Design, Synthesis, and Evaluation of Naphthyl Pyrazino‐Pyrido‐Pyrimidinones Targeting the Phosphoinositide 3‐Kinase/Alpha‐Serine/Protein Kinase B/Mammalian Target of Rapamycin Pathway

Cancer remains a leading global cause of death and a major public health concern, with rising incidence and mortality rates. Current treatments are often limited by tumor complexity and heterogeneity, emphasizing the need for novel, targeted, and personalized therapies. Aberrant activation of the phosphoinositide 3-kinase/alpha-serine/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway plays a key role in cancer development, making it an attractive therapeutic target. In this study, we performed in silico and in vitro analyses to assess the antitumor potential of two pyrazino-pyrido[2,3-d]pyrimidine-5,7-dione Series (A and B) across various cancer cell lines, focusing on possible PI3K/AKT/mTOR inhibition. Guided by these results, we designed a new Series (C) with a fixed C-9 naphthyl group and variable C-6 substitutions. The compounds were synthesized via an optimized one-pot process followed by intramolecular cyclization. Molecular docking and biological assays revealed notable antitumor activity for Series C, particularly for compounds 3 and 4, in BT20, HGC, and CAL-27 cell lines, while showing selectivity over normal fibroblasts (GNP5). These compounds also affected cell cycle progression and phosphorylation of key proteins involved in autophagy and survival (ULK1, LC3, p-AKT, p-STAT3). Overall, this study introduces a promising new scaffold with potent, selective antitumor properties.