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

Abstract

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 GI 50 = 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 GI 50 = 18.60 and 3.46 μM). They exhibited remarkable antiproliferative activity with GI 50 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.

Anticancer agents incorporating the N‐acylhydrazone scaffold: Progress from 2017 to present

“…The activity, however, dropped when this group's position was altered. [94] Ozadali-Sari et al [95] synthesized and tested a number of isoxazolo [4,5-d] The cytotoxic properties of the unsubstituted or nitro-substituted counterparts of the active compounds instead of using the methoxy derivatives were assessed for this purpose. The NCI chose (OC 2 H 5 , F, and Br derivatives, respectively) for additional five-dose research based on the findings of their one-dose screening.…”

“…Ozadali‐Sari et al [ 95 ] synthesized and tested a number of isoxazolo[4,5‐d]pyridazin‐4(5 H )‐one hybrid with N ‐acylhydrazone structures for their cytotoxic properties. The National Cancer Institute (USA) assessed the in vitro antiproliferative effectiveness of the target compounds against a panel of 60 cancer cell lines (NCI‐60).…”