Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by irreversible cognitive decline and memory loss. Targeting the kinase DYRK1A has emerged as a promising therapeutic strategy, as it plays a critical role in multiple key AD pathologies, including tau phosphorylation, β-amyloid (Aβ) production, and the regulation of neuroinflammatory processes. In this study, a series of novel quinazoline derivatives were designed and synthesized as DYRK1A inhibitors. Through preliminary anti-neuroinflammatory screening in a lipopolysaccharide (LPS)-induced BV2 microglial cell model, ZRMQ-22 was identified as a promising candidate that targets neuroinflammatory pathways in AD. This compound exhibits potent nanomolar-range inhibitory activity against DYRK1A, with an IC50 value of 0.35 nM. In LPS-stimulated BV2 cells, ZRMQ-22 concentration-dependently inhibited nitric oxide (NO) production, showing an IC50 of approximately 1 μM. Furthermore, at a concentration of 1 μM, it significantly suppressed the secretion of pro-inflammatory cytokines TNF-α and IL-6, with inhibition rates of 64.99% and 114.35%, respectively. In vivo experiments demonstrated that ZRMQ-22 effectively reduced levels of inflammatory markers and improved cognitive function in an LPS-induced neuroinflammation mouse model using C57BL/6 mice. These findings highlight ZRMQ-22 as a potent and safe DYRK1A inhibitor with significant efficacy in alleviating neuroinflammation and cognitive impairment, supporting its further development as a therapeutic candidate for AD.