The synthesis of some new (E)-6-[2-(furan-2 yl)ethenyl]-1,2,4-triazin-5-ones directly linked to either pyrazole, pyrazoline, pyrazolidine counterparts, or to substituted thio and hydrazono functionalities is described. Six of the newly synthesized compounds were selected by the National Cancer Institute (NCI) to be evaluated for their in vitro antitumor activity according to the protocol of the NCI in vitro disease-oriented human cells screening panel assay. The results revealed that the pyrazole derivative 5c was found to be the most active member in this screen as evidenced by its ability to exert potential growth inhibitory activity against most of the tested subpanel tumor cell lines with selective influence on leukemia subpanel tumor cell lines (GI50 values 2.01–3.03 lM). Moreover, a comparative study for log GI50 values of both compound 5c and 5-fluorouracil (5-FU) revealed that compound 5c showed higher potency than 5-FU against most of the tested subpanel tumor cell lines. Thus compound 5c could be considered as a suitable lead towards the design of broad spectrum antitumor active agents targeting various human tumor cell lines.