Alzheimer’s disease (AD) is a progressive, neurodegenerative disease characterized by progressivememory loss, decline in language skills, and loss of function. Despite decades of intensive study, the specific cause of AD remains enigmatic. Most researchers agree that several pathological phenomena are closely associated with AD lesions, such as a decrease of the neurotransmitter acetylcholine (ACh), formation of amyloid β-protein (Aβ) plaques, and abnormal posttranslational modifications of tau protein to yield neurofibrillary tangles. AChE inhibitors were approved to terminate the decrease of ACh to treat mild to moderate Alzheimer’s disease, but most of them showed limit efficacy and many adverse effects. Therefore, compounds with novel structure are urgently needed to overcome those problems. X-Ray diffraction analysis has revealed that the inhibitor-binding pocket of AChE consists of three subsites, the catalytic active site (CAS), the peripheral active site (PAS), and a narrow channel between CAS and PAS. Therefore, an ideal AChE inhibitor is supposed to consist of three structural units: an aromatic ring as the head to bind with the PAS, another aromatic ring as the tail to interact with the CAS, and a linker to connect the head and tail. Following this hypothesis, we conducted a structure-based design and successfully produced a series of new multi-site AChE inhibitors with a novel framework (Figure 1). We have successfully designed and synthesized a series of novel inhibitors of human AChE and human BChE. As the most promising candidate, compound 2e, with a Ki value of 6.47 nM, showed about 4- fold higher activity than tacrine towards human AChE. Interestingly, compound 2e also showed simultaneously inhibitory effects against BChE, Aβ aggregation, and β-secretase. We therefore conclude that compound 2e is a very promising multi-function lead for the treatment of AD. References 1 Saxena, A. K., Chaudhaery, S. S., Roy, K. K., et al. J. Med. Chem. 2010, 53, 6490-6505. 2 Peng, D. Y., Sun, Q., Zhu, X. L., et al. Bioorg. Med. Chem. 2012, 20, 6739-6750. 3 Al-Tel, T. H., Semreen, M. H., Al-Qawasmeh, R. A., et al. J. Med. Chem. 2011, 54, 8373-8385.

Rational design and bioevaluation for novel acetylcholinesterase inhibitors for treating Alzheimer’s disease

249th National Meeting (2015)

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