Inhibition of monoamine oxidase B by selected benzimidazole and caffeine analogues

Deidré van den Berg, Kevin R. Zoellner, Modupe O. Ogunrombi, Sarel F. Malan, Gisella Terre'Blanche, Neal Castagnoli, Jacobus J. Bergh, Jacobus P. Petzer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

60 Citations (Scopus)

Abstract

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 (Ki 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 Ki 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 Ki 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 (Es) 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 Ki value of 2084 μM. Without the styryl side chain, 1-methylbenzimidazole is not expected to be able to bind simultaneously to both the entrance and substrate cavities.

Original languageEnglish
Pages (from-to)3692-3702
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume15
Issue number11
DOIs
Publication statusPublished - 1 Jun 2007
Externally publishedYes

Keywords

  • Benzimidazole
  • Caffeine
  • Monoamine oxidase B
  • Reversible inhibitors
  • Structure-activity relationship

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