1-Benzylpyrrolidine-3-amine-based BuChE inhibitors with anti-aggregating, antioxidant and metal-chelating properties as multifunctional agents against Alzheimer’s disease

Wichur, Tomasz; Więckowska, Anna; Więckowski, Krzysztof; Godyń, Justyna; Jończyk, Jakub; Valdivieso, Álvaro del Río; Panek, Dawid; Pasieka, Anna; Sabaté, Raimon; Knez, Damijan; Gobec, Stanislav; Malawska, Barbara

doi:10.1016/j.ejmech.2019.111916

Cited by 40 publications

(20 citation statements)

References 75 publications

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“…Despite this inconvenience, conducting experiments using bacterial cells has a great advantage: The conditions of the aggregation process are more comparable and closer to those of mammals than those of in vitro assays . This method has already been validated and used in an efficient evaluation of antiaggregating properties for a series of compounds in several drug discovery projects. − As a reference compound, we used DP-128 whose Aβ and tau antiaggregating properties were revealed in cellulo earlier. , Some of the investigated compounds were previously tested in PAMPA assay (parallel artificial membrane permeability assay) . They were representatives of both series.…”

Section: Resultsmentioning

confidence: 99%

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Dual Inhibitors of Amyloid-β and Tau Aggregation with Amyloid-β Disaggregating Properties: Extended In Cellulo, In Silico, and Kinetic Studies of Multifunctional Anti-Alzheimer’s Agents

Pasieka

Panek

Szałaj

et al. 2021

ACS Chem. Neurosci.

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In Alzheimer’s disease, neurons slowly degenerate due to the accumulation of misfolded amyloid β and tau proteins. In our research, we performed extended studies directed at amyloid β and tau aggregation inhibition using in cellulo ( Escherichia coli model of protein aggregation), in silico , and in vitro kinetic studies. We tested our library of 1-benzylamino-2-hydroxyalkyl multifunctional anti-Alzheimer’s agents and identified very potent dual aggregation inhibitors. Among the tested derivatives, we selected compound 18 , which exhibited a unique profile of biological activity. This compound was the most potent and balanced dual aggregation inhibitor (Aβ 42 inhibition (inh.) 80.0%, tau inh. 68.3% in 10 μM), with previously reported in vitro inhibitory activity against h BuChE, h BACE1, and Aβ ( h BuChE IC 50 = 5.74 μM; h BACE1 IC 50 = 41.6 μM; Aβ aggregation (aggr.) inh. IC 50 = 3.09 μM). In docking studies for both proteins, we tried to explain the different structural requirements for the inhibition of Aβ vs tau. Moreover, docking and kinetic studies showed that compound 18 could inhibit the amyloid aggregation process at several steps and also displayed disaggregating properties. These results may help to design the next generations of dual or selective aggregation inhibitors.

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Section: Resultsmentioning

confidence: 99%

“…The procedure of the assay was described previously in refs ( 24 ) and ( 31 ). All chemicals were purchased from Sigma-Aldrich, and reagents for bacterial media were purchased from Pronadisa (Sevilla, Spain).…”

Section: Methodsmentioning

confidence: 99%

Dual Inhibitors of Amyloid-β and Tau Aggregation with Amyloid-β Disaggregating Properties: Extended In Cellulo, In Silico, and Kinetic Studies of Multifunctional Anti-Alzheimer’s Agents

Pasieka

Panek

Szałaj

et al. 2021

ACS Chem. Neurosci.

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“…The iron accumulation in the brain can result from many sources such as redox-generated free radicals [40]. Metal chelation capability of the compounds for Fe(II), Cu(II), Al(III), Zn(II) ions would be an extra advantage in the treatment of Alzheimer Disease [41,42]. The synthesized Arg-Ag and Arg-Cu CDs have shown promising results for inhibition of AChE enzyme activity, and Fe(II) chelating capability showing potential therapeutic utilization as reversible inhibitors and chelators in Alzheimer's and other neuro degenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Nitrogen-Doped Arginine Carbon Dots and Its Metal Nanoparticle Composites as Antibacterial Agent

