Knez D


Full name : Knez Damanian

First name : Damanian

Mail : Faculty of Pharmacy, University of Ljubljana , Askerceva 7, 1000 Ljubljana

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Country : Slovenia

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References (40)

Title : Biological Evaluation of Valeriana Extracts from Argentina with Potent Cholinesterase Inhibition for the Treatment of Neurodegenerative Disorders and Their Comorbidities-The Case of Valeriana carnosa Sm. (Caprifoliaceae) Studied in Mice - Marcucci_2023_Pharmaceuticals.(Basel)_16_
Author(s) : Marcucci C , Rademacher M , Kamecki F , Pastore V , Bach HG , Ricco RA , Wagner ML , Knez D , Gobec S , Colettis N , Marder M
Ref : Pharmaceuticals (Basel) , 16 : , 2023
Abstract : Alzheimer's disease (AD) is a neurodegenerative disorder whose pathophysiology includes the abnormal accumulation of proteins (e.g., beta-amyloid), oxidative stress, and alterations in neurotransmitter levels, mainly acetylcholine. Here we present a comparative study of the effect of extracts obtained from endemic Argentinian species of valerians, namely V. carnosa Sm., V. clarionifolia Phil. and V. macrorhiza Poepp. ex DC from Patagonia and V. ferax (Griseb.) Hock and V. effusa Griseb., on different AD-related biological targets. Of these anxiolytic, sedative and sleep-inducing valerians, V. carnosa proved the most promising and was assayed in vivo. All valerians inhibited acetylcholinesterase (IC(50) between 1.08-12.69 mg/mL) and butyrylcholinesterase (IC(50) between 0.0019-1.46 mg/mL). They also inhibited the aggregation of beta-amyloid peptide, were able to chelate Fe(2+) ions, and exhibited a direct relationship between antioxidant capacity and phenolic content. Moreover, V. carnosa was able to inhibit human monoamine oxidase A (IC(50): 0.286 mg/mL (0.213-0.384)). A daily intake of aqueous V. carnosa extract by male Swiss mice (50 and 150 mg/kg/day) resulted in anxiolytic and antidepressant-like behavior and improved spatial memory. In addition, decreased AChE activity and oxidative stress markers were observed in treated mouse brains. Our studies contribute to the development of indigenous herbal medicines as therapeutic agents for AD.
ESTHER : Marcucci_2023_Pharmaceuticals.(Basel)_16_
PubMedSearch : Marcucci_2023_Pharmaceuticals.(Basel)_16_
PubMedID: 36678626

Title : Synthesis and Cholinesterase Inhibitory Activity of Selected Indole-Based Compounds - Groselj_2023_Acta.Chim.Slov_70_545
Author(s) : Groselj U , Grsic M , Meden A , Knez D , Jukic M , Svete J , Gobec S
Ref : Acta Chim Slov , 70 :545 , 2023
Abstract : Synthesis and anticholinesterase activity of 18 previously unpublished indole- and tryptophan-derived compounds are disclosed. These sp3-rich compounds containing an indole structural unit exhibit selective submicromolar inhibition of human butyrylcholinesterase (hBChE). The structures of the newly synthesized compounds were confirmed by 1H and 13C NMR, IR spectroscopy, and high-resolution mass spectrometry.
ESTHER : Groselj_2023_Acta.Chim.Slov_70_545
PubMedSearch : Groselj_2023_Acta.Chim.Slov_70_545
PubMedID: 38124635

Title : 8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases - Knez_2023_Acta.Pharmaceutica.Sinica.B_13_2152
Author(s) : Knez D , Diez-Iriepa D , Chioua M , Gottinger A , Denic M , Chantegreil F , Nachon F , Brazzolotto X , Skrzypczak-Wiercioch A , Meden A , Pislar A , Kos J , Zakelj S , Stojan J , Salat K , Serrano J , Patricia Fernandez AP , Sanchez-Garcia A , Martinez-Murillo R , Binda C , Lopez-Munoz F , Gobec S , Marco-Contelle J
Ref : Acta Pharmaceutica Sinica B , 13 :2152 , 2023
Abstract : We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase -hBChE) and monoamine oxidases (hMAO-A/B) for the therapy of neurodegenerative diseases. We identified QN 19, a simple, low molecular weight nitrone, that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde. Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition, yet unexpectedly showed potent inhibition of hBChE (IC50 = 1.06 +/- 0.31 nmol/L) and hMAO-B (IC50 = 4.46 +/- 0.18 micromol/L). The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding, which was further studied by enzyme kinetics. Compound 19 acted as a free radical scavenger and biometal chelator, crossed the blood-brain barrier, was not cytotoxic, and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease. In addition, in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination. Importantly, chronic treatment of double transgenic APPswe-PS1deltaE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN 19
ESTHER : Knez_2023_Acta.Pharmaceutica.Sinica.B_13_2152
PubMedSearch : Knez_2023_Acta.Pharmaceutica.Sinica.B_13_2152
PubMedID: 37250172
Gene_locus related to this paper: human-BCHE

