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

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 H<sub>2</sub>O<sub>2</sub>-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.

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Publication Details

Journal
RSC Medicinal Chemistry
Published
2025-11-10
DOI
https://doi.org/10.1039/d5md00802f
Primary Topic
Alzheimer's disease research and treatments
Type
article
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0.00
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article

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

Sarah S. Darwish, Tsong‐Long Hwang, Mohammad Abdel‐Halim, Annalisa De Palma et al.
RSC Medicinal Chemistry
Alzheimer's disease research and treatments
article

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

Sarah S. Darwish, Tsong‐Long Hwang, Mohammad Abdel‐Halim, Annalisa De Palma, Moustafa T. Gabr, Marco Catto, Ahmed M. El Kerdawy, Rosa Purgatorio, Daniela Valeria Miniero, Alireza Abadi, Yu‐Cheng Chen, Tzu‐Peng Cheng, Maryam Emad, Reham Waheed, Zeinab Mostafa
article en

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 H<sub>2</sub>O<sub>2</sub>-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.

RSC Medicinal ChemistryVol. 17(1)
Ming Chi University of Technology (TW), Chang Gung University of Science and Technology (TW), University of Hertfordshire (GB), Cairo University (EG), National Yang Ming Chiao Tung University (TW), Chang Gung University (TW), Cornell University (US), Chang Gung Memorial Hospital (TW), Ospedale San Giuseppe (IT), Molecular Innovations (United States) (US), Weill Cornell Medicine (US), University of Lincoln (GB), University of Bari Aldo Moro (IT), German University in Cairo (EG)
Openalex Percentile: Top 59%
Alzheimer's disease research and treatments
DOIOpen Access PDFOpenAlex
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