Privileged structures as molecular master keys for targeting (neuro)inflammation

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline and neuronal loss. Growing evidence highlights neuroinflammation as a key driver of disease onset and progression, with dysregulation of the arachidonic acid (AA) cascade and the overactivation of glycogen synthase kinase 3B (GSK-3B) contributing to both amyloid-B (AB) and tau pathology. In this context, multitarget-directed ligands (MTDLs) represent a promising therapeutic strategy to address the complex pathological network underlying AD. This dissertation explores privileged scaffolds as a design tool for developing MTDLs to target neuroinflammatory and neurodegenerative processes. In chapter 3, acylamino pyrazoles and 7-azaindole – previously reported as kinase-binding motifs – were exploited to design and synthesize novel GSK-3B inhibitors with neuroprotective properties. Acylamino pyrazole derivatives were further evaluated for their ability to modulate AB aggregation, chelate metal ions and counteract induced neurotoxicity. In parallel, 7-azaindole analogues were tested for their effects on neuronal viability and inhibition of pathological TDP-43 phosphorylation. Their multitarget profile was a central focus, as simultaneous modulation of multiple pathological mechanisms is critical for treating neurodegenerative disorders. In chapter 4, chromone- and coumarin-based derivatives were designed as multitarget inhibitors of key AA pathway enzymes involved in inflammatory processes at central and peripheral levels. Anti-inflammatory activity was evaluated in vitro and in vivo, together with gastrointestinal safety. Selected derivatives were further investigated for antioxidant properties and their ability to inhibit the Keap1-Nrf2 interaction, leveraging the intrinsic radical scavenging capacity of these scaffolds and their potential to activate Nrf2-dependent endogenous antioxidant responses. Overall, this work integrates chemical design, synthesis and biological evaluations, demonstrating that combining multiple pharmacological activities within a single chemical entity can effectively address the multifactorial nature of AD and support the development of disease-modifying therapeutic strategies.