Anti-fibrillization effects of sulfonamide derivatives on ?-synuclein and hyperphosphorylated tau isoform 1N4R

In contrast to A n plaques, the spatiotemporal distribution of neurofibrillary tangles of hyperphosphorylated tau (p-tau) predicts cognitive impairment in Alzheimer's disease (AD), underscoring the key pathological role of p-tau and the utmost need to develop AD therapeutics centering upon the control of p-tau aggregation and cytotoxicity. Our drug discovery program is focused on compounds that prevent the aggregation and cytotoxicity of p-tau moieties of the tau isoform 1N4R due to its prevalence (1 N) and long-distance trans-synaptic propagation (4R). We prepared and tested twenty-four newly synthesized small molecules representing the urea ( 1, 2, 3 ), sulfonylurea ( 4 ), and sulfonamide ( 5-24 ) series and evaluated their anti-aggregation effects with biophysical methods (thioflavin T and S fluorescence assays, transmission electron microscopy) and intracellular inclusion cell-based assays. Pre-evaluation was performed on alpha-synuclein ( alpha-syn) to identify molecules to be challenged with p-tau. The sulfonamide derivatives 18 and 20 exhibited an anti-fribrillization activity on alpha-syn and p-tau. Sulfonamide compounds 18 and 20 reduced inclusion formation in M17D neuroblastoma cells that express inclusion-prone alpha Synuclein3K::YFP. This project advances new concepts in targeting prone-to-aggregate proteins such as alpha-syn and p-tau, and provides a molecular scaffold for further optimization and pre-clinical studies focused on AD drug development.

Automated summary

Contrary to A n plaques, the distribution of hyperphosphorylated tau (p-tau) neurofibrillary tangles predicts cognitive impairment in Alzheimer's disease (AD). This underscores the importance of controlling p-tau aggregation and cytotoxicity in AD therapeutics. A drug discovery program focusing on the tau isoform 1N4R has developed compounds that prevent p-tau aggregation and cytotoxicity. Among the tested small molecules, sulfonamide derivatives 18 and 20 showed anti-aggregation activity on alpha-synuclein and p-tau, reducing inclusion formation in neuroblastoma cells. This project introduces new concepts in targeting prone-to-aggregate proteins and provides a molecular scaffold for AD drug development.