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  3. Exploiting COX-2 engagement for amplifying anticancer potential of Quinazoline-triazole conjugates with superior EGFR/VEGFR-2 inhibition

Exploiting COX-2 engagement for amplifying anticancer potential of Quinazoline-triazole conjugates with superior EGFR/VEGFR-2 inhibition

  • Bioorg Chem. 2025 Nov:166:109162. doi: 10.1016/j.bioorg.2025.109162.
Marwa I Serag 1,  Abdelrahman Hamdi 2,  Eman E Nasr 1,  Mohamed R Elnagar 3,  Mohamed M Tawfik 4,  Adel S El-Azab 5,  Simone Brogi 6,  Ibrahim A Al-Suwaidan 5,  Mohamed Hefnawy 5,  Alaa A-M Abdel-Aziz 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 2 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: [email protected].
  • 3 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo 11823, Egypt; Department of Pharmacology, College of Pharmacy, The Islamic University, Najaf 54001, Iraq.
  • 4 Zoology Department, Faculty of Science, Port Said University, Port Said 42526, Egypt.
  • 5 Department of Pharmaceutical Chemistry, College of Pharmacy, P.O. Box 2457, King Saud University, Riyadh 11451, Saudi Arabia.
  • 6 Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
PMID: 41175722 DOI: 10.1016/j.bioorg.2025.109162
Abstract

A novel series of quinazoline-1,2,3-triazole hybrid compounds (8-22) were synthesized and evaluated as multi-target directed ligands (MTDLs) against EGFR, VEGFR-2, and COX-2 Enzymes for Anticancer activity. The synthesized compounds demonstrated significant Anticancer activity against four human Cancer cell lines (HeLa, HepG2, HCT-116, and MCF-7), with compound 17 emerging as the most potent derivative. Compound 17 exhibited exceptional Anticancer activity with IC₅₀ values of 4.93, 2.34, 6.07, and 3.35 μM against HeLa, HepG2, HCT-116, and MCF-7 cell lines, respectively, surpassing doxorubicin (DOX) against HepG2 cells (IC50 = 4.50 μΜ). Importantly, compound 17 demonstrated superior selectivity toward Cancer cells over normal human lung fibroblasts (WI-38) with a selectivity index of 11.78, compared to DOX (SI = 1.61). Multi-target enzyme inhibition assays revealed that compound 17 exhibited potent EGFR inhibition (IC₅₀ = 0.0085 μM), comparable to erlotinib (IC₅₀ = 0.0078 μM), strong VEGFR-2 inhibition (IC₅₀ = 0.068 μM), approaching sorafenib's activity (IC₅₀ = 0.056 μM), and significant COX-2 inhibition (IC₅₀ = 0.158 μM), comparable to Celecoxib (IC₅₀ = 0.044 μM). Compound 13 also demonstrated multi-target activity with IC₅₀ values of 0.0323, 0.220, and 0.103 μM against EGFR, VEGFR-2, and COX-2, respectively. Mechanistic studies revealed that compound 17 induces G1-phase cell cycle arrest in MCF-7 cells. The compound triggered a 5.11-fold increase in the Bax/Bcl-2 ratio, 2.90-fold upregulation of Caspase-8, and elevated caspase-9 protein levels from 139.48 to 392.53 ng/mL, confirming the intrinsic apoptotic pathway activation. Molecular docking and dynamics simulations provided structural insights into the multi-target binding modes. These findings establish quinazoline-1,2,3-triazole hybrids as promising multi-target Anticancer agents, with compound 17 demonstrating exceptional therapeutic potential through the simultaneous inhibition of tumor proliferation, angiogenesis, and inflammation pathways while maintaining favorable selectivity profiles.

Keywords

COX-2; EGFR; Molecular docking; Multi-target; Quinazoline-triazole hybrids; VEGFR-2.

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