Misfolding and aggregation of tau protein, into pathological amyloids, are hallmarks of a group of neurodegenerative diseases collectively termed tauopathies and their modulation may be therapeutically valuable. Herein, we describe the synthesis and characterization of a dopaminebased hybrid molecule, naphthoquinone-dopamine (NQDA). Using thioflavin S assay, CD, transmission electron microscopy, dynamic light scattering, Congo Red birefringence, and large unilamellar vesicle leakage assays, we demonstrated its efficacy in inhibiting the in vitro aggregation of key tau-derived amyloidogenic fragments, PHF6 (VQIVYK) and PHF6* (VQIINK), prime drivers of aggregation of full-length tau in disease pathology. Isothermal titration calorimetry analysis revealed that the interaction between NQDA and PHF6 is spontaneous and has significant binding efficiency driven by both entropic and enthalpic processes. Furthermore, NQDA efficiently disassembled preformed fibrils of PHF6 and PHF6* into nontoxic species. Molecular dynamic simulations supported the in vitro results and provided a plausible mode of binding of NQDA with PHF6 fibril. NQDA was also capable of inhibiting the aggregation of full-length tau protein and disrupting its preformed fibrils in vitro in a dose-dependent manner. In a comparative study, the IC 50 value (50% inhibition of fibril formation) of NQDA in inhibiting the aggregation of PHF6 (25 µM) was~17 µM, which is lower than for other bona fide amyloid inhibitors, naphthoquinone-tryptophan, rosmarinic acid, epigallocatechin gallate,~21,~77, or~19 µM, respectively. Comparable superiority of NQDA was observed for inhibition of PHF6*. These findings suggest that NQDA can be a useful scaffold for designing new therapeutics for Alzheimer's disease and other tauopathies.

Accumulationa nd aggregation of the intrinsically disordered protein a-synuclein (a-Syn) into amyloid fibrils are hallmarks of as eries of heterogeneous neurodegenerative disorders, known as synucleinopathies and most notably Parkinson's disease (PD). The crucial role of a-Syn aggregation in PD makes it an attractive targetf or the development of disease-modifying therapeutics that would inhibit a-Syn aggregation or disrupti ts preformed fibrillara ssemblies. To this end, we have designed and synthesized two naphthoquinone-dopamine-basedh ybrid small molecules, NQDA and Cl-NQDA, and demonstrated their abilityt oi nhibit in vitro amyloid formation by a-Syn using ThT assay,C D, TEM, and Congo red birefringence.M oreover, these hybrid molecules efficiently disassembled preformed fibrils of a-Syn into nontoxic species, as evident from LUV leakage assay. NQDA and Cl-NQDA were found to have low cytotoxicity andt hey attenuated the toxicityi nduced by a-Syn towards SH-SY5Y neuroblastoma cells. NQDA was found to efficiently cross an in vitro human blood-brain barrier model. These naphthoquinone-dopamine based derivativesc an be an attractive scaffold for therapeuticd esign towards PD.

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