Synthesis and evaluation of 1-indanone derivatives as inhibitors of monoamine oxidase

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterised by the death of neurons in the substantia nigra pars compacta (SNpc) in the midbrain leading to a dopamine (DA) deficiency. This deficiency is responsible for the motor symptoms in PD. One of the treatment strategies in PD is to conserve DA by inhibiting the enzyme responsible for DA catabolism. The monoamine oxidase B (MAO B) isoform catalyses the oxidation of DA in the central nervous system (CNS) and is therefore an important target for the treatment of PD. Inhibition of MAO B increases endogenous DA levels thus providing PD patients with symptomatic relief. It also enhances the levels of DA after administration of levodopa (L-dopa), the metabolic precursor of DA. In the present study, a series of 2-benzylidene-1-indanone derivatives and a series of 2-heteroarylidene-1-indanone derivatives were synthesised and evaluated as inhibitors of recombinant human MAO A and MAO B. These indanone derivatives are structurally related to a series of benzylidene-1-indanone derivatives, which has been reported to act as MAO B inhibitors. The 2-benzylidene-1-indanone derivatives and 2-heteroarylidene-1-indanone derivatives were successfully synthesised by reacting 1-indanone with the appropriate benzaldehyde or heteroaromatic aldehyde in either acidic (HCl) or basic (KOH or NaOH) conditions. The structures of the compounds were verified with NMR and MS analyses, while the purities were estimated by HPLC. Twenty-two 2-benzylidene-1-indanone derivatives and fifteen 2-heteroarylidene-1-indanone derivatives were synthesised. To determine the inhibition potencies of the synthesised compounds the recombinant human MAO A and MAO B enzymes were used. The inhibition potencies were expressed as the corresponding IC50 values. The results showed that the 2-benzylidene-1-indanone derivatives and 2-heteroarylidene-1-indanone derivatives are highly potent and selective MAO B inhibitors and to a lesser extent inhibitors of MAO A. The most potent MAO B inhibitor was (E)-5-methoxy-2-(5-bromofuran-2-yl)methylene-2,3-dihydro-1H-inden-1-one with an IC50 value of 0.0044 μM. The results indicated that both series are potent MAO inhibitors with most derivatives possessing higher selectivity towards the MAO B isoform compared to MAO A. In general, the 2-benzylidene-1-indanone derivatives were more potent MAO B inhibitors than the 2-heteroarylidene-1-indanone derivatives. It may thus be concluded the 2-benzylidene-1-indanone and 2-heteroarylidene-1-indanone derivatives are promising potent and selective MAO B inhibitors, and thus leads for future development of therapy for PD.