Exploring Pyrazolidinone and Pyrazolidinedione Scaffolds for Alzheimer's Therapy: Multitarget COX-2 Inhibitors with Anti-Amyloid β;  Anti-Tau;  Antioxidant;  and Neuroprotective Activities

doi:10.1039/D5MD00802F

Exploring Pyrazolidinone and Pyrazolidinedione Scaffolds for Alzheimer's Therapy: Multitarget COX-2 Inhibitors with Anti-Amyloid β; Anti-Tau; Antioxidant; and Neuroprotective Activities

2025-11-10

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Daniela Valeria Miniero

DOI：10.1039/D5MD00802F

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COX-2 enzyme is implicated in Alzheimer's disease (AD) through amyloid beta (Aß) accumulation; tau aggregation; and neuroinflammation. However; clinical outcomes of COX-2 inhibitors in AD have been inconsistent. This study explores novel series of pyrazolidinones and pyrazolidinediones as selective COX-2 inhibitors. Among these; 4-hydrazonopyrazolidinediones exhibited potent COX-2 inhibition; reducing PGE2 release in a THP-1 cell model. Compounds 15 and 16 demonstrated multitargeting potential by inhibiting Aß and tau aggregation (PHF6 and R3) and showed significant neuroprotective effects against Aß and H 2 O 2 -induced toxicity in SH-SY5Y cells without cytotoxicity. Additionally; both compounds displayed high permeability in PAMPA and MDCK-MDR1 assays; indicating their potential to cross the blood-brain barrier and reach therapeutic targets. These findings highlight the potential of reviving COX-2 inhibitors as multitargeted therapeutic agents for AD; offering a promising strategy to address multiple pathological aspects of the disease; including neuroinflammation; amyloid aggregation; and tau pathology.

Exploring Pyrazolidinone and Pyrazolidinedione Scaffolds for Alzheimer's Therapy: Multitarget COX-2 Inhibitors with Anti-Amyloid β; Anti-Tau; Antioxidant; and Neuroprotective Activities

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