The antioxidant 2,3‐dichloro,5,8‐dihydroxy,1,4‐naphthoquinone inhibits acetyl‐cholinesterase activity and amyloid β₄₂aggregation: A dual target therapeutic candidate compound for the treatment of Alzheimer's disease

Abstract

Alzheimer's disease is characterized by amyloid β aggregation and cholinergic neurodegeneration. In the present study, pure DDN (2,3‐dichloro‐5,8‐dihydroxy‐1,4‐naphthoquinone) was examined, for the first time, for its dual potential as inhibitor of acetylcholinesterase (AChE) and Aβ42 aggregation. Such investigation was encouraged by the in vitro high antioxidant potential of DDN. Indeed, it revealed interesting antioxidant activity with IC50 values of 9.8 and 4.3 µM for ABTS and reducing power, respectively. The ability of DDN to counteract Aβ42 aggregation was evaluated by thioflavine‐T assay. Strong inhibition of Aβ42 aggregation of more than 90% at 25 µM was measured. Moreover, results showed that DDN inhibited AChE (IC50 = 14.5 µM). To better understand the interactions between DDN and AChE, molecular docking was performed. Obtained data predicted a high interaction characterized by hydrogen bonding at TYR337 as for galanthamine (positive control). Several residues involved in AChE hydrophobic interactions were similarly implicated in binding of this domain to DDN (ASP74, THR83, and TYR124). All these data would be useless if DDN could not pass the blood–brain barrier. So, DDN was loaded into alginate microspheres to enhance its stability and bioavailability. Thereafter, drug release profiles were assessed using immersion cell apparatus.

Antioxidant Compounds in the Treatment of Alzheimer’s Disease: Natural, Hybrid, and Synthetic Products

“…The effect of pure DDN (2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone) on the inhibition of AChE and A β 42 aggregation was assessed, and the inhibition of A β 42 aggregation (more than 90% at 25 μ M) and on AChE (IC 50 = 14.5 μ M) was determined [ 66 ]. Inspired by the widespread use of triazine derivatives, Sinha et al screened the novel triazine derivatives for their cholinesterase inhibition, and the most active compounds were selected for biological evaluation.…”

Journey on Naphthoquinone and Anthraquinone Derivatives: New Insights in Alzheimer’s Disease

“…The last example of natural NQ against AD is DDN (2,3-dichloro-5,8-dihydroxy-1,4naphthoquinone (3), Figure 4), that has been tested by Khelifi et al [112] for its antioxidant potential in two different assays. ABTS assay is based on the exchange of hydrogen atoms between the antioxidant and the stable radical [113], while iron reducing power test is based on the donation of a single electron transfer.…”

“…This result has been related to the absence of 2,3-dichloro substitution in DDN. Thanks to molecular modeling studies, Khelifi et al observed that DDN could share the same binding interaction (to Tyr337) of galantamine, used as reference compound [112].…”

Novel Lawsone–Quinoxaline Hybrids as New Dual Binding Site Acetylcholinesterase Inhibitors

“…Recent studies have also shed light on the neuroprotective effects, acetylcholinesterase inhibition, and Aβ aggregation inhibition performed by 1,4-NQ-derived compounds. − Lawsone (2-hydroxy-1,4-napthoquinone) is the main natural dye from the leaves of Henna plants . AChEI activity of some synthetic lawsone derivatives and lawsone-like derivatives was reported. − According to the in silico simulations, the 1,4-NQ system interacted with amino acid residues along the AChE active site gorge. , The para-quinone moiety primarily interacted with the amino acid residues at the CAS site, while the aromatic ring interacted with the amino acid residues in the PAS. , Therefore, lawsone was proposed to be a CAS ligand for the design of the hybrid molecule that act as dual binding site AChE inhibitors.…”

“… 27 − 29 According to the in silico simulations, the 1,4-NQ system interacted with amino acid residues along the AChE active site gorge. 27 , 28 The para-quinone moiety primarily interacted with the amino acid residues at the CAS site, while the aromatic ring interacted with the amino acid residues in the PAS. 22 , 23 Therefore, lawsone was proposed to be a CAS ligand for the design of the hybrid molecule that act as dual binding site AChE inhibitors.…”