Design, synthesis, and antiproliferative activities of novel substitutedhydrazone/triazolo-linked quinazoline derivatives

Abstract

A series of novel hydrazonoquinazolines and triazoloquinazolines analogues of Erlotinib were synthesized and evaluated for their antiproliferative as well as EGFR kinase inhibitory activities. Most of the quinazoline compounds showed significant antiproliferative against different cancer cells. Among these, both compounds 4b and 5b were the best members of all the tested cancer cell lines with IC50 in the range 1.25–4.92 μM and 1.95–7.60 μM, respectively (c.f. erlotinib (IC50 7.52–16.02 μM) and inhibited EGFR with IC50 0.80 and 0.66 μM, sequentially. Additionally, these two compounds effectively induced cell cycle arrest and triggered apoptosis in HL-60 cancer cells by regulating the pro-apoptotic protein BAX and anti-apoptotic protein Bcl-2 expression. The docking studies revealed that there are interactions like that of erlotinib at the EGFR active site. In conclusion, the synthesized quinazoline compounds 4b and 5b effectively inhibit EGFR. Such a finding can be sited as a good starting point for the development of novel antitumor compounds targeting EGFR kinase.