

• α-amylase
• α-glucosidase
• Antidiabetic activity
• Diabetes mellitus
• Pyrrolidine
• Structure-activity relationship (SAR)