'Transmissible Spongiform Encephalopathies' (TSE) are a group of degenerative, progressive and fatal disorders of CNS which affect both humans and animals, characterised by a long incubation time. The pathogenetic mechanism in TSE is the conversion of normal prion protein (PrP(sen)) to an altered protease resistant isoform (PrP(res)) that accumulates in amyloid deposits into the brain; therefore, PrP(res) is the primary target for therapeutic strategies. The discovery that the sulphonated azo dye Congo red (CR) is able to inhibit the replications of TSE agents and the accumulation of PrP(res) in animals and in scrapie infected mouse neuroblastoma cells induced us to designe molecules structurally related to CR (1a-f, 2f,g). The compounds were tested in vitro to evaluate their interaction with 263K PrP(res). Six of the tested compounds were found to interact with PrP(res) molecules and to over-stabilise the PrP(res) aggregates, as CR does. However, none of them induced the reversion of PrP(res) to PrP(sen).