2. Academic Validation
  3. One destination, three routes: Tacrine-Celecoxib hybrids targeting cholinesterases, COX-2, and carbonic anhydrases in cognitive impairment linked to metabolic dysfunction

One destination, three routes: Tacrine-Celecoxib hybrids targeting cholinesterases, COX-2, and carbonic anhydrases in cognitive impairment linked to metabolic dysfunction

  • Eur J Med Chem. 2026 Oct 5:315:118984. doi: 10.1016/j.ejmech.2026.118984.
Nayera W Hassan 1,  Ola S Afifi 1,  Maryam A Z El-Attar 1,  Yasmine N Kamel 2,  Hend A Yassin 2,  Hanan Mohamed Nomeir 2,  Andrea Angeli 3,  Hala F Labib 4,  Manal A Elsheikh 5,  Mariam Zewail 5,  Evelyn M Gerges 6,  Ahmed F El-Yazbi 7,  Rosaria Spagnuolo 8,  Marina Naldi 8,  Mohamed I Ashmawy 9,  Waheed K Zahra 10,  Sherif F Hammad 11,  Claudiu T Supuran 12,  Manuela Bartolini 13,  Perihan A Elzahhar 14,  Ahmed S F Belal 15,  Shrouk M Abd El Wahab 16
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
  • 2 Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, 21131, Egypt.
  • 3 NEUROFARBA Department, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, Sesto Fiorentino, Firenze, 50019, Italy.
  • 4 Department of Pharmaceutical Chemistry, College of Pharmacy, Arab Academy for Science, Technology and Maritime Transport, Alamein, Egypt.
  • 5 Department of Pharmaceutics, Faculty of Pharmacy, Damanhour University, Damanhour, 22511, Egypt.
  • 6 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
  • 7 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt; Faculty of Pharmacy and the Research & Innovation Hub, Alamein International University, Alamein, 51718, Egypt.
  • 8 Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Bologna, 40126, Italy.
  • 9 Biotechnology Department, Faculty of Basic and Applied Sciences, Egypt-Japan University of Science and Technology, New Borg El-Arab, Alexandria, 21934, Egypt.
  • 10 Department of Mathematics, Institute of Basic and Applied Sciences, Egypt-Japan University of Science and Technology (E-JUST), New Borg El-Arab, Alexandria, 21934, Egypt; Department of Engineering Physics and Mathematics, Faculty of Engineering, Tanta University, Tanta, 31527, Egypt.
  • 11 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Capital University (Formerly Helwan University), Cairo, 11795, Egypt; Medicinal Chemistry Department, Faculty of Pharmacy, Egypt-Japan University of Science and Technology (E-JUST), New Borg El-Arab, Alexandria, 21934, Egypt.
  • 12 NEUROFARBA Department, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, Sesto Fiorentino, Firenze, 50019, Italy. Electronic address: [email protected].
  • 13 Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Bologna, 40126, Italy. Electronic address: [email protected].
  • 14 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. Electronic address: [email protected].
  • 15 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. Electronic address: [email protected].
  • 16 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Damanhour, 22511, Egypt.
PMID: 42190432 DOI: 10.1016/j.ejmech.2026.118984
Abstract

In this study, a series of tacrine-celecoxib hybrid compounds was designed and synthesized to modulate key molecular targets implicated in metabolic dysfunction-associated mild cognitive impairment, including cyclooxygenase-2 (COX-2), carbonic anhydrases, and cholinesterases. Among the investigated derivatives, compound 10b was identified as the most balanced multitarget candidate, exhibiting selective inhibition of human butyrylcholinesterase (BuChE, IC50: 470 nM), potent COX-2 inhibitory activity (IC50: 50 nM), and low nanomolar Ki towards human Carbonic Anhydrase IX (hCA IX). Importantly, 10b showed lower neurotoxicity in neuronal cell models compared with tacrine and staurosporine. In a high-fat diet (HFD)-induced rat model of metabolic dysfunction and cognitive impairment, administration of 10b either orally or via intranasal nanoformulation significantly improved hippocampus-dependent cognitive performance as assessed by a composite behavioral z-score. Administration of 10b was also associated with improvements in glucose homeostasis, Insulin sensitivity, lipid profile, together with a reduction of HFD-induced hepatological stress. Consistent with its multitarget profile, biochemical analyses showed significant attenuation of oxidative stress and neuroinflammatory markers in the hippocampus. Finally, docking and molecular dynamics simulation studies provided a structural rationale for the observed in vitro activities of 10b, highlighting favorable binding modes within the active sites of COX-2, BuChE, and hCA IX.

Keywords

COX-2; Carbonic anhydrases; Celecoxib; Cholinesterases; MTDLs; Metabolic dysfunction; Mild cognitive impairment; Neuroinflammation; Tacrine.

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