Phenylthiazolyl-Hydrazide and Its Derivatives Are Potent Inhibitors of τ Aggregation and Toxicity in Vitro and in Cells

Abstract

Synthesis of this compound showed that it was indeed active in terms of inhibiting de novo tau aggregation and disassembling preformed aggregates (IC 50 ) 7.7 µM and DC 50 ) 10.8 µM). We have now synthesized 49 similar structures and identified the core of the PTHs to be crucial for activity, thus representing a lead structure. Analysis of the binding epitope by saturation transfer difference NMR shows strong interactions between the tau protein and the ligand in the aromatic regions of the inhibitor. By chemical variation of the core, we improved the inhibitory potency five-fold. The compounds showed a low toxicity as judged by an N2A cell model of tau aggregation and lend themselves for further development.

Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models

“…Importantly, targeting tau extends treatment to tau-only dementias, of which there are many. Current strategies in developing tau-directed treatments include inhibition of tau aggregation (34)(35)(36)(37)(38), stabilization of microtubules (39,40), inhibition of kinases (41,42), induction of tau clearance (43)(44)(45), immunotherapy (46), and indirect modulation of tau function (47). So far, however, only a limited number of compounds proved efficacy in tau transgenic mouse models, and even fewer progressed into clinical trials (13).…”

Tau-Based Treatment Strategies in Neurodegenerative Diseases

“…The structure-activity relationship distinguishes PTHs from nonselective inhibitors without a structure-activity relationship. 155 The tau-PTH interaction was studied by saturation transfer difference NMR and appeared to be hydrophobic. 158 The exact structural interaction of tau and PTH still needs to be determined.…”

3D QSAR CoMFA Study on Phenylthiazolylhydrazide (PTH) Derivataives as Tau Protein Aggregation Inhibitors

“…Even though Aβ inhibitors have been a major focus of research on anti-Alzheimer therapy, 5 recent report of a phase II clinical trial of the tau aggregation inhibitor MTC (methylthionium chloride) which significantly slowed down the decline of cognitive functions of AD patients 6 proposes a valuable therapeutic use of the tau aggregation inhibitor as a potential disease-modifying drug for AD. Interests towards inhibitors of the tau aggregation continues to grow by recent findings of several classes of inhibitors such as rhodanines, 7 phenylthiazolylhydrazides, [8][9][10] N-phenylamines, 11 anthraquinones, 12 benzothiazoles, 13 phenothiazines, 14 porphyrins 14 and polyphenols. 14 However, the low membrane permeability of most of the aggregation inhibitors is the key issue which needs to be resolved for future development of new generation of aggregation inhibitors.…”

“…The PTH derivatives show in vitro nanomolar IC50 values for tau aggregation inhibition 10 but, presumably due to the presence of the hydrazothiazole toxicophore, 15 the PTH derivatives are relatively cytotoxic. 10 Thus, in this study, we report a 3D-QSAR study on the PTH derivatives in anticipation of getting a model that would account for the quantitative differences in bioactivity seen in this series and provide insights into designing of novel tau aggregation inhibitors with improved activity.…”

“…10 Thus, in this study, we report a 3D-QSAR study on the PTH derivatives in anticipation of getting a model that would account for the quantitative differences in bioactivity seen in this series and provide insights into designing of novel tau aggregation inhibitors with improved activity.…”