Synthesis and Evaluation of Tacrine-Mefenamic Acid Hybrids as Acetylcholinesterase Inhibitors
Bystrom, Philip V.
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Alzheimer's disease (AD) is a neurodegenerative disease characterized by the progressive deterioration of cognitive and motor functioning. There is no single physiological cause of AD, and thus drugs that can simultaneously target multiple hallmarks of the disease are needed. Tacrine-mefenamic acid hybrids are one such class of potential therapeutics that both scavenge reactive oxygen species (ROS) and inhibit acetylcholinesterase (AChE). Although these hybrids have been discussed previously, the precise mechanism of ROS scavenging and its role in enzyme inhibition remains mostly unknown. In the following study a series of tacrine-Nmethylated mefenamic acid hybrids, designed to impede radical formation on the nitrogen atom of the mefenamic acid moiety, were synthesized and evaluated for their ability to inhibit AChE in the presence and absence of ROS. Although the methylated compounds exhibited improved potency over their non-methylated analogs, they showed a proportionately less drastic increase in potency in the presence of ROS, suggesting that radical formation, on the nitrogen atom. of the mefenamic acid moiety, plays an important role in ROS-induced inactivation of AChE. Molecular modeling studies were performed to rationalize these results.