Synthesis, Bioactivity Evaluation, and Molecular Docking Study of Novel 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl) urea derivatives as Anticancer Agents

This study aims to design, synthesize, and evaluate novel 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl) urea derivatives based on a deguelin-truncated carboxamide scaffold as anticancer agents. Two novel urea derivatives were synthesized from the starting material 5-fluoro-2-nitrophenol through a six-step procedure. Two key amine intermediate compounds, an indazole and an E-stilbene derivative, were obtained before being condensed with phenyl (5-methoxy-2,2-dimethyl-2H-chromen-6-yl) carbamate to form the designed compounds XIa and XIb. The structures of the synthesized compounds were confirmed by spectroscopic methods, including ¹H-NMR, ¹³C-NMR, NOESY, IR, and Mass Spectrometry (MS). Purity was confirmed by thin-layer chromatography (TLC) and melting point analysis. An MTT assay was used to evaluate the cytotoxicity of XIa, XIb, and the parent compound NCT-58. Both XIa and XIb exhibited good anticancer activity against triple-negative breast cancer (MDA-MB-231) and non-small cell lung cancer (A549) cell lines, with IC₅₀ values ranging from 1.24 to 18.77 µM. Compound XIa was over six times more potent than NCT-58 against the A549 cell line and exhibited better anticancer activity than compound XIb in both tested cell lines. The molecular docking assay revealed that XIa and XIb fit well into the C-terminal domain of HSP90 in the same binding mode as NCT-58. Compound XIa showed a higher binding affinity to the C-terminal domain of HSP90 than NCT-58, with a binding energy of -7.12 kcal/mol. Both XIa and XIb satisfied the criteria outlined in Lipinski’s Rule of Five and Veber’s rule as NCT-58.