Galantamine derivatives with indole moiety: Docking, design, synthesis and acetylcholinesterase inhibitory activity

Atanasova, Mariyana; Stavrakov, Georgi; Philipova, Irena; Zheleva, Dimitrina; Yordanov, Nikola; Doytchinova, Irini

doi:10.1016/j.bmc.2015.07.058

Cited by 72 publications

(77 citation statements)

References 54 publications

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“…The 20 newly designed compounds were docked into the rh AChE (pdb code: 4EY6) by GOLD v. 5.1 using a previously optimized docking protocol, as described in Methods. The only difference in the present protocol was the scoring function used.…”

Section: Resultsmentioning

confidence: 99%

“…The X‐ray structure of rh AChE in complex with GAL (pdb id: 4EY6, R=2.15 Å) was used as a template for docking calculations by GOLD v. 5.1 . The molecular docking protocol was optimized previously in several steps using two training sets ,. At each step the correlation between the docking scores and pIC 50 (−logIC 50 ) values of the training compounds was evaluated.…”

Section: Methodsmentioning

confidence: 99%

“…The rational design here is focused on the elongation of N‐side chain ending by a bulky substituent able to interact with PAS. Several series of GAL derivatives with dual‐site binding to the enzyme have been prepared and tested . All of them showed good AChE inhibitory activities.…”

Section: Introductionmentioning

confidence: 99%

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Docking-based Design of Galantamine Derivatives with Dual-site Binding to Acetylcholinesterase

et al. 2016

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The enzyme acetylcholinesterase is a key target in the treatment of Alzheimer's disease because of its ability to hydrolyze acetylcholine via the catalytic binding site and to accelerate the aggregation of amyloid-β peptide via the peripheral anionic site (PAS). Using docking-based predictions, in the present study we design 20 novel galantamine derivatives with alkylamide spacers of different length ending with aromatic fragments. The galantamine moiety blocks the catalytic site, while the terminal aromatic fragments bind in PAS. The best predicted compounds are synthesized and tested for acetylcholinesterase inhibitory activity. The experimental results confirm the predictions and show that the heptylamide spacer is of optimal length to bridge the galantamine moiety bound in the catalytic site and the aromatic fragments interacting with PAS. Among the tested terminal aromatic fragments, the phenethyl substituent is the most suitable for binding in PAS.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Docking-based Design of Galantamine Derivatives with Dual-site Binding to Acetylcholinesterase

et al. 2016

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“…This hydroxyl group acts as a donor in the bonding with Glu202 and, therefore, is involved in the biological activity mechanism. 26 Other galantamine derivatives bearing this allylic hydroxyl group were also reported as potent AChE inhibitors. 27 The presence of the acetoxy group at C-15 in 4 may be responsible for decreasing the activity (65.0 ± 4.5%) of this natural product when compared to 1 (81.6 ± 1.8).…”

Section: Resultsmentioning

confidence: 99%

Structure-activity relationship study of diterpenes for treatment of Alzheimer’s disease

et al. 2017

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Alzheimer's disease is an irreversible, degenerative and age-related disease which is growing more and more with the increase in life expectancy. Kaurane diterpenes are a class of natural products available in large amounts in nature and isolated from plants grown worldwide. In the present work¸ twenty-seven kaurane diterpenes of natural origin and some readily available derivatives were assayed for acetylcholinesterase inhibition and the structure-activity relationship was analyzed. The kaurenoic acid derivatives screened showed to be promising inhibitors of AChE, which could provide new leads for drugs to fight Alzheimer's disease symptoms. Among them, eleven compounds showed activities comparable or higher than the positive control galantamine. Existence of an allylic hydroxyl group showed to be an important structural feature for AChE inhibition. In addition, presence of free hydroxyl groups at C-17 and C-19, furnished a diol especially active, able to completely inhibit AChE.

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“…The derivatives 1d–f showed the highest AChE inhibitory activity with IC 50 values 0.011 μM, 0.012 μM, and 0.015 μM, respectively (Figure ). In galantamine‐indole derivatives, the galantamine moiety interact with the CAS and the indole part binds to the aromatic residues in peripheral anionic site, and these derivatives act as dual site binder to the rhAChE enzyme (Atanasova et al, ).…”

Section: Natural Productsmentioning

confidence: 99%

Natural products and their derivatives as multifunctional ligands against Alzheimer's disease

Patil

Thakur

Sharma

et al. 2019

Drug Development Research

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Alzheimer's disease (AD), a complex neurodegenerative disorder causing multiple cellular changes including impaired cholinergic system, beta‐amyloid (βA) aggregation, tau hyperphosphorylation, metal dyshomeostasis, neuroinflammation, and many other pathways are involved in the pathogenesis of the disease. However, the exact cause of the disease is not known. Natural products such as flavonoids, alkaloids, resveratrol, and curcumin have multifunctional properties, and have drawn the attention of the researchers because these molecules are capable of interacting concurrently with the multiple targets of AD. Therefore, natural products and their derivatives with proven efficacy could be used in the management of the neurodegenerative disorders. This review focuses on the natural product based multitarget directed ligands like tacrine‐coumarin, tacrine‐huperzine A, harmine‐isoxazoline, berberine‐thiophenyl, galantamine‐indole, pyridoxine‐resveratrol, donepezil‐curcumin and their mode of action.

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Galantamine derivatives with indole moiety: Docking, design, synthesis and acetylcholinesterase inhibitory activity

Cited by 72 publications

References 54 publications

Docking-based Design of Galantamine Derivatives with Dual-site Binding to Acetylcholinesterase

Docking-based Design of Galantamine Derivatives with Dual-site Binding to Acetylcholinesterase

Structure-activity relationship study of diterpenes for treatment of Alzheimer’s disease

Natural products and their derivatives as multifunctional ligands against Alzheimer's disease

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