A new family of naphthalenic analogues of phenstatins with modifications on the ketone-bridge has been synthesised. The synthesised compounds have been assayed for tubulin polymerisation inhibitory activity as well as for cytotoxic activity against cancer cell lines. The naphthalene has been confirmed as a good surrogate for the isovanillin moiety (3-hydroxy-4-methoxyphenyl) of phenstatin, when combined with the 3,4,5-trimethoxyphenyl ring, but not when combines with the 2,3,4-trimethoxyphenyl ring. Binding models for the synthesised compounds have been generated and analysed in terms of a pharmacophore proposed for colchicine site ligands. The ketone is the optimal bridge substitution but E-acetyloximes or acetylhydrazones are also tolerated. Significant differences with indole substituted phenstatins are observed and discussed.