Design and synthesis of heterocyclic compounds for neuroprotective enzyme interactions

Abstract

Neurodegenerative diseases are thought to be multifactorial in nature and therefore current research focus has shifted from a ‘one-drug-one-target’ approach to that of multitarget directed ligands (MTDLs). These ligands are designed to address more than one etiological target, thereby increasing patient compliance and decreasing side-effects. Monoamine oxidase (MAO) and nitric oxide synthase (NOS) are enzymes that have long been associated with neurodegenerative diseases. MAO-B is responsible for the metabolism of biogenic amines, including dopamine. During this process hydrogen peroxide (H2O2) is formed leading to the production of highly reactive hydroxyl radicals (·OH), in the presence of free iron cations (Fe2+, Fe3+). NOS is responsible for the oxidation of L-arginine to L-citrulline and NO. Since NO is a free radical, an overproduction thereof by neuronal NOS (nNOS) may cause oxidative damage to neuronal cells in the substantia nigra, linking it to the development of Parkinson’s disease (PD). The selective inhibition of MAO-B and nNOS is therefore hypothesised to be advantageous for the treatment and prevention of neurodegeneration. The aim of this study was therefore to synthesise a series of selective MAO-B inhibitors and to determine if they also exhibit NOS inhibitory activity. Three series of compounds were synthesised comprising pteridine-2,4-diones, benzofuranes and indoles. The pteridine-2,4-diones were obtained by reacting 1,3-dimethyl-5,6-diaminouracil with the appropriate aldehyde to yield the pyrimidines, which were cyclicised by the addition of triethyl orthoformate to obtain the final products. For the benzofuranes activation chemistry using dicyclo-hexylcarbodiimide (DCC) was applied to conjugate the appropriate benzoic or cinnamic acid with 5-hydroxy-3Hbenzofuran- 2-one, producing the final products. The indole derivatives were synthesised by conjugating 5-amino-2-methylindole to the appropriate benzoic or cinnamic acid in the presence of either N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl) or DCC.