Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by multiple factors, such as the progressive decline in the levels of the neurotransmitter acetylcholine, and the deregulation of the homeostasis of bio-metals, such as copper, zinc and iron. Acetylcholine is hydrolyzed by acetylcholinesterase and butyrylcholinesterase and the current therapeutic strategies are based on the treatment of AD patients with these enzymes’ inhibitors. Although these strategies are focused on symptomatic relief of the disease, recent studies have shown that the long-term use of these drugs may lead to disease-modifying benefits. The deregulation of the bio-metals’ homeostasis has been related to oxidative stress and to the induction of Ab aggregation and tau hyperphosphorylation and aggregation. Since AD is a multifactorial disease, discovering a multi-target drug could be an interesting challenge, leading to a disease-modifying therapy. In this context, mannosylpurines synthesized by our group have already shown potent butyrylcholinesterase (BChE) inhibition. Aiming at the discovery of multitarget drug candidates, we have synthesized a new series of mannosyl and rhamnosylpurines and evaluated copper chelation and cholinesterase inhibition. The results obtained will be presented and discussed.
Supplementary Materials
The presentation material of this work is available online at https://www.mdpi.com/article/10.3390/ECMC2022-13451/s1.
Author Contributions
Methodology (synthetic approaches, metal chelation and anticholinesterase activity) was conceived by A.R. and N.C. Synthesis and structure characterization of the new nucleosides was carried out by C.M., supervised by A.R. and N.X., and by J.B., I.S., M.C., and M.J.F. supervised by A.R., while chelation studies were evaluated by C.M., J.B., and I.S. supervised by N.C. and A.R. The anticholinesterase activity was evaluated by M.d.C. Computational studies were carried out by K.S., A.F., and J.N.C.L. The original draft was written by C.M., reviewed and edited by A.R. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by the EUROPEAN UNION project entitled “Diagnostic and Drug Discovery Initiative for Alzheimer’s Disease” (D3i4AD), FP7-PEOPLE-2013-IAPP, grant agreement 612347. FUNDAçãO PARA A CIêNCIA E A TECNOLOGIA (FCT, PORTUGAL) also funded this research through the financial support of Centro de Química Estrutural (project UIDB/00100/2020), Institute of Molecular Sciences (project LA/P/0056/2020) and project PTDC/QUI-QFI/29527/2017.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the abstract and the Supplementary Material. Data for Method 1 is available in at https://doi.org/10.3390/ph16010054.
Conflicts of Interest
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
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