Kumar_2025_Future.Med.Chem__1

Neurodegenerative diseases are progressive conditions marked by the deterioration of neuronal structure and function, often resulting from enzyme dysregulation and disrupted cellular communication, necessitating innovative treatment approaches. Morpholine, a versatile heterocyclic compound, has gained attention for its broad pharmacological activities and its role in modulating critical enzymes implicated in neurodegenerative processes, including acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidases (MAO-A and MAO-B). This review presents a structure-based approach to understanding and optimizing morpholine-clubbed heterocycles, offering insights into SAR, synthetic strategies, and pharmacokinetics to facilitate the rational design of anti-neurodegenerative agents. By compiling and analyzing recent advancements (2019-2024), we identify key molecular features that enhance the efficacy, selectivity, and drug likeliness of the derivatives, which are crucial for drug development. Additionally, we discuss an overview of synthetic approaches to prepare diversely functionalized morpholine hybrids, enabling the design of novel and more effective derivatives of enhanced therapeutic potency. Our coverage of various pharmacokinetics properties and in silico studies further aids in optimizing lead compounds for improved bioavailability and reduced toxicity, providing valuable insight into their clinical translatability. By integrating these insights, this review serves as a framework for advancing drug design, providing the way for next-generation morpholine-based therapeutics against neurodegenerative disorders.