Abstract
Multitarget directed ligands (MTDLs) are emerging as promising treatment options for Alzheimer’s disease (AD). Coumarin derivatives serve as a good starting point for designing MTDLs due to their inherent inhibition of monoamine oxidase (MAO) and cholinesterase enzymes, which are complicit in AD’s complex pathophysiology. A preliminary series of 3,7-substituted coumarin derivatives were synthesised and evaluated for enzyme inhibitory activity, cytotoxicity as well as neuroprotective ability. The results indicated that the compounds are weak cholinesterase inhibitors with five compounds demonstrating relatively potent inhibition and selectivity towards MAO-B with IC50 values between 0.014 and 0.498 hx00B5;µM. Significant neuroprotective effects towards MPP+-compromised SH-SY5Y neuroblastoma cells were also observed, with no inherent cytotoxicity at 10 µM for all compounds. The overall results demonstrated that substitution of the phenylethyloxy moiety at the 7-position imparted superior general activity to the derivatives, with the propargylamine substitution at the 3-position, in particular, displaying the best MAO-B selectivity and neuroprotection.
Highlights
Neurodegenerative diseases (NDs) are a group of cognitive and movement-related disorders resulting from neuronal loss in the brain
The synthesis of the compounds (Scheme 1) commenced with a Pechmann condensation of dihydroxybenzaldehyde to obtain 7hydroxy-3-methyl-coumarin (1) which served as the base scaffold
The 3-propargylamine derivatives 6 and 7 displayed between 130 and 206 times greater selectivity to monoamine oxidase (MAO)-B when compared to MAO-A. These results show that whereas, compounds 2 was more active in the inhibition of MAO-B, compounds 6 and 7 showed better selectivity and this can be attributed to the addition of the propargylamine moiety
Summary
Neurodegenerative diseases (NDs) are a group of cognitive and movement-related disorders resulting from neuronal loss in the brain. Its symptoms are progressive and irreversible, initially characterised by recurring shortterm memory loss which progresses to degeneration of higher cognitive functions such as decision making and language. There is no singular cause or process that is responsible for this neurodegeneration, rather it is the result of different interlinked mechanisms, underpinned by genetic and environmental factors. This complex pathophysiology has made treatment difficult and only symptomatic relief is provided by the drugs currently available on the market[5,6,7]
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