Original article Inhibition of monoamine oxidase by indole and benzofuran derivatives Louis H.A. Prins, Jacobus P. Petzer, Sarel F. Malan * Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa article info Article history: Received 10 March 2010 Received in revised form 8 June 2010 Accepted 3 July 2010 Available online 31 July 2010 Keywords: Monoamine oxidase (MAO) Indole derivatives Benzofuran derivatives Parkinson’s disease (PD) Molecular docking LigandFit abstract Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. A series of indole and benzofuran derivatives were synthesised and evaluated as inhibitors of the two MAO isoforms, MAO-A and MAO-B. In general, the derivatives were found to be selective MAO-B inhibitors with K i values in the nanoMolar (nM) to microMolar (mM) concentration range. The most potent MAO-B inhibitor, 3,4-dichloro-N-(2-methyl-1H-indol-5-yl)benzamide, exhibited a K i value of 0.03 mM and was 99 fold more selective for the B isoform. We conclude that these indole and benzofuran derivatives are promising reversible MAO-B inhibitors with a possible role in the treatment of neurodegenerative diseases such as Parkinson’s disease (PD). Ó 2010 Elsevier Masson SAS. All rights reserved. 1. Introduction Parkinson’s disease (PD) is a condition associated with the degeneration of the dopamine containing nigrostriatal neurons [1]. The resulting depletion of striatal dopamine is responsible for the characteristic PD symptoms such as bradykinesia (slowness of movement), rigidity (stiffness), hypokinesia (reduction in move- ment amplitude), akinesia (absence of normal unconscious move- ments) and other extrapyramidal effects. Since monoamine oxidase A and B (MAO-A and -B) are involved in the metabolic degradation of dopamine in the brain, inhibitors of these enzymes are consid- ered useful for the treatment of PD [2]. The MAO isoform predominantly found in the human brain is MAO-B [3]. It has also been demonstrated that brain MAO-B activity, but not MAO-A activity, increases with aging [4]. As MAO-B appears to be located in glial cells [5], this may be due to gliosis associated with aging. Not only is MAO-B a major dopamine metabolising enzyme but it is also involved in the formation of free radicals and other potentially neurotoxic species. In the catalytic cycle of MAO-B, 1 mol of hydrogen peroxide (H 2 O 2 ) and dop- aldehyde is produced for every mole of dopamine metabolised [6]. Both these metabolic by-products are toxic and may contribute to the pathogenesis of PD [7]. Increased MAO-B levels have also been observed in plaque-associated astrocytes in the brains of Alz- heimer’s disease (AD) patients. This increase in MAO-B activity produces an elevation in hydroxyl radicals (  OH), which has been correlated with amyloid-b (Ab) plaque formation. Hence, the therapeutic potential of selective reversible MAO-B inhibitors does not rely solely on their ability to increase the biological half-life of dopamine (symptomatic effects) but also on their ability to potentially slow PD progression (neuroprotective effects) and to inhibit Ab plaque formation [4]. (R)-Deprenyl (selegiline) (1)(Fig. 1) was one of the first selective MAO-B inhibitors to be identified [8] and has since been shown to possess neuroprotective properties [9,10]. These properties may, in part, be dependent on the ability of (R)-deprenyl to inhibit the MAO-B catalysed formation of H 2 O 2 and dopaldehyde in the brain [11]. In 1981 it was found that an N-demethylated aminoindan propargylamine derivative, AGN 1135, also was a potent and selective inhibitor of MAO-B [12]. Unlike (R)-deprenyl, this compound is not an amphetamine derivative and therefore did not present with amphetamine associated sympathomimetic side- effects. The R(þ)-enantiomer of AGN 1135, now called rasagiline (2), is nearly three orders of a magnitude more potent than the S ()-enantiomer in inhibiting MAO-B [13]. Rasagiline is considered useful as an adjuvant to levodopa for the treatment of PD, as this compound enhances dopamine levels in the primate brain following systemic administration of levodopa. Youdim and co- * Corresponding author. School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa. Tel.: þ27 21 9593190; fax: þ27 21 9591588. E-mail address: sfmalan@uwc.ac.za (S.F. Malan). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2010.07.005 European Journal of Medicinal Chemistry 45 (2010) 4458e4466