Novel indole-sulfonamide hybrids as α-amylase and α-glucosidase inhibitors: a rational approach combining enzyme kinetics and in silico analysis

The development of effective α-amylase and α-glucosidase inhibitors is an important strategy for the management of type 2 diabetes mellitus. In the present study a series of novel indole-sulfonamide hybrids (1–17) were designed synthesized and evaluated for their inhibitory activity against α-amylase and α-glucosidase enzymes. The synthesized compounds were characterized through ¹HNMR, ¹³CNMR and HREIMS. All analogs demonstrated promising enzyme inhibitory activity when compared with the reference drug acarbose. Among all tested compounds, analog 4 (IC₅₀ = 16.6, and 16.4 µM), 11 (IC₅₀ = 15.0 and 15.8 µM), 12 (IC₅₀ = 14.0 and 14.1 µM), and 15 (IC₅₀ = 12.1 and 13.7 µM) demonstrated good inhibitory potentials against α-amylase and α-glucosidase enzymes respectively. Enzyme kinetic studies revealed that the most active compounds (4, 11, 12, and 15) acted as competitive inhibitors with Ki values ranging from 4.2 to 5.8 µM for α-amylase and 28.8–28.5 µM for α-glucosidase. The molecular docking studies have supported the results and showed that these compounds have been involved in various binding interactions within the active site of enzyme.