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.