Novel small molecule-based acetylcholinesterase (AChE) inhibitors: From biological perspective to recent developments

Alzheimer's disease (AD) is a chronic neurodegenerative disorder that imposes a substantial socioeconomic burden globally. The increasing prevalence of AD, coupled with an incomplete understanding of its fundamental etiology and the absence of a definitive cure, has intensified research efforts in this area. Over the past decade, the cholinergic theory has garnered significant attention from researchers, particularly in the development of small molecule-based Acetylcholinesterase (AChE) inhibitors using molecular modelling and computer-aided drug discovery. In recent years, the focus has expanded to include multi-target-directed ligands (MTDLs), which address the multifaceted pathological mechanisms of AD. These ligands offer the potential to reduce amyloid-beta plaque accumulation, neurofibrillary tangle (NFT) formation, oxidative stress, and neuroinflammation, while also providing metal chelation properties and selective MAO-B inhibition. Despite the progress in small molecule-based AD therapeutics, issues related to toxicity and severe side effects have underscored the urgent need for novel drug development. This has spurred interest in the structural modification of existing drugs such as tacrine, donepezil, galantamine, and rivastigmine, as well as the synthesis of new molecules informed by structure-activity relationship (SAR) studies. In this review, we summarize and analyse recent advancements in small molecule-based AChE inhibitors, with a focus on various drug design strategies aimed at generating potent therapeutic candidates. • Alzheimer's disease (AD) is a neurodegenerative disorder that causes neurocognitive dysfunction. • Acetylcholinesterase inhibitors are the main focus of drug development for Alzheimer's disease. • Small molecules targeting AChE inhibitors, design, SAR studies and hit-to-lead advances are covered. • Multi-Target-Directed Ligands (MTDLs) are also being discussed.