On the In Silico and In Vitro Anticancer Activity of Sulfonamide Chalcones: Potential JNKK3 Inhibitors

Abstract Science is constantly looking for new strategies to combat tumor progression and improve patient care due to increasing cancer incidence and high mortality. Although many chalcones analogues have been synthesized and studied because of their activity against tumor cell growth, the use of hybrid compounds containing both sulfonamides and chalcone moieties for this purpose is still scarce. Hereby, this work proposes a series of sulfonamide chalcones presenting biological potential against this disease. After experimentally tested, these compounds showed cytotoxicity against tumor cell lines, SF-295 and PC-3, which motivated us to investigate the possible structural bases for this action. Topological analyses were carried out through Hirshfeld analysis to assign intermolecular interactions sites important for protein-ligand analysis. To identify potential targets, the synthesized compounds were submitted to a structure-based pharmacophoric screening, which suggest strong potential activity as Mitogen-activated protein kinase 10 (JKN3) inhibitors. Considering these results, these compounds were docked within the JKN3 active site. Our hypothesis that these compounds achieve their biological potential by inhibiting JKN3 protein is reinforced when their energies of ligand-protein interaction were compared to co-crystallized ligands: they showed similar or even lower binding energies. Finally, the energy of the different conformations (solid phase, aqueous phase and within the protein active site) of these sulfonamide chalcones was investigated from theoretical calculations. Our findings enable further studies on more sulfonamide chalcone analogues toward the development of new anticancer drugs.