Rational Design of Chlorinated Hydroxyxanthone as Anticancer Agent: Molecular Docking, Molecular Dynamic Simulation, ADMET, One-Pot Synthesis, and In Vitro Evaluation

Nowadays, the discovery of active anticancer agents has become urgent research due to the high mortality of cancer patients. Herein, we designed some chlorinated hydroxyxanthones to examine the effect of the presence and position of the chloro group on the inhibitory activity of the PDGFR. The molecular docking reveals that 5-chloro-1-hydroxyxanthone (5Cl) exhibited the strongest binding energy (−7.95 kcal/mol) against PDGFR. The molecular dynamic simulation results demonstrated a high stability of the 5Cl-PDGFR complex as revealed by the average RMSD (0.37 ± 0.15 Å) and RMSF (0.83 ± 0.64 Å), and two maintained hydrogen bonds with Cys673 through hydroxyl and carbonyl groups with an average bond distance of 2.29 ± 0.54 and 2.49 ± 0.64 Å, respectively. Afterward, 5Cl and other chlorinated hydroxyxanthones were synthesized in a one-pot reaction with a 15.1–25.2% yield. From the in vitro experiment, 5Cl exhibited the lowest IC50 value of 3.065–3.785 µM against breast (MCF-7), cervical (HeLa), and colorectal (WiDr) cancer cells. Furthermore, 5Cl exhibited the highest selectivity index (8.737–10.79), showing that 5Cl is not toxic to the Vero normal cells, which agreed with the ADMET predictions. These findings highlight the potential application of 5Cl as a new anticancer agent that will be investigated further and developed in the future.