Alzheimer’s disease (AD) is a progressive neurodegenerative disorder commonly found among the elderly. In 2021 a total of 6.2 million in the U.S. were living with Alzheimer’s, which represents 1 in 9 people over the age of 65. It is projected to affect nearly 14 million Americans by 2060. There is no definitive cure, and little is known about the formation of the hallmark trait(s) of the disease. On a biochemical level, the disease is associated with decreased levels of the neurotransmitter acetylcholine (ACh) in the brain. Acetylcholinesterase (AChE) is the enzyme responsible for the hydrolyzing of ACh. Current pharmaceuticals used to treat AD are reversible inhibitors of AChE. Previous research has shown that AChE inhibitors with isoflavone scaffolds and others with carbamate moieties have all been exhibiting great potential to be potent inhibitors of AChE. For example, the carbamate moiety is present in rivastigmine, a pharmaceutical currently used to treat AD, and many non-approved FDA AChE inhibitors like neostigmine, physostigmine, and pyridostigmine. Carbamates are a key structural motif in many other FDA-approved drugs. Thus, we have designed and are currently preparing a library of novel AChE inhibitors that combine both the isoflavone and carbamate functionalities within the same molecule. Up to this point, our isoflavone diol synthesis has been successfully completed in a 35% overall yield. Next, we attempted to install carbamates onto one or both alcohols of our isoflavone diol to no avail. However, we did successfully prepare diester compounds that were then assessed for inhibitory activity against AChE using Ellman’s assay. Thankfully, several newly prepared and tested compounds showed some inhibitory activity, which was also consistent with our findings from computational docking studies carried out using PyRx and Chimera. Currently, we are troubleshooting other reaction conditions to yield carbamates on the isoflavone diol, and we are preparing other isoflavone derivatives and testing all new compounds for their inhibitory activity. Inhibitor design, synthetic efforts, computational docking studies, and preliminary biological activity will all be presented.

Development of potent isoflavone derivatives to target Alzheimer’s disease

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.