Exploring pyrazolidinone and pyrazolidinedione scaffolds for Alzheimer's therapy: multitarget COX-2 inhibitors with anti-amyloid β, anti-tau, antioxidant, and neuroprotective activities.

ABSTRACT: COX-2 enzyme is implicated in Alzheimer's disease (AD) through amyloid beta (Aβ) accumulation, tau aggregation, and neuroinflammation. However, clinical outcomes of COX-2 inhibitors in AD have been inconsistent. This study explores a 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 Aβ and tau aggregation (PHF6 and R3) and showed significant neuroprotective effects against Aβ and H₂O₂-induced toxicity in SH-SY5Y cells without cytotoxicity. Additionally, both compounds displayed high permeability in PAMPA and MDCK-MDR1 assays, indicating thei

SUBMITTER: Emad M 

PROVIDER: S-EPMC12683544 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature