Design, synthesis and antitumor effects of novel benzimidazole derivatives as PI3K inhibitors

Wenping Wu; Sisi Li; Junjie Chen; Tena Duo; Cheng Ma

doi:10.1016/j.bmcl.2023.129469

Design, synthesis and antitumor effects of novel benzimidazole derivatives as PI3K inhibitors

Bioorg Med Chem Lett. 2023 Oct 15:95:129469. doi: 10.1016/j.bmcl.2023.129469. Epub 2023 Sep 7.

Authors

Wenping Wu¹, Sisi Li¹, Junjie Chen¹, Tena Duo¹, Cheng Ma²

Affiliations

¹ Department of Medicinal and Organic Chemistry, College of Pharmacy, Xinjiang Medical University, Urumqi 830011, China.
² Department of Medicinal and Organic Chemistry, College of Pharmacy, Xinjiang Medical University, Urumqi 830011, China; State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi 830011, China; Xinjiang Key Laboratory of Active Components of Natural Medicine and Drug Release Technology, Xinjiang Medical University, Urumqi 830011, China. Electronic address: mac2008hk@126.com.

PMID: 37689214
DOI: 10.1016/j.bmcl.2023.129469

Abstract

Blocking the PI3K/Akt pathway has been widely recognized as an attractive cancer therapeutic strategy because of its crucial role in cell growth and survival. This study presents the synthesis of 24 new 5-Methoxy-6-substituted-1H-benzimidazole derivatives (4a-4x) and the evaluation of their anti-proliferative activities against A549, Siha, MCF-7, HepG2, PC3, and HCT-116 tumor cell lines through MTT assay. Compound 4w exhibited superior anti-tumor activity against the A549 cells with IC₅₀ values of 1.55 ± 0.18 μM, and better than the BKM120 (IC₅₀ = 9.75 ± 1.25 µM). Further studies indicated that 4w could induce G₀/G₁ phase arrest, cell apoptosis, and down-regulate expression of p-PI3K and p-Akt. These results indicate that 4w could be served as a lead compound of PI3K inhibitor for the treatment of human lung cancers.

Keywords: Antitumor; Benzimidazole derivatives; PI3K inhibitor; Proliferation.