Two progressive series of molecules with two polyhydroxybenzamide substructures were synthesized and tested as potential inhibitors of catechol-O-methyltransferase (COMT). These compounds were designed for the purpose of enhanced enzyme binding with duplicated substructures separated by a linker section of various lengths. Our results show that potency and mode of inhibition observed with the "bifunctional" compounds were a reflection of their bifunctional nature. Furthermore, potency and mode of inhibition were dependent on the length of the linker section. Of the assayed compounds, the optimum linker was found to be diaminopropane. For example, N,N'-1,3-propanediylbis(3,4-dihydroxybenzamide) and N,N'-1,3-propanediylbis(3,4,5-trihydroxybenzamide) demonstrated strong inhibitory action against COMT, with apparent Ki values of 0.3 and 6.0 microM, respectively.