Integrated DFT, topological, and ADME analysis of isatin-based Schiff bases: Synthesis and in silico antidiabetic evaluation

Abstract

This paper presents a comparative reactivity analysis of three isatin-derived Schiff bases for in silico antidiabetic applications. The synthetic accessibility of the isatin derivatives ISAN, ISOPD, and ISPPD was achieved through a wet-lab manner, followed by their characterisation using FT-IR, NMR, and HRMS analyses. The electronic environment, stability, and reactivity were comprehensively evaluated using geometry optimisation, FMO analysis, vibrational assignments, MEP plot, and NBO analysis based on DFT calculations. The reactivity profiling of the title compounds was validated through Fukui function analysis, grounded in conceptual DFT. Covalent and non-covalent interactions, including intramolecular hydrogen bond energies, were elucidated through topological analyses using ELF, LOL, RDG, and QTAIM methods. ADMET studies were conducted to determine the physicochemical properties of the title compounds. Subsequently, the potential of the isatin-appended molecules was evaluated computationally through molecular docking with two α-glucosidase enzymes, along with binding energy calculations. ISPPD exhibits higher binding energy than the reference compound acarbose, along with twice the number of active site interactions, highlighting its potential as a promising antidiabetic candidate.