Nath_2026_Mol.Divers__

Oxygen-containing heterocycles were reviewed as privileged scaffolds that had driven recent advances in rational drug design and synthetic methodology. The manuscript synthesized literature (2015-2025) on oxadiazoles, coumarins, morpholines, pyrans, furans, benzofurans and chromones and summarized how these scaffolds were engineered to optimize potency, selectivity and CNS drug-like properties. Mechanistic analyses demonstrated that oxygen atoms and carbonyl or ether functionalities consistently mediated key hydrogen-bonding and Pi-interactions within the catalytic anionic site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), rationalizing observed AChE/BChE SAR and dual-site binding. Representative medicinal chemistry campaigns were highlighted: coumarin and coumarin-hybrid series provided potent dual-site inhibitors; 1,2-oxadiazoles or 1,3,4-oxadiazoles produced sub to low-nanomolar AChE/BChE leads; morpholine-bearing scaffolds afforded favourable BBB permeability and mixed-type inhibition; and pyranone-carbamate hybrids delivered highly BChE-selective inhibitors with promising in vivo cognitive effects. Synthetic strategies (multicomponent reactions, metal-catalysed cyclizations and green/one-pot protocols) were reviewed and correlated with scaffold diversification and improved ADME profiles. The review concluded by identifying gaps limited unified docking/SAR databases and sparse translational safety data and proposed a workflow combining fragment-based design, dual-site targeting and early ADME profiling to accelerate lead optimisation toward clinically relevant cholinesterase modulators. This focused synthesis of structure activity, mechanism and synthetic access was intended to inform future heterocycle-centric programs against neurodegenerative targets.