Thio- and aminocaffeine analogues as inhibitors of human monoamine oxidase Hermanus P. Booysen a , Christina Moraal a , Gisella Terre’Blanche a , Anél Petzer b , Jacobus J. Bergh a , Jacobus P. Petzer a,⇑ a Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa b Unit for Drug Research and Development, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa article info Article history: Received 26 August 2011 Revised 4 October 2011 Accepted 13 October 2011 Available online 20 October 2011 Keywords: Monoamine oxidase Reversible inhibition Caffeine Sulfanylcaffeine Thiocaffeine Aminocaffeine abstract In a recent study it was shown that 8-benzyloxycaffeine analogues act as potent reversible inhibitors of human monoamine oxidase (MAO) A and B. Although the benzyloxy side chain appears to be particularly favorable for enhancing the MAO inhibition potency of caffeine, a variety of other C8 oxy substituents of caffeine also lead to potent MAO inhibition. In an attempt to discover additional C8 substituents of caf- feine that lead to potent MAO inhibition and to explore the importance of the ether oxygen for the MAO inhibition properties of C8 oxy-substituted caffeines, a series of 8-sulfanyl- and 8-aminocaffeine analogues were synthesized and their human MAO-A and -B inhibition potencies were compared to those of the 8-oxycaffeines. The results document that the sulfanylcaffeine analogues are reversible competi- tive MAO-B inhibitors with potencies comparable to those of the oxycaffeines. The most potent inhibitor, 8-{[(4-bromophenyl)methyl]sulfanyl}caffeine, exhibited an IC 50 value of 0.167 lM towards MAO-B. While the sulfanylcaffeine analogues also exhibit affinities for MAO-A, they display in general a high degree of MAO-B selectivity. The aminocaffeine analogues, in contrast, proved to be weak MAO inhibitors with a number of analogues exhibiting no binding to the MAO-A and -B isozymes. The results of this study are discussed with reference to possible binding orientations of selected caffeine analogues within the active site cavities of MAO-A and -B. MAO-B selective sulfanylcaffeine derived inhibitors may act as lead compounds for the design of antiparkinsonian therapies. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction The monoamine oxidases (MAO) A and B are mitochondrial bound flavin adenine dinucleotide (FAD) enzymes which catalyze the a-carbon oxidation of a variety of aminyl substrates. 1 Human MAO-A and -B consist of 529 and 520 amino acids, respectively, and the FAD is covalently bound to a cysteinyl residue in both enzymes (Cys-406 and Cys-397 in MAO-A and -B, respectively). While MAO-A and -B are products of separate genes they share approximately 70% amino acid sequence identity. 2 The X-ray crys- tallographic structures of MAO-A and -B indicate that the amino acid residues comprising the active sites and their relative geome- tries are similar with only 6 of the 16 active site amino acid residues differing between the two enzymes. 3,4 In spite of these similarities, MAO-A and -B have different substrate and inhibitor specificities. Most notably, MAO-A metabolizes the neurotransmitters, serotonin and norepinephrine, as well as the dietary amine, tyramine. MAO-B is well known to metabolize extraneous amines such as benzyl- amine and phenylethylamine. Dopamine is considered to be a substrate for both isozymes. 5 Since MAO-A and -B are both involved in the degradation of neu- rotransmitter amines, inhibitors of these enzymes are employed as drugs in the treatment of several disorders. 5 For example, MAO-A inhibitors block the central oxidation of serotonin by MAO-A and are used as antidepressants. MAO-B inhibitors reduce the MAO-B catalyzed oxidative metabolism of dopamine in the brain and are used in the treatment of Parkinson’s disease. Of importance is the observation that MAO-B activity and density increase in most brain regions including the basal ganglia with age while MAO-A activity remains unchanged. 6,7 In the aged parkinsonian brain MAO-B is therefore thought to be the principal MAO isozyme responsible for dopamine catabolism. MAO-B inhibitors may conserve dopa- mine in the basal ganglia and offer a symptomatic benefit in the treatment of Parkinson’s disease. 8–10 MAO-B inhibitors are frequently combined with levodopa therapy since inhibitors of this enzyme have been shown to enhance the elevation of dopamine lev- els derived from levodopa. 11 MAO-B inhibitors may permit a reduc- tion of the dose of levodopa required for a therapeutic effect and therefore the occurrence of levodopa associated side effects. 12 MAO may also play an important role in the neurodegenerative pro- cesses associated with Parkinson’s disease. The oxidation of dopa- mine by MAO stoichiometrically yields potentially toxic metabolic by-products. 13 For each mole of dopamine oxidized by MAO, one mole of hydrogen peroxide (which may lead to oxidative damage) and dopaldehyde (which may react with exocyclic amino groups of nucleosides and N-terminal and lysine e-amino groups of pro- teins) are formed. 13 Inhibitors of MAO reduce the MAO-catalyzed 0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2011.10.036 ⇑ Corresponding author. Tel.: +27 18 2992206; fax: +27 18 2994243. E-mail address: jacques.petzer@nwu.ac.za (J.P. Petzer). Bioorganic & Medicinal Chemistry 19 (2011) 7507–7518 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc