TY - JOUR
T1 - Discovery of Neuroprotective Agents Based on a 5-(4-Pyridinyl)-1,2,4-triazole Scaffold
AU - Gitto, Rosaria
AU - Vittorio, Serena
AU - Bucolo, Federica
AU - Peña-Díaz, Samuel
AU - Siracusa, Rosalba
AU - Cuzzocrea, Salvatore
AU - Ventura, Salvador
AU - Di Paola, Rosanna
AU - De Luca, Laura
N1 - Funding Information:
The authors thank the “Programma Operativo Nazionale Ricerca & Innovazione 2014-2020, Azione I.1 “Dottorati Innovativi con caratterizzazione industriale” for financial support in form of a PhD scholarship “DOT1314952” granted to S.V. and F.B.
Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/3/2
Y1 - 2022/3/2
N2 - Parkinson's disease (PD) is characterized by the death of dopaminergic neurons. The common histopathological hallmark in PD patients is the formation of intracellular proteinaceous accumulations. The main constituent of these inclusions is alpha-synuclein (α-syn), an intrinsically disordered protein that in pathological conditions creates amyloid aggregates that lead to neurotoxicity and neurodegeneration. The main goal of our study was to optimize our previously identified α-syn aggregation inhibitors of 5-(4-pyridinyl)-1,2,4-triazole chemotype in terms of in vivo efficacy. Our efforts resulted in the identification of ethyl 2-((4-amino-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)thio)acetate (15), which displayed the ability to prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine-induced bradykinesia as well as to affect the levels of PD markers after the administration of the same neurotoxin. In addition to the in vivo evaluation, for the 5-(4-pyridinyl)-1,2,4-triazole-based compounds, we measured the prevention of the fibrillization process using light scattering and a ThT binding assay; these compounds have been shown to slightly reduce the α-syn aggregation.
AB - Parkinson's disease (PD) is characterized by the death of dopaminergic neurons. The common histopathological hallmark in PD patients is the formation of intracellular proteinaceous accumulations. The main constituent of these inclusions is alpha-synuclein (α-syn), an intrinsically disordered protein that in pathological conditions creates amyloid aggregates that lead to neurotoxicity and neurodegeneration. The main goal of our study was to optimize our previously identified α-syn aggregation inhibitors of 5-(4-pyridinyl)-1,2,4-triazole chemotype in terms of in vivo efficacy. Our efforts resulted in the identification of ethyl 2-((4-amino-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)thio)acetate (15), which displayed the ability to prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine-induced bradykinesia as well as to affect the levels of PD markers after the administration of the same neurotoxin. In addition to the in vivo evaluation, for the 5-(4-pyridinyl)-1,2,4-triazole-based compounds, we measured the prevention of the fibrillization process using light scattering and a ThT binding assay; these compounds have been shown to slightly reduce the α-syn aggregation.
KW - 5-(4-pyridinyl)-1,2,4-triazoles
KW - alpha synuclein
KW - MPTP
KW - Parkinson's disease
KW - synthesis
UR - http://www.scopus.com/inward/record.url?scp=85125405311&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.1c00849
DO - 10.1021/acschemneuro.1c00849
M3 - Article
C2 - 35179861
AN - SCOPUS:85125405311
SN - 1948-7193
VL - 13
SP - 581
EP - 586
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 5
ER -