Design, synthesis and bioevaluation of novel substituted triazines as potential dual PI3K/mTOR inhibitors

A series of novel substituted triazines bearing a benzimidazole scaffold were designed and synthesized based on the structures of known anti-cancer agents, namely gedatolisib and alpelisib. All the target compounds were screened for inhibitory activity against PI3Kα and mTOR kinases. Notably, most analogs exhibited IC50 in the nanomolar range. Investigation of the isozyme selectivity indicated that the compounds exhibited remarkable inhibitory activity against PI3Kδ, especially compound 19f showed an IC50 value of 2.3 nM for PI3Kδ and moderate δ-isozyme selectivity over other class I PI3K isoforms and mTOR (with IC50 values of 14.6, 34.0, 849.0 and 15.4 nM for PI3Kα, β, γ and mTOR, respectively). An in vitro MTT assay was conducted to assess the antiproliferative and cytotoxic effects of…