Design and Synthesis of New Quinazolinone Derivatives Conjugated with Chalcone or Pyridazine Moieties: Anticancer Activities and Apoptotic Induction

Abstract

Two new series of quinazolinone derivatives, conjugated with chalcone 4a–k and pyridazine 8a–f moieties, were designed and synthesized as promising anticancer agents and apoptotic inducers. Using MTT assay, they were assessed for their cytotoxicity against HepG-2, HCT-116, and MCF-7 cancer cell lines and normal cell lines, compared to Doxorubicin as a reference drug. Quinazolinone-Pyridazinone hybrid 8a exhibited the highest cytotoxicity against all examined cancer cells and was safe against normal cells. Compounds 4i, 4k, and 8e showed good cytotoxicity against the cancer cell lines. The four most potent compounds were then screened for their effect on cell cycle distribution and apoptosis induction. Compounds 4i and 8a led to a cell cycle arrest at the G1 phase in MCF-7 cancer cells, while compounds 4k and 8e led to cell cycle arrest of HepG-2 cancer cells at the G1 phase and G2/M phase, respectively. The four hybrids induced total apoptosis which was proved via testing their effect on different apoptotic markers. They were further docked into a BCL-2 binding pocket showing good binding interactions. Therefore, the new quinazolinone derivatives might be identified as promising apoptotic inducers and can be used as lead compounds in the future investigations.