Current Landscape of Indole Hybrids in the Design and Development of Anti‐Alzheimer Agents: Structural Insights, Therapeutic Potential and In Silico Studies

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder characterised by progressive cognitive decline, neuronal loss and accumulation of β-amyloid plaques and neurofibrillary tangles. Even after many years of intensive research, scientists still have not found a cure for AD. The current medications can only help to manage the symptoms of AD or slow down the disease progression. This highlights an urgent and unmet need for the development of novel therapeutic agents capable of simultaneously modulating the multifactorial pathological pathways that drive the onset and progression of AD. The multitarget-directed ligand approach has garnered considerable attention in this context, aiming to simultaneously modulate multiple disease-relevant targets, including AChE, BChE, MAO-A and MAO-B, BACE1, and oxidative stress mediators. Indole, a fortunate heterocyclic scaffold, has become a valuable tool for the design and development of multi-target directed ligands in anti-Alzheimer drug discovery due to its favourable physicochemical properties, BBB permeability and medicinal attributes. This review summarises recent advancements in the medicinal chemistry of indole hybrids as anti-Alzheimer agents, highlighting the impact of structural modifications on biological activity, including the underlying molecular mechanisms, structure-activity relationships, and computational studies. The findings summarised in the article can pave the way for future anti-Alzheimer drug discovery.