2. Academic Validation
  3. Pyrazole derivatives as dual COX-2/EGFR inhibitors with anticancer potential: Optimization of difenamizole Analogs

Pyrazole derivatives as dual COX-2/EGFR inhibitors with anticancer potential: Optimization of difenamizole Analogs

  • Bioorg Chem. 2026 Mar:170:109444. doi: 10.1016/j.bioorg.2025.109444.
Kawther O Farag 1,  Mai S Nour 1,  Mai M Abdelhafez 2,  Noha M Ibrahim 3,  Hatem A Abdel-Aziz 4,  Samar H Fahim 5
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry Department, Faculty of Pharmacy, October University of Modern Sciences and Arts (MSA), 6th of October City, Giza, Egypt.
  • 2 Pharmacology and Toxicology Department, Faculty of Pharmacy, October University of Modern Sciences and Arts (MSA), 6th of October City, Giza, Egypt.
  • 3 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St, Cairo 11562, Egypt. Electronic address: [email protected].
  • 4 Applied Organic Chemistry Department, National Research Center, Cairo 12622, Egypt. Electronic address: [email protected].
  • 5 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St, Cairo 11562, Egypt.
PMID: 41505979 DOI: 10.1016/j.bioorg.2025.109444
Abstract

COX-2 and EGFR are overexpressed in glioblastoma multiforme (GBM) representing attractive therapeutic targets. Based on the non-selective COX Inhibitor "Difenamizole", which is characterized by its BBB-penetrating ability, we designed novel analogues with larger N-substituents to enhance COX-2 selectivity and introduce EGFR inhibition. Derivatives 6c, 7c, 8c, 8d, 9d, and 10a showed potent analgesic effects with AUC values: 31.69-39.23, comparable to Celecoxib (AUC = 31.57) and better than Difenamizole (AUC = 27.05). Compounds 8d and 10a demonstrated potent COX-2 inhibitory activity, comparable to Celecoxib (IC50 = 0.06, 0.05, and 0.05 μM, respectively) with high selectivity for COX-2 over COX-1 (SI = 148.83, 199.4, and 298.6, respectively). Additionally, compound 10a showed potent inhibitory activity against EGFR (IC50 = 0.098 μM), approaching that of Erlotinib (IC50 = 0.06 μM). In glioblastoma cytotoxicity assays, compound 10a displayed significant cytotoxicity against U-251 cells (IC50 = 8.8 μM), comparable to Staurosporine (IC50 = 7.5 μM) and exceeding NS-398 (IC50 = 23.14 μM), as well as marked superior potency against SNB-75 cells (IC50 = 2.6 μM), exceeding both Staurosporine and NS-398 (IC50 = 12.9 and 16.2 μM). Taken together, compound 10a represents a promising dual-targeted candidate for controlling GBM, with particular efficacy against the SNB-75 cell line, and reveals a distinctive profile compared with previously reported pyrazole derivatives by combining high COX-2 selectivity, EGFR inhibition, and GBM cytotoxicity.

Keywords

Analgesic; Anticancer; COX-2; EGFR; Glioblastoma; Pyrazole.

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