Aggregation inhibitors of tau protein with anti-inflammatory potential against neurodegeneration

Alzheimer's disease (AD) is characterized by two pathological hallmarks: extracellular β-amyloid plaques and intracellular neurofibrillary tangles (NFTs) formed by aggregated Tau protein. Ongoing research focuses on identifying inhibitors that either block Tau aggregation or destabilize pre-formed fibrils. In this study, we evaluated derivatives of Rhodanine (RDN), Anthraquinone (AQ), Phenylaminopyrimidine (PhNH₂), Phenylthiazol hydrazide (PTH) and Benzothiazole (BZT) as potential modulators of Tau aggregation. We synthesized target compounds using Pd- and Cu-catalyzed coupling reactions and confirmed their structures via NMR spectroscopy. Thioflavin T fluorescence assays and ¹H¹⁵N Heteronuclear Single Quantum Coherence (HSQC) NMR experiments demonstrated that PhNH₂ and PTH effectively inhibited Tau polymerization by interacting with key hexapeptide motifs. Additionally, AQ, RDN, and PhNH₂ reduced iNOS and COX-2 expression in LPS-stimulated monocytes, underscoring their anti-inflammatory activity. These findings suggest PhNH₂ and PTH as promising candidates for modulating Tau aggregation, with PhNH₂ exhibiting dual anti-aggregation and anti-inflammatory properties.