Adamantane-based scaffolds: Synthesis, DFT, docking and potential as anticancer agents via CDC25A inhibition.

Various 2-fluorophenyl-adamantane analogs were studied to examine the potential for developing anticancer agents. This approach combined the synthesis of novel analogs spanning several structural variations, followed by in vitro cytotoxicity assessment, then computational studies utilizing network pharmacology, molecular docking, and density functional theory (DFT) techniques. 2-fluorophenyl-adamantanyl amides were synthesized by reacting a primary amine scaffold with the required acid chlorides. Anticancer activity was performed on PANC-1, DU145, A375, and MCF7 cells using a Sulforhodamine B colorimetric assay. IC50 values were determined to be as low as 0.53 µM for the most potent analog (AD-CA). Network pharmacology methods predicted biological targets including CDC25A enzyme. Molecular docking demonstrated binding within CDC25A. DFT calculations support the experimental findings by showing that AD-CA combines high nucleophilicity and electronic stability with a localized polar region around the chloroacetamide group. Molecular electrostatic potential and reduced density gradient (RDG) analyses further indicated favorable noncovalent interactions and limited steric congestion, consistent with its strong cytotoxic activity. Our findings suggest adamantane as a feasible backbone to develop anticancer agents which may act in-part via CDC25A interaction.