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  3. Design and development of 1,5-diarylpyrazole-based multitarget-directed ligands as dual COX-2/HDAC6 inhibitors for Alzheimer's disease therapy: Molecular dynamics and experimental insights

Design and development of 1,5-diarylpyrazole-based multitarget-directed ligands as dual COX-2/HDAC6 inhibitors for Alzheimer's disease therapy: Molecular dynamics and experimental insights

  • Eur J Med Chem. 2026 Mar 2:309:118738. doi: 10.1016/j.ejmech.2026.118738.
Kamal S Abdelrahman 1,  Osama M Soltan 1,  Hend E Abo Mansour 2,  Amany E Nofal 3,  Eman A Eissa 4,  Heba Rady Salem 5,  Marwa M Mahfouz 6,  Samar A El-Adawy 7,  Ghada S A Ewies 8,  Abdelrahman Hamdi 9,  Mostafa M Elbadawi 10,  Ahmed H A Abusabaa 11,  Ahmed A El-Rashedy 12,  Hiroyuki Konno 13,  Amr K A Bass 14
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt.
  • 2 Biochemistry Department, Faculty of Pharmacy, Menoufia University, Shibin El-Kom, Egypt; Biochemistry Department, Faculty of Pharmacy, Menoufia National University, km Cairo-Alexandria Agricultural Road, Egypt.
  • 3 Zoology Department, Faculty of Science, Menoufia University, Shebin El- Kom, Menoufia, 32511, Egypt.
  • 4 Department of Anatomy and Embryology, Faculty of Medicine, Menoufia University, Menoufia, Egypt.
  • 5 Department of Physiology, Faculty of Medicine, Menoufia University, Menoufia, Egypt.
  • 6 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Menoufia University, Shibin El-Kom, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Menoufia National University, km Cairo-Alexandria Agricultural Road, Egypt.
  • 7 Biochemistry Department, Faculty of Pharmacy, Menoufia National University, km Cairo-Alexandria Agricultural Road, Egypt; Department of Biochemistry, Faculty of Pharmacy, Tanta University, Egypt.
  • 8 Medical Pharmacology Department, Faculty of Medicine, Fayoum University, Fayoum, Egypt.
  • 9 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
  • 10 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
  • 11 Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, Fayoum University, Fayoum, Egypt.
  • 12 Department of the Chemistry of Natural and Microbial Products, Pharmaceutical and Drug Industries Institute, National Research Centre (NRC), 33 El-Behouth St., Dokki, Giza, 12622, Egypt.
  • 13 Department of Chemistry and Biological Engineering, Graduate School of Science and Engineering, Yamagata University, Jonan 4-3-16, Yonezawa, Yamagata, 992-8510, Japan. Electronic address: [email protected].
  • 14 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Menoufia University, Menoufia, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Menoufia National University, 70 km Cairo-Alexandria Agricultural Road, Menoufia, Egypt.
PMID: 41785827 DOI: 10.1016/j.ejmech.2026.118738
Abstract

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder, requiring multitarget-directed ligands capable of modulating interconnected pathological pathways. Here, a pharmacophore-hybridization strategy combining COX-2-selective 1,5-diarylpyrazole scaffolds with a zinc-binding group was used to design dual COX-2/HDAC6 inhibitors. Twenty hybrids were synthesized and evaluated, identifying 10a and 11e as the most potent compounds, with IC50 values of 0.18 and 0.66 μM for COX-2, and 0.15, 0.12 μM for HDAC6, respectively. Molecular dynamics simulations confirmed stable binding of 11e to both Enzymes, with persistent hydrogen bonding, minimal RMSD fluctuations, and favorable binding free energies (ΔG_bind = -29.3 and -51.5 kcal/mol for HDAC6 and COX-2, respectively). Compound 11e exhibited potent neuroprotective activity by markedly enhancing α-tubulin acetylation, suppressing the expression of pro-inflammatory mediators (COX-2, IL-1β, IL-6, and TNF-α), promoting Amyloid-β clearance, restoring memory-related gene expression, and significantly reducing Tau hyperphosphorylation. Histopathological analyses confirmed decreased phosphorylated STAT3 and Tau levels, preserved neuronal morphology via MAP2 stabilization, and protection of synaptic integrity through synaptophysin regulation. Behavioral studies in a scopolamine-induced AD mouse model demonstrated substantial improvements in learning and memory. These findings establish 11e as a potent dual COX-2/HDAC6 Inhibitor and a promising multitarget scaffold for developing disease-modifying therapies for AD and related neurodegenerative disorders.

Keywords

1,5 diarypyrazole; Dual COX-2/HDAC6 inhibitors; Molecular dynamic simulation; Multitarget anti-Alzheimer hybrids.

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