Design, synthesis, molecular modeling and anti-cancer activity of novel fluorinated naphtho[2,3-b]thiophene-4,9-dione...

Novel naphtho[2,3-b]thiophene-4,9-dione derivatives were successfully synthesized in moderate yields via a two-step procedure. This involved a three-component reaction of 2-hydroxy-1,4-naphthoquinone, fluorinated aromatic aldehydes, and pyridinium bromide, followed by oxidative ring editing with elemental sulfur. All the synthesized derivatives exhibited high to moderate cytotoxicity on all tested cancer cell lines with IC₅₀ values ranging from 1.33 ± 0.02 to 23.78 ± 1.61 µM. Flow cytometric analysis showed that compound 8n could arrest the cell cycle of A549 cells at the G0/G1 phase, without inducing apoptosis. Molecular docking studies revealed strong binding of potent compounds within the atirmociclib binding site of CDK4/cyclin D1, consistent with their in vitro potency, while physicochemical and ADMET calculations revealed suitable drug-likeness with acceptable safety profiles. These findings confirm the potential of these compounds as promising CDK4-targeted anticancer agents.