Abstract: To discover an efficient modification for shifting from an antibacterial fluoroquinolone to an antitumor one based on the topological similarities between targeting topoisomerases as the eukaryotic ones and mammals, using oxadiazole heterocycle as an intermediate for the isostere of C-3 carboxylic group of norfloxacin(1), 1-ethyl-6-fluoro-7-piperazin-1-yl-3-(5-mercapto-1,3,4-oxadiazol-2-yl)-quinolin-4(1H)-one(3) was subjected to thioetherfication with each of chloromethyl oxadiazole(4a~4e) to give bis-oxadiazole methylsulfides(5a~5e), respectively. The following N-methylations and quaternizations yielded the corresponding N-methyl bis-oxadiazole methylsulfides(6a~6e) and N,N-dimethyl bis-oxadiazole methylsulfide iodides(7a~7e). The structures of fifteen title compounds were characterized by elemental analysis, 1H NMR and MS, and their anticancer activities in vitro against Hep-3B cancer cell lines were also evaluated  with a MTT assay. The results reveal that fifteen title compounds show higher cytotoxicity than that of comparison 1, in which quaternary ammonium salts exhibit potential anticancer activity with IC50 values below 25.0 μmol/L.

Key words: fluoroquinolone, isostere, oxadiazole, quatemary ammonium salt, antitumor evaluation