Synthesis, biological evaluation, and computational analysis of chromone-based carboxamides targeting Alzheimer’s disease

Alzheimer's disease (AD) is among the most serious long-term health problems of the last few decades. Regrettably, the current lack of treatment options for AD has made it a highly sought-after topic of drug development research. The utilization of multitarget directed ligand design (MTDL) has been the primary focus of research on developing pharmaceuticals for AD. By this approach, we designed novel cholinesterase inhibitors (ChEI) that may also exhibit additional monoamine oxidase (MAO) inhibitory, antioxidant, and metal chelator properties. Within the scope of the current work, twenty N-(2-(tertiaryamine-substituted)ethyl)-4-oxo-4H-chromene-2/3-carboxamide derivatives were synthesized and characterized. Subsequently, we conducted biological investigations for enzyme inhibitory (ChEs and MAO), antioxidant, and metal-chelating activities. Furthermore, we assessed the in silico physicochemical parameters of the compounds to evaluate their drug-likeness or druggability. Additionally, comprehensive computational studies were conducted, including density functional theory (DFT)-based frontier molecular orbital (FMO) analysis, global chemical reactivity descriptors, and molecular electrostatic potential (MEP) surface analysis, along with molecular docking, to elucidate the electronic properties, reactive sites, and binding interactions of the compounds with ChE enzymes.