Design, synthesis and evaluation of some 1,6-disubstituted-1H-benzo[d]imidazoles derivatives targeted PI3K as...

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Cancer Research

Background:

• The Phosphatidylinositol 3-kinase (PI3K) pathway is crucial for cellular functions and frequently dysregulated in human cancers.
• Class I PI3K is a validated therapeutic target for cancer treatment due to its common mutations and overexpression.

Purpose of the Study:

• To design, synthesize, and evaluate novel 1,6-disubstituted-1H-benzo[d]imidazole derivatives as potential anticancer agents.
• To identify and characterize a lead compound with potent inhibitory activity against the PI3K pathway.

Main Methods:

• Synthesis of 1,6-disubstituted-1H-benzo[d]imidazole derivatives.
• Anticancer activity screening and lead compound identification (compound 8i).
• In vitro PI3K kinase assays, molecular docking, western blot analysis, and cell migration/invasion assays.

Main Results:

• Compound 8i demonstrated significant antiproliferative activity and was identified as the lead compound.
• Compound 8i potently inhibited four subtypes of PI3K (IC50: 0.5–1.9 nM) and showed potential H-bonding interactions via molecular docking.
• Western blot analysis confirmed that 8i suppresses PI3K/Akt pathway activation, inhibits HCT116 cell migration and invasion, and induces apoptosis.

Conclusions:

• The novel benzoimidazole derivative, compound 8i, is a potent inhibitor of the PI3K pathway.
• Compound 8i exhibits significant anticancer properties, including inhibition of proliferation, migration, invasion, and induction of apoptosis, making it a promising candidate for cancer therapy.