Discovery of Neuroprotective Agents Based on a 5-(4-Pyridinyl)-1,2,4-triazole Scaffold

Abstract

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-1,2,3,6tetrahydropiridine-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.

Ligand-Based Discovery of a Small Molecule as Inhibitor of α-Synuclein Amyloid Formation

“…The misfolded proteins are generally considered “low druggable” targets, as they lack specific ligand-binding sites that efficiently establish strong binding with inhibitors or modulators. However, there are recently developed synthetic and natural small molecules that inhibit α-Syn aggregation and fibril formation in cell-based assays [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. These therapeutics are generally defined as disaggregators and might be characterized by a distinct mode of action.…”

Anti-Inflammatory Activity of 4-(4-(Heptyloxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one via Repression of MAPK/NF-κB Signaling Pathways in β-Amyloid-Induced Alzheimer’s Disease Models

“…Triazole-based compounds are now under study for the treatment of a variety of central nervous system (CNS) diseases. The study of Gitto et al revealed 1,2,4-triazole-based compounds could inhibit α-syn aggregation to prevent Parkinson’s disease [ 19 ]. Wu et al worked on 1,2,4-triazole derivatives and found a series of anticonvulsant compounds by using epilepsy models during both in vivo and in vitro studies [ 20 ].…”

Development of Small Molecules Targeting α-Synuclein Aggregation: A Promising Strategy to Treat Parkinson’s Disease

“…Interestingly, SC-D and ZPD-2 have been used as scaffolds to rationally design variants with enhanced activity or pharmacological properties [ 340 , 341 ]. More recently, SC-D and ZPD-2 chemical scaffolds were used to generate a library of 34 different compounds obtained through a similarity-based virtual screening filtered to contain exclusively molecules with good drug-like properties [ 342 ]. In vitro studies confirmed the inhibitory capacity of MeSC-04 (an SC-D derivate) against α-Syn aggregation.…”

“…In vitro studies confirmed the inhibitory capacity of MeSC-04 (an SC-D derivate) against α-Syn aggregation. Computational analysis using two different α-Syn recombinant fibrils (PDB: 2N0A and 6FLT) suggested that MeSC-04 established Van der Waals contacts and hydrogen bonds with the α-Syn region comprising residues from A53 to V74 [ 342 ].…”