Suner

Şahiner

Ayyala

et al. 2020

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Nitrogen (N)-doped arginine carbon dots (Arg CD) were successfully synthesized using arginine as the amine source and citric acid as the carbon source via a one-pot green synthesis microwave-assisted technique in 2 min. Ag and Cu nanoparticles (NP) were generated within N-doped Arg CDs as composite Arg-Ag CDs and Arg-Cu CDs to render enhanced antibacterial properties. TEM analysis revealed that Arg CDs are in graphitic structures with d spacing ranging from 0.5 nm to 10 nm. The minimum inhibition concentration (MIC) values of Arg CDs with 6.250 mg/mL were decreased by about 100-fold for Arg-Ag CDs and ten-fold for Arg-Cu CDs with 0.062 and 0.625 mg/mL MIC values against Staphylococcus aureus (S. aureus). The highest antibacterial susceptibility was observed for the Arg-Ag CD composite with 0.125 and 0.312 mg/mL minimum bactericidal concentration (MBC) values against Gram negative S. aureus and Gram positive Escherichia coli (E. coli) bacteria strains, respectively. It was found that the metal NPs within Arg CDs significantly increased the antibacterial properties of CDs making them available in the treatment of infections caused by different bacterial species. Furthermore, Arg-Ag CD and Arg-Cu CD composites were tested for Acetylcholinesterase (AChE, E.C. 3.1.1.7) that break down acetylcholine (ACh) into choline and acetic acid leading to the loss of ACh which plays an essential role as neurotransmitter in Alzheimer disease. It was found that Arg-Cu CDs inhibited 74.9 ± 0.8% and Arg-Ag CDs inhibited 52.1 ± 3.8% of AChE at a 1.82 mg/mL concentration versus no inhibition for Arg-CD. Moreover, the chelating activity of Arg-Cu CDs and Arg-Ag CDs were tested for Fe(II) and it was found that almost 100% chelating was attained at 116 μg composites versus no measurable chelation for bare Arg CDs, suggesting the potential neurodegenerative disease treatment properties of these composite CDs in the brain.

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“…Wichur et al designed and synthesized novel 1-benzylpyrrolidine-3-amine-based BuChE and BACE-1 inhibitors with activities towards Aβ and tau protein aggregation, as well as concomitant antioxidant and metal-chelating properties [ 171 ] ( Figure 15 ).…”

Section: Multi-target Strategy For Admentioning

confidence: 99%

Perspectives for New and More Efficient Multifunctional Ligands for Alzheimer′s Disease Therapy

Zagórska

Jaromin

2020

Molecules

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Despite tremendous research efforts at every level, globally, there is still a lack of effective drugs for the treatment of Alzheimer′s disease (AD). The biochemical mechanisms of this devastating neurodegenerative disease are not yet clearly understood. This review analyses the relevance of multiple ligands in drug discovery for AD as a versatile toolbox for a polypharmacological approach to AD. Herein, we highlight major targets associated with AD, ranging from acetylcholine esterase (AChE), beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), glycogen synthase kinase 3 beta (GSK-3β), N-methyl-d-aspartate (NMDA) receptor, monoamine oxidases (MAOs), metal ions in the brain, 5-hydroxytryptamine (5-HT) receptors, the third subtype of histamine receptor (H3 receptor), to phosphodiesterases (PDEs), along with a summary of their respective relationship to the disease network. In addition, a multitarget strategy for AD is presented, based on reported milestones in this area and the recent progress that has been achieved with multitargeted-directed ligands (MTDLs). Finally, the latest publications referencing the enlarged panel of new biological targets for AD related to the microglia are highlighted. However, the question of how to find meaningful combinations of targets for an MTDLs approach remains unanswered.

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1-Benzylpyrrolidine-3-amine-based BuChE inhibitors with anti-aggregating, antioxidant and metal-chelating properties as multifunctional agents against Alzheimer’s disease

Cited by 40 publications

References 75 publications

Dual Inhibitors of Amyloid-β and Tau Aggregation with Amyloid-β Disaggregating Properties: Extended In Cellulo, In Silico, and Kinetic Studies of Multifunctional Anti-Alzheimer’s Agents

Dual Inhibitors of Amyloid-β and Tau Aggregation with Amyloid-β Disaggregating Properties: Extended In Cellulo, In Silico, and Kinetic Studies of Multifunctional Anti-Alzheimer’s Agents

Nitrogen-Doped Arginine Carbon Dots and Its Metal Nanoparticle Composites as Antibacterial Agent

Perspectives for New and More Efficient Multifunctional Ligands for Alzheimer′s Disease Therapy

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