Design and Evaluation of Indole-Based Schiff Bases as α-Glucosidase Inhibitors: CNN-Enhanced Docking, MD Simulations, ADMET Profiling, and SAR Analysis
Seema K. Bhagwat, Sachin V. Patil, Abraham Marcelino Vidal Limón, J. Óscar C. Jiménez‐Halla, Balasaheb K. Ghotekar, Vivek D. Bobade, Irving David Pérez-Landa, Enrique Delgado‐Alvarado, Fabiola Hernández-Rosas, Tushar Janardan Pawar · Molecules · 2025
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.