| Summary: | Three novel pyrazolo-[4,3-<i>e</i>][1,2,4]triazolopyrimidine derivatives (<b>1</b>, <b>2</b>, and <b>3</b>) were designed, synthesized, and evaluated for their in vitro biological activity. All three compounds exhibited different levels of cytotoxicity against cervical and breast cancer cell lines. However, compound <b>1</b> showed the best antiproliferative activity against all tested tumor cell lines, including HCC1937 and HeLa cells, which express high levels of wild-type epidermal growth factor receptor (EGFR). Western blot analyses demonstrated that compound <b>1</b> inhibited the activation of EGFR, protein kinase B (Akt), and extracellular signal-regulated kinase (Erk)1/2 in breast and cervical cancer cells at concentrations of 7 and 11 µM, respectively. The results from docking experiments with EGFR suggested the binding of compound <b>1</b> at the ATP binding site of EGFR. Furthermore, the crystal structure of compound <b>3</b> (7-(4-bromophenyl)-9-(pyridin-4-yl)-7<i>H</i>-pyrazolo[4,3-<i>e</i>][1,2,4]triazolo[1,5-<i>c</i>]pyrimidine) was determined by single crystal X-ray analysis. Our work represents a promising starting point for the development of a new series of compounds targeting EGFR.
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