A new 2-(p-nitrobenzylidene)-4-phenyl-5-oxo(thioxo)-1,2,4-triazino-[2,1-a]-1,2,4-triazine-1,7-diones (2a,b) and 2- (5-phenylthiazol-2-yl)-3-phenyl-5-(p-nitrobenzylidene)-1,2,4-triazine-6-one (5) were prepared via cyclocondensation of 2-substituted-1,2,4-triazine (1a,b) with ethyl chloroacetate and phenacyl bromide in presence of fused sodium acetate. Alkylation of compounds 2a,b with ethyl chloroacetate in dimethyl formamide yielded Nalkylated products (3a,b). Condensation of compound 2a with aromatic aldehydes afforded the corresponding arylidene derivatives (4a,b). N-acetyl derivative (6) was obtained via acetylation of compound 5 with acetic anhydride. The structures of the compounds were elucidated by using spectral and elemental analysis. All the prepared fused triazino- and thiazolyl-1,2,4-triazine were evaluated for their cytotoxicity against HepG-2 cell line. Some of newly synthesized 1,2,4-triazine derivatives emerged as a potential candidate for the development of future cytotoxic compounds.