New tacrine–acridine hybrids as promising multifunctional drugs for potential treatment of Alzheimer's disease

Abstract

The synthesis, biological tests, and computer modeling of a series of novel promising tacrine hybrids for the therapy of Alzheimer's disease are reported. Firstly, new tacrine-acridine hybrids with different carbon linker lengths were synthesized. Secondly, all the compounds were tested in vitro for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzyme activity. After that, the most promising compound 3d was tested using the amyloid-β aggregation assay. To evaluate possible toxic effects, cytotoxicity tests were conducted. The most active compound 3d (IC = 7.6 pM for AChE and 1.7 pM for BuChE) appeared to be a much more active inhibitor than tacrine (IC = 89.9 nM for AChE and 14.9 nM for BuChE). At the highest concentration (100 μM), 3d exhibited 57.77% activity, retaining it as the concentration decreased: 50 μM - 54.74%, 20 μM - 48.28%, 10 μM - 31.66%. The compound showed no significant cytotoxic effect at the tested concentrations. At the end, docking studies using methods of computer modeling were performed to visualize the binding mode of the inhibitor 3d. It showed dual-binding mode for AChE, by binding to the catalytic anionic site and the peripheral anionic site simultaneously. Thus, compound 3d is a promising multitarget hybrid that can be used for the treatment of Alzheimer's disease.

Cholinesterase inhibitors as Alzheimer's therapeutics (Review)

“…Recently, a donepezil-chromone-melatonin hybrid has been developed as a multi-target agent with strong BChE and moderate hAChE inhibitory capacities, and with anti-MAO-A/B and antioxidant properties (78). Furthermore, tacrine-acridine hybrids have been developed as multi-target drugs for the treatment of AD (79). In addition, tacrine-carbohydrate (80) and tacrin-T6FA (81) hybrids have shown potent ChE inhibitory potential.…”

“…Therefore, there is a need to develop multi-functional drugs that are able to targ et al l symptoms of AD, including the decreased levels of ACh, protein misfolding and associated Aβ aggregation, hyperphosphorylation of τ protein, metal dyshomeostasis and oxidative stress. However, only a limited number of studies have focused on the development of multi-target drugs (79,81,89).…”

The State of The Art on Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease

“…60 Furthermore, tacrine-acridine hybrids are currently under study as multi-target drugs in AD treatment. 61…”

“…60 Furthermore, tacrine-acridine hybrids are currently under study as multi-target drugs in AD treatment. 61 Natural organic compounds Flavonoids. Flavonoids are a group of natural compounds with a well-known free-radical-scavenging capacity.…”

A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors

“…On the other hand, AD is one of the therapeutic areas where the development of multitarget drugs has been more intensively pursued in the past decade [20][21][22]. Most of these compounds are hybrids that combine distinct pharmacophoric moieties to confer multiple activities [for recent examples see [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. A crucial point in the design of multitarget anti-Alzheimer compounds is the selection of the biological targets to hit, and, hence, of the pharmacophores to be used.…”