Title : Repurposing of 8-Hydroxyquinoline-based Butyrylcholinesterase and Cathepsin B Ligands as Potent Non-peptidic Deoxyribonuclease I Inhibitors - Gajic_2022_ChemMedChem__
Author(s) : Gajic M , Knez D , Sosic I , Mravljak J , Meden A , Kosak U , Leitzbach L , George S , Hofmann B , Zivkovic A , Steinhilber D , Stark H , Gobec S , Smelcerovic A , Anderluh M
Ref : ChemMedChem , : , 2022
Abstract : A library of 31 butyrylcholinesterase (BChE) and cathepsin B (CatB) inhibitors, was screened in vitro for inhibition of deoxyribonuclease I (DNase I). Compounds 22, 8 and 7 are among the most potent synthetic non-peptide DNase I inhibitors reported up to date. Three 8-hydroxyquinoline analogues inhibited both DNase I and BChE with IC50 values below 35 microM and 50 nM, respectively, while 2 nitroxoline derivatives inhibited DNase I and Cat B endopeptidase activity with IC50 values below 60 microM and 20 microM, respectively. Selected derivatives were screened for various co-target binding affinities at dopamine D2 and D3, histamine H3 and H4 receptors and inhibition of 5-lipoxygenase. Compound 8 bound to the H3 receptor and is highlighted as the most promising multifunctional ligand with a favorable pharmacokinetic profile and one of the most potent non-peptide DNase I inhibitors. The present study demonstrates that 8-hydroxyquinoline is a structural fragment critical for DNase I inhibition in the presented series of compounds.
ESTHER : Gajic_2022_ChemMedChem__
PubMedSearch : Gajic_2022_ChemMedChem__
PubMedID: 34994078

Title : Screening of Big Pharma's Library against Various in-house Biological Targets - Knez_2022_Molecules_27_
Author(s) : Knez D , Gobec S , Hrast M
Ref : Molecules , 27 : , 2022
Abstract : Open innovation initiatives provide opportunities for collaboration and sharing of knowledge and experience between industry, academia, and government institutions. Through open innovation, Merck is offering a Mini Library of 80 carefully selected compounds from previous research and development projects to a broader scientific community for testing in academic drug discovery projects. These compounds are predominantly drug-like and cover a broad range of molecular targets. They could potentially interact with other enzymes, receptors, transporters, and ion channels of interest. The Mini Library was tested on seven in-house enzymes (bacterial MurA, MurC ligase, and DdlB enzyme, human MAO-A/B, human BChE, and murine AChE), and several hits were identified. A follow-up series of structural analogues provided by Merck gave a more detailed insight into the accessibility and the quality of the hit compounds. For example, sartan derivatives were moderate inhibitors of MurC, whereas bisarylureas were potent, selective, nanomolar inhibitors of hMAO-B. Importantly, 3-n-butyl-substituted indoles were identified as low nanomolar selective inhibitors of hBChE. All in all, the hit derivatives provide new starting points for the further exploration of the chemical space of high-quality enzyme inhibitors.
ESTHER : Knez_2022_Molecules_27_
PubMedSearch : Knez_2022_Molecules_27_
PubMedID: 35889355

Title : From tryptophan-based amides to tertiary amines: Optimization of a butyrylcholinesterase inhibitor series - Meden_2022_Eur.J.Med.Chem_230_114248
Author(s) : Meden A , Knez D , Brazzolotto X , Nachon F , Dias J , Svete J , Stojan J , Groselj U , Gobec S
Ref : Eur Journal of Medicinal Chemistry , 230 :114248 , 2022
Abstract : Lead optimization of a series of tryptophan-based nanomolar butyrylcholinesterase (BChE) inhibitors led to tertiary amines as highly potent, achiral, sp rich analogues with better synthetic accessibility and high selectivity over acetylcholinesterase (one to ten thousandfold) (Chierrito et al., 2018).. Taking it one step further, the introduction of a carbamate warhead on the well-explored reversible scaffold allowed conversion to pseudoirreversible inhibitors that bound covalently to BChE and prolonged the duration of inhibition (half-life of 14.8 h for compound 45a-carbamoylated enzyme). Additionally, N-hydroxyindole was discovered as a novel leaving group chemotype. The covalent mechanism of action was confirmed by time-dependency experiments, progress curve analysis, and indirectly by co-crystallization with the human recombinant enzyme. Two crystal structures of BChE-inhibitor complexes were solved and coupled with the supporting molecular dynamics simulations increased our understanding of the structure-activity relationship, while also providing the neccessary structural infromation for future optimization of this series. Overall, this research demonstates the high versatility and potential of this series of BChE inhibitors.
ESTHER : Meden_2022_Eur.J.Med.Chem_230_114248
PubMedSearch : Meden_2022_Eur.J.Med.Chem_230_114248
PubMedID: 35299116
Gene_locus related to this paper: human-BCHE

