N-Acylaminophenothiazines: Neuroprotective agents displaying multifunctional activities for a potential treatment of Alzheimer’s disease

González-Muñoz, Gema C.; Arce, Mariana P.; López, Beatriz; Pérez, Concepción; Romero, Alejandro; Barrio, Laura; Martín-de-Saavedra, María Dolores; Egea, Javier; León, Rafael; Villarroya, Mércedes; López, Manuela G.; Garcı́a, Antonio G.; Conde, Santiago; Rodríguez‐Franco, María Isabel

doi:10.1016/j.ejmech.2011.03.003

Cited by 48 publications

(39 citation statements)

References 65 publications

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“…We selected for additional studies only those molecules that showed a good score value together with a plausible distance to R94 (Table S1): FD35, FD16, FD44, and chlorpromazine (CPZ). These compounds, sharing the same tricyclic phenothiazine central scaffold, were previously known for their butirylcholinesterase inhibition in vitro and neuroprotective activity in cell assays (26,27). The main structural differences among them are in the substituent attached to the heterocyclic nitrogen atom and in the presence or not of chlorine atoms in some of the benzene moieties.…”

Section: Resultsmentioning

confidence: 99%

Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome

Mansilla

Chaves-Sanjuán

Campillo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The protein complex formed by the Ca 2+ sensor neuronal calcium sensor 1 (NCS-1) and the guanine exchange factor protein Ric8a coregulates synapse number and probability of neurotransmitter release, emerging as a potential therapeutic target for diseases affecting synapses, such as fragile X syndrome (FXS), the most common heritable autism disorder. Using crystallographic data and the virtual screening of a chemical library, we identified a set of heterocyclic small molecules as potential inhibitors of the NCS-1/Ric8a interaction. The aminophenothiazine FD44 interferes with NCS-1/Ric8a binding, and it restores normal synapse number and associative learning in a Drosophila FXS model. The synaptic effects elicited by FD44 feeding are consistent with the genetic manipulation of NCS-1. The crystal structure of NCS-1 bound to FD44 and the structure-function studies performed with structurally close analogs explain the FD44 specificity and the mechanism of inhibition, in which the small molecule stabilizes a mobile C-terminal helix inside a hydrophobic crevice of NCS-1 to impede Ric8a interaction. Our study shows the drugability of the NCS-1/Ric8a interface and uncovers a suitable region in NCS-1 for development of additional drugs of potential use on FXS and related synaptic disorders.fragile X syndrome | synapse regulation | NCS-1 | protein-protein interaction inhibitor | X-ray crystallography

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Section: Resultsmentioning

confidence: 99%

Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome

Mansilla

Chaves-Sanjuán

Campillo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Gonzales-Munoz and co-workers [13] presented a series of N-Acylaminophenothiazines as a potential BuChE inhibitors. Similar activity was observed by Tasso [14] with quinolizidinyl derivatives of bi-and tricyclic structures.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, biological activity and HPLC validation of 1,2,3,4-tetrahydroacridine derivatives as acetylcholinesterase inhibitors

Szymański

Karpiński²,

Mikiciuk-Olasik

2011

European Journal of Medicinal Chemistry

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“…Their structure and purity has been confirmed by the NMR spectra which were recorded on Bruker Fourier 300 spectrometers ( 1 H at 500 MHz, 13 C at 125 and 75 MHz) in CDCl 3 or DMSO-d 6 and fast atom bombardment mass spectra which were run on a Finnigan MAT 95 spectrometer at 70 eV. These data were presented for azaphenothiazines (7-9, 14, 17, 20) 41 for 21 42 and for remaining compounds were described elsewhere 43,44 .…”

Section: Chemistrymentioning

confidence: 99%

“…Progress in researching the properties of phenothiazine derivatives has recently been reviewed 1,2 . Moreover, phenothiazine-like compounds possess potential anti-Alzheimer's properties, due to their inhibitory potency against acetyl-and butyrylcholinesterase 3,4 , neuroprotective activity 5,6 as well as the ability to inhibit formation of amyloid beta (Ab) fibrils and to inhibit the aggregation of tau protein 7 . Such properties of bioactive molecules are important from the point of view of neurodegeneration processes and dementia.…”

Section: Introductionmentioning

confidence: 99%

Discovery of butyrylcholinesterase inhibitors among derivatives of azaphenothiazines

Lodarski

Jończyk

Guzior

et al. 2014

Journal of Enzyme Inhibition and Medicinal Chemistry

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The study presents the discovery of novel butyrylcholinesterase (BuChE) inhibitors among derivatives of azaphenothiazines by application of in silico and in vitro screening methods. From an in-house library of compounds, 143 heterocyclic molecules derived from the azaphenothiazine scaffold were chosen for virtual screening. Based on results of the docking procedure, 15 compounds were identified as exhibiting the best fit for the two screening complexes (ligand -AChE and ligand -BuChE). Five compounds displayed moderate AChE and good BuChE inhibitory activity at screening concentrations of 10 mM. The IC 50 values for active BuChE inhibitors were in the 11.8-122.2 nM range. Three of the most active inhibitors are tetra-or pentacyclic derivatives of azaphenothiazines with the same N-methyl-2-piperidinethyl substituent.

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N-Acylaminophenothiazines: Neuroprotective agents displaying multifunctional activities for a potential treatment of Alzheimer’s disease

Cited by 48 publications

References 65 publications

Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome

Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome

Synthesis, biological activity and HPLC validation of 1,2,3,4-tetrahydroacridine derivatives as acetylcholinesterase inhibitors

Discovery of butyrylcholinesterase inhibitors among derivatives of azaphenothiazines

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