SYNTHESIS AND IN-VITRO EVALUATION OF 2 PROGRESSIVE SERIES OF BIFUNCTIONAL POLYHYDROXYBENZAMIDE CATECHOL-O-METHYLTRANSFERASE INHIBITORS

Two progressive series of molecules with two polyhydroxybenzamide subs tructures were synthesized and tested as potential inhibitors of catec hol-O-methyltransferase (COMT). These compounds were designed for the purpose of enhanced enzyme binding with duplicated substructures separ ated by a linker section of various lengths. Our results show that pot ency and mode of inhibition observed with the ''bifunctional'' compoun ds were a reflection of their bifunctional nature. Furthermore, potenc y and mode of inhibition were dependent on the length of the linker se ction. Of the assayed compounds, the optimum linker was found to be di aminopropane. For example, N,N'-1,3-propanediylbis(3,4-dihydroxybenzam ide) and N,N'-1,3-propanediylbis(3,4,5-trihydroxybenzamide) demonstrat ed strong inhibitory action against COMT, with apparent K-i values of 0.3 and 6.0 mu M, respectively.