Synthesis of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-1,2,3-triazoles as potent EGFR targeting anti-breast cancer agents

Synthetic chemists have organized easy and effective ways for perfect synthesis in response to the requirement for scaffolds that are crucial for medical applications. A general strategy was developed for the synthesis of new 1,2,3-triazoles (7a-7l & 8a-8g) containing fused [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine from 3-ethynyl-6-(4-nitrophenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine 8,8-dioxide (6) and several azides using Cu(I)-catalyzed [3+2] cycloaddition method. The cancer activity of the synthesized compounds was then tested in vitro against two breast cancer cell lines, MCF-7 and MDA-MB-231, and the majority of the examined compounds 7h, 7i, 8d, and 8e showed significant activity, with compounds 7h and 8d surpassing the standard drug against two cancer cell lines, and 7i and 8e equipotent activity against tested cell lines. Later, in vitro, EGFR results revealed that compounds 7i (IC50 = 0.38 ± 0.02 μM) and 8d (IC50 = 0.41 ± 0.05 μM) were more effective than the conventional medicine Erlotinib (IC50 = 0.42 ± 0.02 μM). Finally, in silico molecular docking studies and ADMET predictions were performed for six potent compounds using the Discovery Studio 2021 protocol to support the wet lab results and drug-likeness of the compounds.