Design and discovery of new 1,2,4‐triazolo[4,3‐<i>c</i>]quinazolines as potential DNA intercalators and topoisomerase II inhibitors

Abstract

A new series of 1,2,4-triazolo[4,3-c]quinazoline derivatives was designed and synthesized as Topo II inhibitors and DNA intercalators. The cytotoxic effect of the new members was evaluated in vitro against a group of cancer cell lines including HCT-116, HepG-2, and MCF-7. Compounds 14_c , 14_d , 14_e , 14_e , 15_b , 18_b , 18_c , and 19_b exhibited the highest activities with IC₅₀ values ranging from 5.22 to 24.24 µM. Furthermore, Topo II inhibitory activities and DNA intercalating affinities of the most promising candidates were evaluated as a possible mechanism for the antiproliferative effect. The results of the Topo II inhibition and DNA binding tests were coherent with that of in vitro cytotoxicity. Additionally, the most promising compound 18_c was analyzed in HepG-2 cells for its apoptotic effect and cell cycle arrest. It was found that 18_c can induce apoptosis and arrest the cell cycle at the G2-M phase. Finally, molecular docking studies were carried out for the designed compounds against the crystal structure of the DNA-Topo II complex as a potential target to explore their binding modes. On the basis of these studies, it was hypothesized that the DNA binding and/or Topo II inhibition would participate in the noted cytotoxicity of the synthesized compounds.