Se. Brevitt et Ew. Tan, SYNTHESIS AND IN-VITRO EVALUATION OF 2 PROGRESSIVE SERIES OF BIFUNCTIONAL POLYHYDROXYBENZAMIDE CATECHOL-O-METHYLTRANSFERASE INHIBITORS, Journal of medicinal chemistry, 40(13), 1997, pp. 2035-2039
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.