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

Two new series of quinazolinone derivatives, conjugated with chalcone <b>4a</b>–<b>k</b> and pyridazine <b>8a</b>–<b>f</b> 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 <b>8a</b> exhibited the highest cytotoxicity against all examined cancer cells and was safe against normal cells. Compounds <b>4i</b>, <b>4k,</b> and <b>8e</b> 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 <b>4i</b> and <b>8a</b> led to a cell cycle arrest at the G1 phase in MCF-7 cancer cells, while compounds <b>4k</b> and <b>8e</b> 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 <i>via</i> 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. New quinazolinone chalcone/pyridazine hybrids were designed and synthesized.Using MTT assay, all hybrids were evaluated for their cytotoxic activities.The impact on cell cycle distribution and apoptosis induction was investigated.The effect on caspase 3, caspase 7, cytochrome c, p53, BAX, and BCL-2 markers was examined.Hybrids <b>4k</b> and <b>8a</b> were the most apoptotic inducers and the results were matched with docking studies. New quinazolinone chalcone/pyridazine hybrids were designed and synthesized. Using MTT assay, all hybrids were evaluated for their cytotoxic activities. The impact on cell cycle distribution and apoptosis induction was investigated. The effect on caspase 3, caspase 7, cytochrome c, p53, BAX, and BCL-2 markers was examined. Hybrids <b>4k</b> and <b>8a</b> were the most apoptotic inducers and the results were matched with docking studies.