AbstractBackgroundGlobally, a number of individuals who live with Alzheimer’s disease (AD), an incurable and debilitating disease, is increasing. Tau protein has a structural role, maintains integrity of microtubules and is one of the underlying causes of the tauopathies [1]. It is unfolded and highly soluble under physiological conditions. Dopamine receptor agonists have been used to target motor symptoms of AD [2] but there is a gap in knowledge on how these compounds play a role in tau protein aggregation.MethodHerein, we propose to evaluate the use of a unique class of multivalent inhibitors with various moieties (catechol, non‐catechol, biphenyl, piperazine, and thiazole) [3] as potential inhibitors for in vitro full‐length tau protein aggregation induced by heparin. Fluorescence aggregation assay, transmission electron microscopy and 4,4′‐Dianilino‐1,1′‐binaphthyl‐5,5′‐disulfonic acid dipotassium salt (Bis‐ANS) fluorescence spectroscopy were used to obtain IC50 values, characterize the aggregation morphologies and evaluate the hydrophobicity of tau aggregates, respectively.ResultThe catechol containing compounds, D‐519 and D‐520, prevented aggregation of tau whereas the non‐catechol and thiazole containing compounds (D‐264 and D‐636) were poor inhibitors. Based on the inhibitors’ density function theory calculations, effective aggregation inhibitors are characterized by their high polarity and polarizability.ConclusionData indicate that small molecule inhibitors may be useful therapeutics targeting tau aggregation related neurodegenerative diseases.