Design, synthesis, anticancer and in silico assessment of 8-caffeinyl chalcone hybrid conjugates

In this paper, we report the design, synthesis, and characterization of novel 8-caffeinyl chalcone hybrid conjugates, which were studied for their anticancer properties, toxicity, and in silico behavior. The synthesized compounds consist of 8-caffeinyl and chalcone structures with diverse substituents. The synthesis involved three main stages: bromination of caffeine to produce 8-BC, synthesis of chalcones, and subsequent coupling of these chalcones with 8-BC. The anticancer activity of the resulting compounds was evaluated in vitro against breast cancer MCF-7 and melanoma A-375 cell lines, revealing certain compounds to have significant efficacy compared to the reference drug methotrexate. Toxicity assessments using a healthy cell line indicated that most compounds displayed some level of toxicity, with only a few exceptions. Molecular docking studies indicated robust binding affinities of selected compounds to B-RAF kinase and hDHFR enzymes. In silico analyses of pharmacokinetic and physicochemical properties demonstrated that the majority of the compounds adhered to Lipinski's rule of five. Furthermore, density functional theory (DFT) studies were performed to gain deeper insights into the properties of the intermediates used throughout the research.