Synthesis, Anticancer and EGFR Inhibitory Activity of Novel [1,2,4]Triazolo[3,4-b][1,3,4]thiadiazine-isoxazoles

A novel approach was utilized for the synthesis of new [1,2,4]triazolo[3,4-b] [1,3,4]thiadiazine containing isoxazoles (6a-o) from 3-ethynyl-6-(4-fluorophenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-8,8-dioxide (4) in combination with freshly prepared substituted nitrile oxides (5) using Cu(I)-catalyzed [3+2] cycloaddition method. The in vitro cancer activity of the synthesized compounds was carried out against two lung cancer cell lines, A-549 and H1299. Among the compounds tested, 6h, 6k and 6l exhibited significantly stronger anticancer activity compared to standard drug erlotinib, with IC50 values ranging from 0.62 ± 0.20 to 4.40 ± 0.14 µM. The cytotoxicity of the more potent compounds was also tested against HEK-293 normal cell line and showed no toxic activity. Compound 6k appears to have higher inhibitory activity against EGFR (IC50 = 0.41 ± 0.03 µM) compared to the standard drug erlotinib (IC50 = 0.42 ± 0.03 µM), while compounds 6h and 6l demonstrated prominent activity. Further potent molecule believed to be a future drug for lung cancer.