Benzo[e][1,2,4]triazolo[1,5-c][1,2,3]triazines: Design, Synthesis, and Cytotoxic Effects.

A strategy has been developed for identification of biologically active compounds among unknown benzo[e][1,2,4]triazolo[1,5-c][1,2,3]triazines, based on the application of conformational restriction in the series of ([2-(3-R-1H-[1,2,4]triazol-5-yl)phenyl]amines with known chemotherapeutic activity. The target compounds were synthesized by diazotization of the corresponding ([2-(3-R-1H-[1,2,4]triazol-5-yl)phenyl]amines followed by cyclization of the formed diazo-compounds. The structures of products have been proven by IR, LC-MS, NMR spectroscopy, and x-ray structural analysis. Cytotoxicity screening was performed on a panel of cell lines derived from various tumor types and pseudo-normal cell lines. It was demonstrated that benzo[e][1,2,4]triazolo[1,5-c][1,2,3]triazines have selective antiproliferative activity against Jurkat cell lines with IC50 ranging from 7.64 to >100 µM. We identified 2-(naphthaline-1-ylmethyl)benzo[e][1,2,4]triazolo[1,5-c][1,2,3]triazine (2e) with high cytotoxic activity against this cell line with an IC50 of 7.64 µM. It is noteworthy that the conformational restrictions imposed proved to be a promising strategy for searching for biologically active compounds, and additional structural modification may lead to more effective and promising antitumor agents.