INTRODUCTION: Flavone derivatives are naturally occurring compounds with diverse biological activities, including anticancer effects. However, the anticancer potential of sulfonamide-substituted flavones remains largely unexplored. MATERIALS AND METHODS: Compounds 7a-7l were synthesized via Claisen-Schmidt condensation of N-(3-acetyl-4-hydroxyphenyl)acetamide with various aromatic aldehydes. Structural characterization was performed using 1H, 13C, and 19F NMR spectroscopy, LC-MS, and elemental analysis. Molecular docking was conducted using AutoDock Vina, with input files prepared via AutoDockTools (ADT). The pharmacokinetic properties of compound 7f were predicted in silico using the PreADMET web tool. RESULTS: Among the synthesized compounds, 7f exhibited the highest anticancer activity against the NCI-60 panel, with GI50 values ranging from 0.58 to 14.6 μM and total growth inhibition (TGI) values from 9.17 μM to >100 μM. The strongest activity was observed against leukemia (K-562, GI50 = 0.58 μM), melanoma (MDA-MB-435, GI50 = 1.03 μM), renal (TK-10, GI50 = 1.08 μM; A498, GI50 = 1.88 μM), lung (HOP-92, GI50 = 1.34 μM), and CNS (SNB-75, GI50 = 1.63 μM) cancer cell lines. Low cytotoxicity was observed for most subpanels (LC50 > 100 μM). Molecular docking analysis suggested poly( ADP-ribose) polymerases (PARP1, TNKS1, and TNKS2) as potential molecular targets, with TNKS1 exhibiting the most favorable binding affinity (ΔG = -11.1 kcal/mol). in silico ADME predictions indicated a favorable pharmacokinetic profile. DISCUSSION: A series of sulfonamide-flavone hybrids was designed, synthesized, and evaluated using a combination of in vitro and in silico approaches. The results support the flavone-sulfonamide scaffold as a viable platform for further anticancer drug development. CONCLUSION: In summary, twelve novel flavone-sulfonamide hybrids were successfully synthesized and characterized. Biological evaluation identified compound 7f as the most active derivative against the NCI-60 panel, exhibiting broad-spectrum anticancer activity with low cytotoxicity. Molecular docking and ADME analyses further supported its potential, identifying compound 7f as a promising lead compound for further optimization. Incorporation of a sulfonamide group at the 6-position of the flavone scaffold resulted in an eightfold increase in anticancer activity (GI), from 7% for the flavone to 55% for lead compound 7f.
Semenyuta et al. (Wed,) studied this question.