Design and Evaluation of Indole-Based Schiff Bases as α-Glucosidase Inhibitors: CNN-Enhanced Docking, MD Simulations, ADMET Profiling, and SAR Analysis

Type 2 diabetes mellitus (T2DM) remains a global health challenge, prompting the development of novel α-glucosidase inhibitors (AGIs) to regulate postprandial hyperglycemia. This study reports the design, synthesis, and evaluation of indole-based Schiff base derivatives (4a–j) bearing a fixed methoxy group at the C₅ position. This substitution was strategically introduced to enhance lipophilicity, electronic delocalization, and π-stacking within the enzyme active site. Among the series, compound 4g (3-bromophenyl) exhibited the highest inhibitory activity (IC₅₀ = 10.89 µM), outperforming the clinical reference acarbose (IC₅₀ = 48.95 µM). The mechanism was supported by in silico analyses, such as the Density Functional Theory (DFT), molecular electrostatic potential (MEP) mapping, and molecular dynamics simulations, and CNN-based docking revealed that 4g engages in stable hydrogen bonding and π–π interactions with key residues (Asp327, Asp542, and Phe649), suggesting a potent and selective mode of inhibition. In silico ADMET predictions indicated favorable pharmacokinetic properties. Together, these results establish C₅–methoxy substitution as a viable strategy to enhance α-glucosidase inhibition in indole-based scaffolds.