Design, synthesis and antitumor activity of 3-arylidene-4-fluoroquinolin-4-ones as ciprofloxacin derivatives

To identify an effective structural modification strategy for improving the antitumor activity of fluoroquinolones, sixteen new 1-cyclopropyl-6-fluoro-7-(4-methyl-piperazin-1-yl)-3-arylidene-2,3-dihydroquinolin-4(1H)-ones compounds (4a-4p), were designed and synthesized by a condensation reaction of dihydroquinolin-4-one (3) and aromatic aldehydes, based on the structure of ciprofloxacin (1). Their structures were characterized by elemental analysis and spectral data, and anti-cell proliferative activities against Hep-3B, Capan-1 and HL60 cell lines were measured by an MTT assay. Preliminary pharmacological results indicated that the synthesized target compounds had greater potency than ciprofloxacin (1). SAR revealed that the halophenyl compounds such as fluorophenyl (4h, 4i), chlorophenyl (4j, 4k) or bromophenyl compounds (4l, 4m) and aromatic heterocyclic compounds such as furanly (4n) or pyridyl compounds (4o, 4p) demonstrated better activity than the control compounds, and the IC₅₀ values of the chlorophenyl compounds 4j and 4k against Capan-1 cell growth were comparable to that of doxorubicin. Thus, a 3-arylidene as an isostere of the C-3 carboxylic acid group appears to be beneficial in improving the antitumor activity of fluoroquinolone. Furthermore, an α,β-unsaturated ketone fragment used as a potential bioisostere of C-3 carboxylic acid group may warrant further study.