Multitarget Drug Design Strategy: Quinone–Tacrine Hybrids Designed To Block Amyloid-β Aggregation and To Exert Anticholinesterase and Antioxidant Effects

Abstract

We report the identification of multitarget anti-Alzheimer compounds designed by combining a naphthoquinone function and a tacrine fragment. In vitro, 15 compounds displayed excellent acetylcholinesterase (AChE) inhibitory potencies and interesting capabilities to block amyloid-β (Aβ) aggregation. The X-ray analysis of one of those compounds in complex with AChE allowed rationalizing the outstanding activity data (IC50 = 0.72 nM). Two of the compounds showed negligible toxicity in immortalized mouse cortical neurons Neuro2A and primary rat cerebellar granule neurons. However, only one of them was less hepatotoxic than tacrine in HepG2 cells. In T67 cells, both compounds showed antioxidant activity, following NQO1 induction. Furthermore, in Neuro2A, they were able to completely revert the decrease in viability induced by Aβ. Importantly, they crossed the blood-brain barrier, as demonstrated in ex vivo experiments with rats. When ex vivo results were combined with in vitro studies, these two compounds emerged to be promising multitarget lead candidates worthy of further pursuit.

Novel Tacrine‐Grafted Ugi Adducts as Multipotent Anti‐Alzheimer Drugs: A Synthetic Renewal in Tacrine–Ferulic Acid Hybrids

“…[64,77] Briefly, the compound was administered intraperitoneally (i.p.) to young adult Wistar rats (2 months of age) at either 10 or 50 mmol kg…”

Molecular Docking and PLIF Studies of Novel Tacrine-Naphtoquinone Hybrids Based on Multi-Target-Directed Ligand Approach for Alzheimer’s Disease

“…The potential of a naphthoquinone substructure in the chemical space related to neurodegenerative diseases such as Alzheimer's were proved in recent works (11,12). Naphtoquinone as an anti-amyloid preferential motif, interact with several amyloid proteins, owing to its capability to form favorable π-stacking and hydrogen bond interactions.…”

“…Naphtoquinone as an anti-amyloid preferential motif, interact with several amyloid proteins, owing to its capability to form favorable π-stacking and hydrogen bond interactions. Naphthoquinone has anti-cholinesterase activity, displays anti-aggregating features, and allows recognition of Trp286 of the peripheral anionic site (PAS) of the human acetylcholinesterase (hAChE) (11). This site of AChE lies at the entrance to the active site pharynx.…”

Molecular Docking Studies of <i>Alpinia galanga</i> Phytoconstituents for Psychostimulant Activity

“…The selected crystal structure (4TVK) has been explored for multi-target drug designing of Acetylcholine esterase inhibitors [20]. AchE is a key enzyme responsible for the hydrolysis of acetylcholine, an essential neurotransmitter re- [21].…”