Benzoxazole Derivatives as Dual p38α Mitogen-Activated Protein Kinase and Acetylcholinesterase Inhibitors: Design, Synthesis, and Evaluation for Alzheimer's Disease and Cancer Therapy

Alzheimer's disease (AD), the most prevalent form of dementia, leads to progressive cognitive decline due to pathological hallmarks including amyloid plaques, neurofibrillary tangles, synaptic loss, neuroinflammation, and neuronal cell death, highlighting the urgent need for multitarget therapeutic strategies. The p38α mitogen-activated protein kinase (p38α MAPK) pathway is a key regulator of neuroinflammation and has been implicated in AD pathogenesis. Additionally, dysregulation of p38α MAPK is associated with tumorigenesis, making it a promising target for both neurodegenerative and proliferative diseases. In this article, a series of benzoxazole derivatives is designed and synthesized to evaluate their dual inhibitory potential against p38α MAPK and acetylcholinesterase (AChE), aiming for a multifaceted therapeutic approach to AD. A total of 31 compounds are synthesized and assessed for their antiproliferative activity, p38α MAPK inhibition, and AChE inhibitory effects. In vitro assays demonstrate that several compounds exhibit potent dual inhibition of p38α MAPK and AChE, while molecular docking studies provide insights into their binding interactions within the active sites. These findings suggest that benzoxazole-based scaffolds offer a promising framework for the development of dual-acting inhibitors targeting both neuroinflammation and tumorigenesis. Further in vivo and mechanistic studies are warranted to explore their therapeutic potential. © 2025 Wiley-VCH GmbH.