Part I: Design, synthesis and biological evaluation of novel pyrazole-benzimidazole conjugates as checkpoint kinase 2 (Chk2) inhibitors with studying their activities alone and in combination with genotoxic drugs. Academic Article uri icon


  • Activated checkpoint kinase 2 (Chk2) is a tumor suppressor as one of the main enzymes that affect the cell cycle. 2-Biarylbenzimidazoles are potent selective class of Chk2 inhibitors; the structure-based design was applied to synthesize a new series of this class with replacing the lateral aryl group by substituted pyrazoles. Ten pyrazole-benzimidazole conjugates from the best fifty candidates according to docking programs have been subjected to chemical synthesis in this study. The activities of the conjugates 5-14 as checkpoint kinase inhibitors and as antitumor alone and in combination with genotoxic drugs were evaluated. The effect of compounds 7 and 12 on cell-cycle phases was analyzed by flow cytometry analysis. Antitumor activity of compounds 7 and 12 as single-agents and in combinations with doxorubicin was assessed in breast cancer bearing animals induced by MNU. The Results indicated that compounds 5-14 inhibited Chk2 activity with high potency (IC50 52.8nM-5.5nM). The cytotoxicity of both cisplatin and doxorubicin were significantly potentiated by the most of the conjugates against MCF-7cell lines. Compounds 7 and 12 and their combinations with doxorubicin induced the cell cycle arrest in MCF-7cells. Moreover, compound 7 exhibited marked higher antitumor activity as a single agent in animals than it's combination with doxorubicin or doxorubicin alone. The combination of compound 12 with doxorubicin was greatly effective on animal than their single-dose treatment. In conclusion, pyrazole-benzimidazole conjugates are highly active Chk2 inhibitors that have anticancer activity and potentiate activity of genotoxic anticancer therapies and deserve further evaluations.

published proceedings

  • Eur J Med Chem

altmetric score

  • 0.25

author list (cited authors)

  • Galal, S. A., Abdelsamie, A. S., Shouman, S. A., Attia, Y. M., Ali, H. I., Tabll, A., ... El-Diwani, H. I.

citation count

  • 26

complete list of authors

  • Galal, Shadia A||Abdelsamie, Ahmed S||Shouman, Samia A||Attia, Yasmin M||Ali, Hamed I||Tabll, Ashraf||El-Shenawy, Reem||El Abd, Yasmine S||Ali, Mamdouh M||Mahmoud, Abeer E||Abdel-Halim, Abeer H||Fyiad, Amal A||Girgis, Adel S||El-Diwani, Hoda I

publication date

  • July 2017