In silico identification and experimental validation of novel anti-Alzheimer’s multitargeted ligands from a marine source featuring a “2-aminoimidazole plus aromatic group” scaffold

Vitale, R. M. et al. (2018) In silico identification and experimental validation of novel anti-Alzheimer’s multitargeted ligands from a marine source featuring a “2-aminoimidazole plus aromatic group” scaffold. ACS Chemical Neuroscience, 9(6), pp. 1290-1303. (doi: 10.1021/acschemneuro.7b00416)

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Abstract

Multitargeting or polypharmacological approaches, looking for single chemical entities retaining the ability to bind two or more molecular targets, are a potentially powerful strategy to fight complex, multifactorial pathologies. Unfortunately, the search for multiligand agents is challenging because only a small subset of molecules contained in molecular databases are bioactive and even fewer are active on a preselected set of multiple targets. However, collections of natural compounds feature a significantly higher fraction of bioactive molecules than synthetic ones. In this view, we searched our library of 1175 natural compounds from marine sources for molecules including a 2-aminoimidazole+aromatic group motif, found in known compounds active on single relevant targets for Alzheimer’s disease (AD). This identified two molecules, a pseudozoanthoxanthin (1) and a bromo-pyrrole alkaloid (2), which were predicted by a computational approach to possess interesting multitarget profiles on AD target proteins. Biochemical assays experimentally confirmed their biological activities. The two compounds inhibit acetylcholinesterase, butyrylcholinesterase, and β-secretase enzymes in high- to sub-micromolar range. They are also able to prevent and revert β-amyloid (Aβ) aggregation of both Aβ1–40 and Aβ1–42 peptides, with 1 being more active than 2. Preliminary in vivo studies suggest that compound 1 is able to restore cholinergic cortico-hippocampal functional connectivity.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Vassalli, Dr Massimo
Authors: Vitale, R. M., Rispoli, V., Desiderio, D., Sgammato, R., Thellung, S., Canale, C., Vassalli, M., Carbone, M., Ciavatta, M. L., Mollo, E., Felicità, V., Arcone, R., Gavagnin Capoggiani, M., Masullo, M., Florio, T., and Amodeo, P.
College/School:College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:ACS Chemical Neuroscience
Publisher:American Chemical Society
ISSN:1948-7193
ISSN (Online):1948-7193
Published Online:23 February 2018

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