Design, synthesis, and computational explorations of novel 2‐thiohydantoin nucleosides with cytotoxic activities

A novel series of S‐alkylated, N‐alkylated, and N‐glycosylated 2‐thiohydantoin derivatives were synthesized via the reaction of (E)‐5‐(arylidene)‐1‐phenyl‐2‐thiohydantoins 5a–d with alkyl halides/glycosyl bromides under aqueous, anhydrous alkaline/glycosylation conditions, respectively. The structures of the novel compounds were confirmed by elemental analyses and spectral data. Computational studies using DFT calculations with B3LYP/6‐31 + G (d,p) level were performed to study the electronic and geometric properties obtained from the stable structure of the investigated compounds. A good correlation was found between the quantum chemical parameters and experimental observations. The synthesized derivatives exhibited good binding interactions towards the cyclin‐dependent kinase 2, especially (E)‐5‐(chlorobenzylidene)‐3‐(2′0.3′0.4′0.6′‐tetra‐O‐acetyl‐β‐d‐galactopyranosyl)‐1‐phenyl‐2‐thiohydantoin (11g), which have good key interactions such as the co‐crystallized ligand. In addition, it had selective cytotoxic activities with IC50 = 12.4 μM against lung cancer A549 cells.