Design, Synthesis and Cytotoxic Evaluation of N-Acylhydrazone-Incorporated Isoxazolo[4,5-d]pyridazin-4(5H)-one Derivatives.

A series of isoxazolo[4,5-d]pyridazin-4(5H)-one hybrids with N-acylhydrazone structure was prepared and screened for their cytotoxic activities. The in vitro antiproliferative activity of the target molecules was evaluated against a panel of sixty cancer cell lines (NCI-60) by the National Cancer Institute. Seven of the target compounds showed prominent % inhibition against various cancer cell lines at the one-dose assay and were subsequently screened for five-dose assay. 4d, 4e and 4g (full panel mean graph midpoint GI50 =9.33, 5.25 and 7.94 µM) emerged as the most promising derivatives against multiple cancer cell lines in comparison with 5-fluorouracil and gefitinib (full panel mean graph midpoint GI50 =18.60 and 3.46 µM). They exhibited remarkable antiproliferative activity with GI50 values submicromolar concentrations against some of the cell lines. The compounds were also found to display mild toxicity to the healthy cells compared to the cancer cell lines indicating safety. Druglikeness and high oral bioavailability were predicted for most of the compounds. As a result, a current study unveiled isoxazolo[4,5-d]pyridazin-4(5H)-ones bearing N-acylhydrazone as promising anticancer agents with antiproliferative effects.