Insights on synthetic strategies and structure-activity relationship of donepezil and its derivatives

This comprehensive review focuses on the synthesis and derivatives of donepezil, a pivotal Alzheimer’s disease (AD) medication introduced in 1997. As a selective acetylcholinesterase inhibitor with 100% oral bioavailability and a 70-h half-life, donepezil’s success in neurodegenerative disorder management has spurred extensive research into its synthesis and structural modifications. The review examines diverse synthetic approaches, evaluating their efficiency, cost, toxicity, and scalability. Methods range from traditional hazardous chemicals to eco-friendly strategies. Structural modifications and their impact on biological activities are explored, emphasizing their role in developing therapeutic agents for neurodegenerative diseases. The versatility of donepezil in drug design is demonstrated through discussions on analogues and hybrids, including those with lipoic and ferulic acid. Given projections of increased AD cases, the synthesis and modification of drugs like donepezil gain paramount importance. This review consolidates information for medicinal chemists, offering insights to guide the development of efficient compounds for neurodegenerative disorder management.