Iodine catalyzed three component synthesis of 1-((2-hydroxy naphthalen-1-yl)(phenyl)(methyl))pyrrolidin-2-one derivatives: Rationale as potent PI3K inhibitors and anticancer agents

A series of 1-((2-hydroxynaphthalen-1-yl)(phenyl)(methyl))pyrrolidin-2-one derivatives by an efficient iodine catalyzed domino reaction involving various aromatic aldehydes, 2-pyrrolidinone and β-naphthol was achieved and the structures were elucidated by FTIR ¹H NMR, ¹³C NMR, and HRMS. Subsequently they were evaluated for cytotoxicity against breast cancer (MCF-7), colon cancer (HCT116) cell lines. In the cytotoxicity, the relative inhibition activity was remarkably found to be high in MCF-7 cell lines as 79% (4c), 83% (4f) and the IC₅₀values were 1.03 µM (4c), 0.98 µM (4f). Compounds 4a, 4e, 4k–m, and 4q were found to be inactive and rest showed a moderate activity. In order to get more insight into the binding mode and inhibitor binding affinity, compounds (4a–q) were docked into the active site phosphoinositide 3-kinase (PI3K) (PDB ID: 4JPS) which is a crucial regulator of apoptosis or programmed cell death. Results suggested that the hydrophobic interactions in the binding pockets of PI3K exploited affinity of the most favourable binding ligands (4c and 4f: inhibitory constant (ki) = 66.22 nM and 107.39 nM). The SAR studies demonstrated that the most potent compounds are 4c and 4f and can be developed into precise PI3K inhibitors with the capability to treat various cancers.