Cholinesterase Inhibitors in Alzheimer's Disease: Medicinal Chemistry, Mechanistic Insights, and Emerging Multitarget Strategies.

Abstract

Alzheimer's disease (AD) is the leading neurodegenerative disorder in the world. Although several decades of research have focused on its multifactorial pathogenesis, treating it remains a great challenge. The approved treatment options include cholinesterase inhibitors (ChEIs), which are the most common symptomatic treatment choice. These drugs act by inhibiting acetylcholinesterase (AChE) and, in some cases, butyrylcholinesterase (BuChE), preventing the breakdown of acetylcholine and increasing cholinergic neurotransmission in the brain. This review provides a broad consideration of ChEIs, focusing on their bioactivity, biochemical action, clinical significance, and SAR trends. It provides a comparative analysis of all the major chemical classes of ChEIs, namely the carbamates and organophosphates, as well as multiple heterocyclic scaffolds, with particular assessment of BBB permeability, metabolic stability, and toxicity attributes. Recent advances in medicinal chemistry have led to a shift in interest toward multi-target-directed ligands (MTDLs) that are designed not only to inhibit ChEs but also to exert antioxidant, anti-inflammatory, anti-amyloid, and metalchelating activity. These can target multiple pathogenic mechanisms to achieve a better therapeutic effect and neuroprotection. This review is based on a robust literature search conducted between 2020 and 2025. The progress, limitations, and prospects of ChEIs in the treatment of AD are critically assessed in this work. It also underscores the need for rational drug design to develop multitargetdirected drugs that may have disease-modifying effects, to overcome the limitations of existing symptomatic cholinesterase-inhibitor monotherapy.