Key result
Bifunctional polyhydroxybenzamides strongly inhibit COMT with a Ki as low as ~0.3 microM.
Why the study?
The study aimed to develop and evaluate bifunctional polyhydroxybenzamide compounds with varying linker lengths to enhance inhibition of catechol-O-methyltransferase (COMT).
Bifunctional polyhydroxybenzamide compounds with a diaminopropane linker demonstrate strong in vitro inhibition of COMT.
Bifunctional COMT inhibitors merit further design optimization; leaves open in vivo efficacy and cardiovascular translation.
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.
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Brevitt et al. (1997) studied this question. Bifunctional polyhydroxybenzamide catechol-O-methyltransferase inhibitors was evaluated on COMT inhibition (Ki values).
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