Synthesis and Anticancer Activity Study of New Bis-1,3-Oxazole-5-Sulfonylamides.

In the present study, eight novel substituted 4-cyano-N-(4-cyano-1,3-oxazol-5-yl)-N-alkyl-1,3-oxazole-5-sulfonylamides have been synthesized. Compounds are characterized by IR, 1H, 13C NMR spectroscopy, elemental analysis, and chromato-mass-spectrometry. The anticancer activities of six compounds are evaluated against the NCI-60 human tumor cell line panel. The tested compounds exhibit the strongest antiproliferative (TGI) and cytotoxic (LC50) activities within the leukemia, non-small-cell lung cancer, melanoma, and colon cancer subpanels. Overall, the mean activity parameters (GI50, TGI, and LC50) calculated for three compounds do not differ significantly and are within the range of 1-100 µM, and for some lines, it reaches the value 10-8 mol L-1. Structure-activity relationship analysis reveals markedly higher activity for bisoxazole derivatives bearing 4-MeC6H4 or 4-FC6H4 at the second position of the oxazole rings (compounds 2, 3, and 7), whereas derivatives with diphenyl, di-tolyl substituents (compounds 1 and 6), or 4-ClC6H4 (compound 8) exhibit substantially lower anticancer activity. In addition, the potential molecular mechanisms of anticancer action of these compounds are investigated using molecular docking methods. Derivatives show the highest affinity for tubulin and cyclin-dependent kinases. Docking of 4-cyano-N-[4-cyano-2-(4-fluorophenyl)-1,3-oxazol-5-yl]-N-methyl-2-(4-methylphenyl)-1,3-oxazole-5-sulfonamide into the colchicine-binding site of αβ-tubulin reveals a binding affinity of -10.9 kcal mol-1, with the ligand located at the subunit interface.