Affiliation:
1. Centro de Quimica Estrutural and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001, Lisboa, Portugal
2. Department of Inorganic and Analytical Chemistry, University of Debrecen, Egyetem ter 1, H-4032 Debrecen, Hungary
Abstract
Alzheimer´s disease (AD) is the most common and severe age-dependent neurodegenerative
disorder worldwide. Notwithstanding the large amount of research dedicated
to both the elucidation of this pathology and the development of an effective drug,
the multifaceted nature and complexity of the disease are certainly a rationale for the
absence of cure so far. Currently available drugs are used, mainly to compensate the decline
of the neurotransmitter acetylcholine by acetylcholinesterase (AChE) inhibition,
though they only provide temporary symptomatic benefits and cannot stop AD progression.
Although the multiple factors that contribute to trigger AD onset and progression
are not yet fully understood, several pathological features and underneath pathways have
been recognized to contribute to its pathology, such as metal dyshomeostasis, protein misfolding,
oxidative stress and neurotransmitter deficiencies, some of them being interconnected.
Thus, there is widespread recent interest in the development of multitarget-directed
ligands (MTDLs) for simultaneous interaction with several pathological targets of
AD. In this review, a selection of the most recent reports (2016-up to present) on metal
chelators of MTDLs with multifunctionalities is presented. These compounds enable the
hitting of several AD targets or pathways, such as modulation of specific biometal ions
(e.g., Cu, Fe, Zn) and of protein misfolding (β-amyloid and tau protein), anti-oxidant activity
and AChE inhibition. The properties found for these hybrids are discussed in comparison
with the original reference compounds, some MTDLs being outlined as leading
compounds for pursuing future studies in view of efficient potential applications in AD
therapy.
Funder
COST Action, NECTAR, supported by COST
Hungarian Scientific Research Fund
Fundação para a Ciência e Tecnologia
Publisher
Bentham Science Publishers Ltd.
Subject
Pharmacology,Molecular Medicine,Drug Discovery,Biochemistry,Organic Chemistry
Cited by
15 articles.
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