Publication Type Journal Article
Title Exploring the chelating capacity of 2-hydroxyphenyl-benzimidazole based hybrids with multi-target ability as anti-Alzheimer s agents
Authors Sílvia Chaves Asha Hiremathad Daniel Tomás Rangappa S. Keri Luca Piemontese M. Amélia Santos
Groups BIOIN
Journal NEW JOURNAL OF CHEMISTRY
Year 2018
Month October
Volume 42
Number 20
Pages 16503-16515
Abstract Alzheimer s disease (AD) is the most common (60-70\%) form of dementia in the elderly population. Its complex and multifactorial nature requires the development of drugs capable of hitting several disease targets, such as cholinergic dysfunction, oxidative stress, deposits of amyloid- (A) and metal ion dyshomeostasis. Two series of hybrids, mimetics of donepezil (DNP) and tacrine (TAC), containing a 2-hydroxyphenyl-benzimidazole (BIM) chelating moiety (DNP-BIM and TAC-BIM), were formerly developed and found to exhibit multi-target ability as anti-AD compounds. Due to the recognized role of metal ions as age triggers of AD, namely responsible for oxidative stress and A aggregation, the copper and zinc chelating capacity is herein evaluated for two DNP-BIM hybrids (PP-BIM and PZ-BIM) and one TAC-BIM (TAC-BIM1) hybrid, as well as the role of copper in their A aggregation inhibitory capacity. The compounds exhibit good chelating capacity towards Cu(ii) (pCu approximate to 11) and moderate towards Zn(ii) (pZn approximate to 6) in a 50\% w/w DMSO/water medium, with the formation of 1:1 (MHL) and 1:2 (MH2L2, ML2 and MH-1L2) complex species involving the phenolic oxygen and the imidazole nitrogen N(3) of the BIM moiety in the coordination shell. All hybrids are able to improve the inhibition of self-induced A aggregation, probably by ligand intercalation between the -sheets of A fibrils, with markedly higher inhibitory capacity for the tacrine conjugates than for the donepezil conjugates. Nevertheless, the compounds do no t seem able to retrieve Cu(ii) from A peptide and so they may have no relevant role in Cu(ii)-induced-A aggregation.
DOI http://dx.doi.org/10.1039/c8nj00117k
ISBN
Publisher
Book Title
ISSN 1144-0546
EISSN 1369-9261
Conference Name
Bibtex ID ISI:000447975700013
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