Benzothiazole Substitution Analogs of Rhodacyanine Hsp70 Inhibitors Modulate Tau Accumulation

The buildup of the microtubule-associated protein tau (tau) into intracellular tangles is a key feature of various progressive neurodegenerative disorders known as tauopathies, including Alzheimer’s disease (AD), frontotemporal dementia, Pick’s disease, and progressive supranuclear palsy. In AD, abnormal phosphorylation of tau is linked to the formation of these aggregates. Heat shock proteins in the 70 kDa family (Hsp70) interact directly with tau, influencing its clearance and aggregation. Inhibiting these chaperones with small molecules has been shown to reduce the accumulation of both total and phosphorylated tau.

In this study, eight analogs of the rhodacyanine inhibitor JG-98 were synthesized and assessed. Like JG-98, many of these compounds suppressed the ATPase activity of the cytosolic heat shock cognate 70 protein (Hsc70) and decreased levels of total, aggregated, and phosphorylated tau in cultured cells. Three compounds, selected to represent a range of clogP values, were further evaluated for their ability to cross the blood-brain barrier and reduce tau in an ex vivo brain slice model. Among them, AL69, which had the lowest clogP and minimal membrane retention in a parallel artificial membrane permeability assay (PAMPA), effectively reduced phosphorylated tau accumulation. These findings indicate that modifying JG-98 with benzothiazole groups to enhance hydrophilicity may improve the efficacy of Hsp70 inhibitors in reducing phosphorylated tau.