Oxadiazoles as multi-target therapeutic agents in Alzheimer’s Disease: A review of cholinesterase, MAO, β-Secretase, and Aβ aggregation inhibition

Abstract

Alzheimer's disease (AD) is a complex neurodegenerative disorder with a poorly understood etiology and limited therapeutic options. It is a leading cause of global morbidity and mortality, with an economic burden surpassing that of HIV and cancer combined together. These challenges underscore the urgent need for devising novel and efficient therapeutic strategies. This review focuses on the potential of oxadiazole ring systems as privileged scaffolds to offer potential anti-AD agents. Recent advancements in their synthesis and structure–activity relationships (SAR) are discussed, with an emphasis on their activity against key AD targets, which include acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase, monoamine oxidase B (MAO-B) and anti-oxidant potential. Additionally, molecular docking and molecular dynamics simulations are highlighted for their crucial role in understanding molecular binding interactions, predicting target protein–ligand complex stability, target specificity, and guiding the optimization strategies for the designing of potentially active anti-AD agents. Integration of these approaches demonstrates the immense potential of oxadiazoles in addressing the multifactorial etiology of AD and advancing the discovery of more effective treatments.