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‐1 H ‐[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‐1 H ‐[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 IC 50 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 IC 50 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.