Inhibition of monoamine oxidase B by selected benzimidazole and caffeine analogues.
We have recently reported that a series of (E)-8-styrylcaffeines and (E)-2-styrylbenzimidazoles are moderate to very potent competitive inhibitors of monoamine oxidase B (MAO-B). The most potent member of the series was found to be (E)-8-(3-chlorostyryl)caffeine (CSC) with an enzyme-inhibitor dissociation constant (K(i) value) of 128 nM. In the present study, we have prepared additional caffeine and benzimidazole analogues in an attempt to identify compounds with improved MAO-B inhibition potency while still acting reversibly. The most potent inhibitor among the caffeine analogues was (E)-8-(3,4-dichlorostyryl)caffeine with a K(i) value of 36 nM, approximately 3.5 times more potent than CSC. The most potent inhibitor among the benzimidazole analogues was (E)-2-(4-trifluoromethylstyryl)-1-methylbenzimidazole with a K(i) value of 430 nM. An SAR analysis indicated that the potency of MAO-B inhibition by (E)-2-styryl-1-methylbenzimidazole analogues depended upon the Taft steric parameter (E(s)) of the substituents attached to C-4 of the styryl phenyl ring. Substituents with a large degree of steric hindrance appear to enhance inhibition potency. The proposal that potent MAO-B inhibition by (E)-8-styrylcaffeines and (E)-2-styrylbenzimidazoles can be explained by a mode of binding that involves traversing both the entrance and substrate cavities was supported by the finding that 1-methylbenzimidazole only weakly inhibited MAO-B with a K(i) value of 2084 microM. Without the styryl side chain, 1-methylbenzimidazole is not expected to be able to bind simultaneously to both the entrance and substrate cavities.
van den Berg
Deidré
D
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Zoellner
Kevin R
KR
Ogunrombi
Modupe O
MO
Malan
Sarel F
SF
Terre'Blanche
Gisella
G
Castagnoli
Neal
N
Bergh
Jacobus J
JJ
Petzer
Jacobus P
JP
D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D002110:Caffeine / Q000031:analogs & derivatives*; D006801:Humans; D008995:Monoamine Oxidase / Q000187:drug effects*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D008996:Monoamine Oxidase Inhibitors; D002110:Caffeine; D008995:Monoamine Oxidase