In vitro antiamyloidogenic properties of 1,4-naphthoquinones

The aim of this study is to find out whether several 1,4-naphthoquinones (1,4-NQ) can interact with the amyloidogenic pathway of the amyloid precursor protein processing, particularly targeting at β-secretase (BACE), as well as at β-amyloid peptide (Aβ) aggregation and disaggregating preformed Aβ fibrils. Compounds bearing hydroxyl groups at the quinoid (2) or benzenoid rings (5, 6) as well as some 2- and 3-aryl derivatives (11–15) showed BACE inhibitory activity, without effect on amyloid aggregation or disaggregation. The halogenated compounds 8 and 10 were selective for the inhibition of amyloid aggregation. On the other hand, 1,4-naphthoquinone (1), 6-hydroxy-1,4-naphthoquinone (4) and 2-(3,4-dichlorophenyl)-1,4-naphthoquinone (26) did not show any BACE inhibitory activity but were active on amyloid aggregation and disaggregation preformed Aβ fibrils. Juglone (5-hydroxy-1,4-naphthoquinone (3), and 3-(p-hydroxyphenyl)-5-methoxy-1,4-napththoquinone (19) were active on all the three targets. Therefore, we suggest that 1,4-NQ derivatives, specially 3 and 19, should be explored as possible drug candidates or lead compounds for the development of drugs to prevent amyloid aggregation and neurotoxicity in Alzheimer’s disease.

Research highlights
► 1,4-NQ with OH groups at the quinoid or benzenoid rings were BACE inhibitors.
► 2- and 3-Aryl 1,4-NQ derivatives showed BACE inhibitory activity.
► Halogenated 1,4-NQ inhibited the amyloid aggregation.
► 1,4-Naphthoquinone, 6-OH-1,4-naphthoquinone and 2-(3,4-dichlorophenyl)-1,4-naphthoquinone were active on amyloid aggregation process.
► Juglone and 3-(p-OH-phenyl)-5-methoxy-1,4-napththoquinone were active on all targets.