N-alkylpiperidine carbamates as potential anti-Alzheimer’s agents

Košak, Urban; Strašek, Nika; Knez, Damijan; Jukič, Marko; Žakelj, Simon; Zahirović, Abida; Pišlar, Anja; Brazzolotto, Xavier; Nachon, Florian; Kos, Janko; Gobec, Stanislav

doi:10.1016/j.ejmech.2020.112282

Cited by 36 publications

(30 citation statements)

References 45 publications

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“…Higher inhibitory potencies of meta derivatives could be explained by the superior binding of more branched meta analogues to the large hBChE cavity compared to the 1,4-derivatives (e.g., para 14 , IC 50 = 75.5 ± 8.4 µM vs. meta 15 , IC 50 = 4.3 ± 0.8 µM). The docking results support this rationale; however, the precise binding pose of the compounds in the active site should be unambiguously clarified with crystallographic studies [ 30 ]. The time-dependent inhibition of hBChE by N -ethyl- N -methyl carbamate 15, as seen in Figure 7 , indicates carbamoylation of catalytic Ser198, which is also supported by the non-covalent and covalent docking studies ( Figure 8 and Figure 9 , respectively).…”

Section: Resultsmentioning

confidence: 99%

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4-Phenethyl-1-Propargylpiperidine-Derived Dual Inhibitors of Butyrylcholinesterase and Monoamine Oxidase B

et al. 2021

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The multi-target-directed ligands (MTDLs) strategy is encouraged for the development of novel modulators targeting multiple pathways in the neurodegenerative cascade typical for Alzheimer’s disease (AD). Based on the structure of an in-house irreversible monoamine oxidase B (MAO-B) inhibitor, we aimed to introduce a carbamate moiety on the aromatic ring to impart cholinesterase (ChE) inhibition, and to furnish multifunctional ligands targeting two enzymes that are intricately involved in AD pathobiology. In this study, we synthesized three dual hMAO-B/hBChE inhibitors 13–15, with compound 15 exhibiting balanced, low micromolar inhibition of hMAO-B (IC50 of 4.3 µM) and hBChE (IC50 of 8.5 µM). The docking studies and time-dependent inhibition of hBChE confirmed the initial expectation that the introduced carbamate moiety is responsible for covalent inhibition. Therefore, dual-acting compound 15 represents an excellent starting point for further optimization of balanced MTDLs.

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Section: Resultsmentioning

confidence: 99%

“…In the study presented herein, we introduced a carbamate moiety on the aromatic ring to gain ChE inhibition as well, through the carbamoylation of catalytic Ser198. This approach led to the development of multifunctional ligands targeting two enzymes that are intricately involved in AD pathobiology ( Figure 1 ) [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

4-Phenethyl-1-Propargylpiperidine-Derived Dual Inhibitors of Butyrylcholinesterase and Monoamine Oxidase B

et al. 2021

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“…24). 17 Pouramiri et al synthesized a library of 2-aryl benzofuran derivatives through four-step reactions from 2-hydroxybenzyl alcohol in good yield. In comparison with donepezil, the synthesized compound 48 with the piperidine moiety exhibited the most optimal AChE inhibition activity of 74% at 23 mM (Fig.…”

Section: Miscellaneous Mtdlsmentioning

confidence: 99%

The recent development of donepezil structure-based hybrids as potential multifunctional anti-Alzheimer's agents: highlights from 2010 to 2020

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“…Crystal structures of AChE, BChE, factor Xa, and thrombin were retrieved from the Protein Data Bank (PDB) by selecting entries 1EVE, 6SAM, 3K9X and 1UVS, respectively [34][35][36][37]. Protein structures were geometrically optimized and energetically minimized by employing the protein preparation tool available in the Schrodinger Suite [38,39].…”

Section: Molecular Modellingmentioning

confidence: 99%

First-in-Class Isonipecotamide-Based Thrombin and Cholinesterase Dual Inhibitors with Potential for Alzheimer Disease

et al. 2021

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Recently, the direct thrombin (thr) inhibitor dabigatran has proven to be beneficial in animal models of Alzheimer’s disease (AD). Aiming at discovering novel multimodal agents addressing thr and AD-related targets, a selection of previously and newly synthesized potent thr and factor Xa (fXa) inhibitors were virtually screened by the Multi-fingerprint Similarity Searching aLgorithm (MuSSeL) web server. The N-phenyl-1-(pyridin-4-yl)piperidine-4-carboxamide derivative 1, which has already been experimentally shown to inhibit thr with a Ki value of 6 nM, has been flagged by a new, upcoming release of MuSSeL as a binder of cholinesterase (ChE) isoforms (acetyl- and butyrylcholinesterase, AChE and BChE), as well as thr, fXa, and other enzymes and receptors. Interestingly, the inhibition potency of 1 was predicted by the MuSSeL platform to fall within the low-to-submicromolar range and this was confirmed by experimental Ki values, which were found equal to 0.058 and 6.95 μM for eeAChE and eqBChE, respectively. Thirty analogs of 1 were then assayed as inhibitors of thr, fXa, AChE, and BChE to increase our knowledge of their structure-activity relationships, while the molecular determinants responsible for the multiple activities towards the target enzymes were rationally investigated by molecular cross-docking screening.

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N-alkylpiperidine carbamates as potential anti-Alzheimer’s agents

Cited by 36 publications

References 45 publications

4-Phenethyl-1-Propargylpiperidine-Derived Dual Inhibitors of Butyrylcholinesterase and Monoamine Oxidase B

4-Phenethyl-1-Propargylpiperidine-Derived Dual Inhibitors of Butyrylcholinesterase and Monoamine Oxidase B

The recent development of donepezil structure-based hybrids as potential multifunctional anti-Alzheimer's agents: highlights from 2010 to 2020

First-in-Class Isonipecotamide-Based Thrombin and Cholinesterase Dual Inhibitors with Potential for Alzheimer Disease

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