Abstract: To search for an efficient modification strategy for a bioisostere of the C-3 carboxylic acid group of antitumor fluoroquinolones, an aminomethylation reaction based on the structural characteristics of the C-3 s-triazole-oxadiazole sulfides( 6a - 6j )was carried out on a five-member azole ring of s-triazole to give 1-ethyl-6-fluoro-7-(4-methyl-piperazin-1-yl)-3-［1-dimethy-l amino-methyl-5-(5-substituted-phenyl-［1, 3, 4］oxadia-zol-2-yl methylsulfanyl)-1H-［1, 2, 4］-triazol-3-yl］-quinolin-4(1H)-ones( 7a - 7j )as novel C-3 s-triazole-oxadiazole sulfide Mannich-base derivatives starting from pefloxacin( 1 ). The structures of the title compounds were characterized by elemental analysis and spectral data and their in vitro antitumor activity against SMMC-7721, L1210 and HL60 cell lines was evaluated by a MTT assay. The results showed that the of sulfides( 6a - 6j )and their corresponding Mannich-base compounds( 7a - 7j )had more potent inhibitory activity than the compound 1 , and the Mannich-base compound 7 also exhibited more potent cytotoxicity than the corresponding compound 6 , especially both had better activity against SMMC-7721 cell line than the other cancer cell lines.