Synthesis and evaluation of 7-substituted 3-propargylamine coumarin derivatives as multifunctional monoamine oxidase and cholinesterase inhibitors for Alzheimer’s Disease treatme

>Magister Scientiae - MScAlzheimer’s Disease (AD) is a neurodegenerative disease which results from the irreversible loss of neurons in the brain. The disease is characterized by progressive cognitive impairment with recurrent short-term memory loss. AD is the leading cause of dementia and 4th leading cause of death in the elderly. Success in the treatment of AD has been limited, with drugs only treating it at a symptomatic level due to its pathology being complex and poorly understood. However, it is known that the cholinesterase and MAO-B enzymes play an important role in the disease through their association with production of amyloid plaques and oxidative stress respectively, two mechanisms associated with cell death and the symptoms seen in AD

Design, synthesis, and evaluation of 3,7-substituted coumarin derivatives as multifunctional Alzheimer’s disease agents

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;mM. Significant neuroprotective effects towards MPPþ-compromised SH-SY5Y neuroblastoma cells were also observed, with no inherent cytotoxicity at 10 mM 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