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  3. Click chemistry synthesis of triazole-grafted quinazolinones as new multi-panel anticancer agents: mechanistic insights into apoptosis and cell cycle arrest in colorectal cancer

Click chemistry synthesis of triazole-grafted quinazolinones as new multi-panel anticancer agents: mechanistic insights into apoptosis and cell cycle arrest in colorectal cancer

  • Bioorg Chem. 2026 Jul 15:176:109846. doi: 10.1016/j.bioorg.2026.109846.
Mohammad M Al-Sanea 1,  Mohamed R Elnagar 2,  Hamed W El-Shafey 3,  Marwa I Serag 3,  Nimah Saad Alanzi 4,  Mahmoud S Elkotamy 5,  Rofaida Salem 6,  Wagdy M Eldehna 7,  Abdelrahman Hamdi 8
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 72388, Saudi Arabia. Electronic address: [email protected].
  • 2 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.
  • 3 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 4 Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 72388, Saudi Arabia.
  • 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alsalam University, Kafr Alzayat 31611, Algharbia, Egypt.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt. Electronic address: [email protected].
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
  • 8 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt. Electronic address: [email protected].
PMID: 41962189 DOI: 10.1016/j.bioorg.2026.109846
Abstract

The epidermal growth factor receptor (EGFR) is a critical oncogenic driver in colorectal Cancer, establishing the need for novel small-molecule inhibitors. We designed and synthesized two new triazole-grafted quinazolinones, T6 and T7, utilizing click chemistry to efficiently construct their hybrid architecture. Biological evaluations demonstrated that both compounds possess multi-panel antiproliferative activity across nine NCI Cancer subtypes, with mean growth inhibition (GI%) exceeding 100% against CNS Cancer (128.54% and 87.98%), melanoma (122.75% and 136.30%), and colon Cancer (114.34% and 88.22%) for T6 and T7, respectively. In the five-dose screening, T6 and T7 showed notable activity against HT29 colon Cancer cells, with GI₅₀ values of 0.53 μM and 0.39 μM, respectively. Both compounds exhibited markedly lower cytotoxicity against normal WI-38 fibroblasts (IC50: 156.59 μM for T6 and 191.80 μM for T7) compared to the reference kinase inhibitor dasatinib (IC50: 37.87 μM), supporting a favorable in-vitro safety profile. Both quinazolinones effectively inhibited EGFR kinase activity with IC50 values of 0.198 μM and 0.131 μM, respectively, compared to 0.046 μM for the reference inhibitor erlotinib. Mechanistic studies revealed that T6 and T7 induce G₀/G₁ cell cycle arrest and significantly trigger Apoptosis in HT29 cells, with total Apoptosis rates of 67.40% for T6 and 89.62% for T7, versus 30.16% in untreated controls. Both compounds also demonstrated notable anti-migratory effects, with T6 limiting wound closure to 16.85% and T7 to 33.71%, compared to 57.18% in untreated HT29 cells over 48 h. Molecular docking suggested favorable initial EGFR binding of the synthesized quinazolinones, while molecular dynamics analysis supported improved dynamic stability of T7 relative to T6. The results support T6 and T7 as viable and safe candidates for further development in colorectal Cancer treatment.

Keywords

Cancer; Colorectal cancer; EGFR; Molecular dynamics; Public health; Quinazolin-4(3H)-one.

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