Exploring the Quantum Chemical and Inhibitory Footprint of Coumarin Derivatives Against α-Amylase: A Unified in Silico and ADMET Profiling Study

Abstract Diabetes mellitus is a prevalent metabolic disease associated with persistent elevation of blood glucose and represents a significant challenge in the search for effective and well-tolerated therapeutic agents. Targeting α-amylase, a key enzyme involved in the hydrolysis of dietary carbohydrates, offers a promising approach for controlling postprandial glucose excursions. In this study, a novel series of pyrazole-linked coumarin derivatives was rationally designed, synthesized, and investigated for their potential as α-amylase inhibitors through a combination of computational and experimental methodologies. Molecular docking analysis was employed to elucidate the binding modes of the synthesized compounds within the α-amylase active site and to identify important ligand–protein interactions contributing to their inhibitory activity. In silico ADMET assessment was subsequently performed to examine their physicochemical characteristics, drug-likeness, pharmacokinetic profiles, and potential toxicity, with most compounds displaying favorable predicted properties. DFT calculations further provided insights into the structural and electronic characteristics of the derivatives by analyzing optimized geometries, frontier molecular orbitals, HOMO–LUMO energy gaps, and molecular electrostatic potential distributions. The synthesized compounds were structurally characterized using appropriate analytical methods and subjected to in vitro α-amylase inhibition assays, with acarbose serving as the standard inhibitor. The experimental results, supported by the computational investigations, identified several derivatives with notable inhibitory activity and favorable molecular properties. Overall, the findings suggest that pyrazole–coumarin hybrids represent a promising chemical framework for further optimization and development of potential α-amylase-targeting antidiabetic agents. Keywords: Pyrazole–coumarin hybrids, α-Amylase inhibition, Molecular docking, Frontier Molecular Orbital, Molecular Electrostatic Potential.