Targeting Lung Cancer: Synthesis, Characterization, Enzyme Inhibition, and Antiproliferative Activity of 1H-Benzo[f]chromen-1-One-Thiosemicarbazones Supported by Molecular Docking

The aim of this study is to design, synthesize, and characterize novel benzo[f]chromene-substituted thiosemicarbazone derivatives as potential anticancer agents, based on the rationale of simultaneously targeting key cancer-related enzymes and signaling pathways to improve therapeutic efficacy against lung cancer. For these purposes, 18 novel thiosemicarbazone derivatives 4a-r were synthesized. Among them, compound 4p exhibited the most promising anticancer effects against A549 cells, with an IC50 value of 5.11 µM and a selectivity index (SI) of 10.55, surpassing the reference drug sorafenib. Compound 4p also demonstrated potent enzyme inhibitory activity, particularly against hCA I (IC50 = 104.26 nM) and hCA II (IC50 = 95.18 nM), outperforming acetazolamide. In anticancer assays, compound 4p (SI = 10.55) was about twice as effective as sorafenib (SI = 5.34), and in enzyme inhibition, it showed ~1.5-fold greater potency than acetazolamide. Molecular docking studies show strong binding interactions of 4p with hCA I, hCA II, and BRAF, with favorable docking scores and stable protein-ligand complexes confirmed by 100-ns and 250-ns triplicate random seed MD simulations. Additionally, pharmacokinetic predictions indicated excellent drug-like properties for 4p, including high permeability, oral absorption, and adherence to Lipinski's rule. These findings highlight compound 4p as a promising candidate for an anticancer agent targeting key enzymes involved in lung cancer progression.