Multifunctional
Mono-Triazole Derivatives Inhibit
Aβ42 Aggregation and Cu2+-Mediated Aβ42 Aggregation and Protect Against Aβ42-Induced
Cytotoxicity
Version 2 2019-08-23, 15:17
Version 1 2019-08-23, 13:35
Posted on 2019-08-23 - 15:17
Amyloid
beta (Aβ) peptide aggregation is considered as one
of the key hallmarks of Alzheimer’s disease (AD). Moreover,
Aβ peptide aggregation increases considerably in the presence
of metal ions and triggers the generation of reactive oxygen species
(ROS), which ultimately leads to oxidative stress and neuronal damage.
Based on the ‘multitarget-directed ligands’ (MTDLs)
strategy, we designed, synthesized, and evaluated a novel series of
triazole-based compounds for AD treatment via experimental and computational
methods. Among the designed MTDLs [4(a–x)], the
triazole derivative 4v exhibited the most potent inhibition
of self-induced Aβ42 aggregation (78.02%) with an
IC50 value of 4.578 ± 0.109 μM and also disassembled
the preformed Aβ42 aggregates significantly. In addition,
compound 4v showed excellent metal chelating ability
and maintained copper in the redox-dormant state to prevent the generation
of ROS in copper-ascorbate redox cycling. Further, 4v significantly inhibited Cu2+-induced Aβ42 aggregation and disassembled the Cu2+-induced Aβ42 protofibrils as compared to the reference compound clioquinol
(CQ). Importantly, 4v did not show cytotoxicity and was
able to inhibit the toxicity induced by Aβ42 aggregates
in SH-SY5Y cells. Molecular docking results confirmed the strong binding
of 4v with Aβ42 monomer and Aβ42 protofibril structure. The experimental and molecular docking
results highlighted that 4v is a promising multifunctional
lead compound for AD.
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Kaur, Amandeep; Narang, Simranjeet Singh; Kaur, Anupamjeet; Mann, Sukhmani; Priyadarshi, Nitesh; Goyal, Bhupesh; et al. (2019). Multifunctional
Mono-Triazole Derivatives Inhibit
Aβ42 Aggregation and Cu2+-Mediated Aβ42 Aggregation and Protect Against Aβ42-Induced
Cytotoxicity. ACS Publications. Collection. https://doi.org/10.1021/acs.chemrestox.9b00168
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AUTHORS (8)
AK
Amandeep Kaur
SN
Simranjeet Singh Narang
AK
Anupamjeet Kaur
SM
Sukhmani Mann
NP
Nitesh Priyadarshi
BG
Bhupesh Goyal
NS
Nitin Kumar Singhal
DG
Deepti Goyal
KEYWORDS
CQ4 vcopper-ascorbate redox cyclingmetal chelating abilityInduced Cytotoxicity Amyloid betacompound 4 vgenerationβ 42 protofibrilsSH-SY 5Y cellsMTDLreference compound clioquinolROSMultifunctional Mono-Triazole Derivatives InhibitMolecular docking resultsβ 42 protofibril structureβ 42 Aggregationβ 42 aggregationβ peptide aggregation increasesCureactive oxygen speciesβ 42 monomerβ 42 aggregatesADIC 50 value