Synthesis, biological evaluation and molecular modeling of new tetrahydroacridine derivatives as potential multifunctional agents for the treatment of Alzheimer’s disease

Bajda, Marek; Jończyk, Jakub; Malawska, Barbara; Czarnecka, Kamila; Girek, Małgorzata; Olszewska, Paulina; Sikora, Joanna; Mikiciuk-Olasik, Elżbieta; Skibiński, Robert; Gumieniczek, Anna; Szymański, Paweł

doi:10.1016/j.bmc.2015.07.029

Cited by 27 publications

(23 citation statements)

References 26 publications

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“…To estimate inhibitory activity against AChE an BuChE we used Ellman's method . AChE (EC 3.1.1.7, from electric eel), BuChE (EC3.1.1.8, from equine serum), DTNB (Ellman's reagent), and acetylthiocholine iodide (ACT) were acquired from Sigma–Aldrich (Steinheim, Germany).…”

Section: Methodsmentioning

confidence: 99%

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

Chufarova

Czarnecka

Skibiński

et al. 2018

Archiv der Pharmazie

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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.

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Section: Methodsmentioning

confidence: 99%

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

Chufarova

Czarnecka

Skibiński

et al. 2018

Archiv der Pharmazie

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“…These in vitro/in vivo/ex vivo results indicated that it has potential as a multi-target drug lead for further development. A novel series of tacrine-4-dimethylaminobenzoic acids was evaluated for its role against AChE for AD treatment [70]. Among all the tested analogs the analog 35a exhibited efficient hAChE (IC 50 = 142 nM) and AChE-induced Aβ aggregation inhibition (80.6% at 50 μM).…”

Section: Tacrine Analogsmentioning

confidence: 99%

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

Saxena¹

2019

AND

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Alzheimer's Disease (AD) is characterized by the loss of memory and learning ability in elderly patients affecting large population worldwide. The enzyme Acetylcholinesterase (AChE), (E.C.3.1.1.7) plays a major role in the hydrolysis of the released neurotransmitter acetylcholine. Most of the clinically used drugs to treat AD are Acetylcholinesterase Inhibitors (AChEIs). These drugs can provide symptomatic benefits only and suffer with loss of therapeutic potential with time. Therefore, there is an urgent need of novel cholinesterase inhibitors with wider therapeutic window for the treatment of AD. The strategies targeting the AChE enzyme along with other target(s) like Butyrylcholinesterase (BChE), amyloid-β (Aβ), β-secretase-1 (BACE), metals (Cu 2+ , Zn 2+ , or Fe 2+), antioxidant properties and free radical scavenging capacity have been mainly focused in the last five years. A number of hybrid molecules incorporating sub-structures with the desired well-established pharmacological profile into a single scaffold have been investigated. The main sub structures used in developing these molecules are derived from diverse chemical classes such as acridine, quinoline, carbamates, huperzine and other heterocyclic analogs. It has been followed by optimization of activity through structural modifications of the prototype molecules for developing the Structure Activity Relationship (SAR). This has led to the development of novel molecules with desired AChE inhibitory activity along with other desirable pharmacological properties. This review summarizes the current therapeutic strategies for the development of these AChEI in the last seven years.

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“…[4,13] Formation of β-amyloid aggregates is accelerated through the interaction with PAS of AChE. [30,33,34] The aim of the study was to synthesize and investigate new 9-amino-tetrahydroacridine derivatives with iodobenzoic moiety as novel cholinesterase inhibitors. [3] Due to the complexity of AD, it is proposed to investigate multitargetdirected ligands (MTDLs).…”

Section: Introductionmentioning

confidence: 99%

Novel tetrahydroacridine derivatives with iodobenzoic acid moiety as multifunctional acetylcholinesterase inhibitors

et al. 2017

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New synthesized series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with iodobenzoic acid moiety were studied for their inhibitory activity toward cholinesterase and against β-amyloid aggregation. All novel molecules 3a-3i interacted with both cholinesterases-acetylcholinesterase and butyrylcholinesterase-delivered nanomolar IC values. The structure-activity relationship showed that N-butyl moiety derivatives are stronger inhibitors toward AChE and BuChE than N-ethyl and N-propyl moieties compounds. The most potent compound toward acetylcholinesterase was inhibitor 3f (IC = 31.2 nm), and it was more active than reference drug, tacrine (IC = 100.2 nm). Compound 3f showed strong inhibition of butyrylcholinesterase (IC = 8.0 nm), also higher than tacrine (IC = 16.3 nm). In the kinetic studies, compound 3f revealed mixed type of acetylcholinesterase inhibition. The computer modeling was carried out. The most active compound 3f was confirmed as peripheral anionic site inhibitor of acetylcholinesterase. Moreover, molecule 3f inhibited β-amyloid aggregation (at the concentration 10 μm-24.96% of inhibition, 25 μm-72%, 50 μm-78.44%, and 100 μm-84.92%). Therefore, among all examined, compound 3f is the most promising molecule for further, more detailed research of novel multifunctional agents in the therapy of Alzheimer's disease.

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Synthesis, biological evaluation and molecular modeling of new tetrahydroacridine derivatives as potential multifunctional agents for the treatment of Alzheimer’s disease

Cited by 27 publications

References 26 publications

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

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

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

Novel tetrahydroacridine derivatives with iodobenzoic acid moiety as multifunctional acetylcholinesterase inhibitors

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