This article by Dr. Jamshed Iqbal is published in Medicinal Chemistry, Volume 14, Issue 8, 2018
Hyperactivation of cholinesterases (acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)) results in decreased acetylcholine levels in the cortex of the brain. Decreased levels of acetylcholine have, in turn, been linked with the onset of Alzheimer's Disease (AD) which is characterized by a loss of memory functions in patients. Inhibition of these enzymes leads to increased levels of the neurotransmitter and this has been suggested as a promising strategy for the management of AD.
While existing medications (donepezil, tacrine and rivastigmine) target AChE, there is currently no medication available targeting BChE. Very recently, hybrid compounds such as acridinechromenones, quinoline-chromenones, and triazole-chromenones have been developed as new anti-Alzheimer's agents. However, most of these hybrid compounds exhibit only moderate potency against AChE.
In this study, two series of chromenone-based derivatives - viz. 6-oxo-6H-benzo[c]chromene-8,10-dicarboxylate and 6H-benzo[c]chromen-6-ones derivatives - were tested by Ellmann's calorimetric method for AChE and BChE inhibition. Molecular docking studies were then performed to explore the probable binding modes of the 2 most potent dual inhibitors. These potent dual AChE/BChE inhibitors showed favorable orientations within the active sites of the target enzymes. Therefore, the researchers conclude that these inhibitors of AChE/BChE may be considered for the treatment of neurodegenerative disorders including Alzheimer's and age-related cholinesterase damage.