Unlocking the Potential of Isatin Scaffolds in Acetylcholinesterase Inhibition

The therapeutic significance of acetylcholinesterase (AChE) inhibition is most prominently observed in the management of various neurodegenerative and neuromuscular disorders, including Alzheimer's disease (AD), and myasthenia gravis (MG). The present review examines isatin-based compounds as a promising class of drugs for treating these conditions, focusing on their ability to inhibit AChE. While AD is characterized by a significant loss of cholinergic neurons leading to a deficiency in acetylcholine (ACh), MG is an autoimmune disease where the body produces antibodies that block or destroy ACh receptors at the neuromuscular junction. By inhibiting AChE, therapeutic agents increase the availability of ACh, thereby enhancing cholinergic neurotransmission and improving muscle strength or cognitive function. The underlying issue in MG is the reduced number of functional receptors rather than a primary decrease in AChE production. However, inhibition of the enzyme remains a vital strategy for symptom management. Accordingly, this review provides a systematic overview of the various synthetic strategies reported in the literature over the last decade for enhancing isatin-based AChE inhibitory activity. These strategies include modifications of the isatin nitrogen, such as N-alkylation, N-acylation, or N-arylation. Another strategy is aromatic ring substitution, where various substituents (e.g., halogens, nitro, amino, and alkyl groups) are introduced typically at the C₅, C₆, and/or C₇ positions. C₃-carbonyl functionalization is also reported, exemplified by the formation of Schiff bases, hydrazones, or spirocyclic derivatives. Our findings highlight the exceptional potential and adaptability of isatin derivatives in medicinal chemistry, highlighting the major advances within the last 10 years and the future directions.