Title : Pseudo-irreversible butyrylcholinesterase inhibitors: Structure-activity relationships, computational and crystallographic study of the N-dialkyl O-arylcarbamate warhead - Meden_2022_Eur.J.Med.Chem_247_115048
Author(s) : Meden A , Knez D , Brazzolotto X , Modeste F , Perdih A , Pislar A , Zorman M , Zorovic M , Denic M , Pajk S , Zivin M , Nachon F , Gobec S
Ref : Eur Journal of Medicinal Chemistry , 247 :115048 , 2022
Abstract : Alongside reversible butyrylcholinesterase inhibitors, a plethora of covalent butyrylcholinesterase inhibitors have been reported in the literature, typically pseudo-irreversible carbamates. For these latter, however, most cases lack full confirmation of their covalent mode of action. Additionally, the available reports regarding the structure-activity relationships of the O-arylcarbamate warhead are incomplete. Therefore, a follow-up on a series of pseudo-irreversible covalent carbamate human butyrylcholinesterase inhibitors and the structure-activity relationships of the N-dialkyl O-arylcarbamate warhead are presented in this study. The covalent mechanism of binding was tested by IC(50) time-dependency profiles, and sequentially and increasingly confirmed by kinetic analysis, whole protein LC-MS, and crystallographic analysis. Computational studies provided valuable insights into steric constraints and identified problematic, bulky carbamate warheads that cannot reach and carbamoylate the catalytic Ser198. Quantum mechanical calculations provided further evidence that steric effects appear to be a key factor in determining the covalent binding behaviour of these carbamate cholinesterase inhibitors and their duration of action. Additionally, the introduction of a clickable terminal alkyne moiety into one of the carbamate N-substituents and in situ derivatisation with azide-containing fluorophore enabled fluorescent labelling of plasma human butyrylcholinesterase. This proof-of-concept study highlights the potential of this novel approach and for these compounds to be further developed as clickable molecular probes for investigating tissue localisation and activity of cholinesterases.
ESTHER : Meden_2022_Eur.J.Med.Chem_247_115048
PubMedSearch : Meden_2022_Eur.J.Med.Chem_247_115048
PubMedID: 36586299
Gene_locus related to this paper: human-BCHE

Title : Pseudo-irreversible butyrylcholinesterase inhibitors: SAR, kinetic, computational, and crystallographic study of the N-dialkyl O-arylcarbamate warhead - Meden_2022_Chemrxiv__
Author(s) : Meden A , Knez D , Brazzolotto X , Modeste F , Perdih A , Pislar A , Zorman M , Denic M , Pajk S , Nachon F , Gobec S
Ref : Chemrxiv , : , 2022
Abstract : Beside reversible butyrylcholinesterse inhibitors (BChEIs), a plethora of covalent ones, typically pseudo-irreversible carbamates, have been reported in literature. For the latter, however, in most cases the proper confirmation of their covalent mode of action is lacking. Additionally, the available reports on the structure-activity relationships of the O-arylcarbamate warhead are incomplete. Therefore, a follow-up on a series of pseudo-irreversible covalent carbamate human butyrylcholinesterase inhibitors (hBChEIs) and the structure-activity relationships of the N-dialkyl O-arylcarbamate warhead is presented. The covalent mechanism of binding was tested by IC50 time-dependency profiles, and sequentially and increasingly confirmed by kinetic analysis, whole protein LC-MS, and crystallographic evidence. The computational studies provided valuable insights into the steric constraints and identified problematic, bulky carbamate warheads that could not reach and carbamoylate the catalytic Ser198. QM calculations lent further evidence that the steric effects seemed to be a key factor in determining the covalent binding behaviour of these carbamate ChEIs and their duration of action. Furthermore, the introduction of a clickable terminal alkyne moiety into one of the carbamate N-substituents and in situ derivatization with an azide-containing fluorophore enabled fluorescent labelling of plasma hBChE. This proof-of-concept study highlighted the potential of this novel approach and these compounds to be further developed as clickable molecular probes for investigating tissue localization and activity of ChEs
ESTHER : Meden_2022_Chemrxiv__
PubMedSearch : Meden_2022_Chemrxiv__
Gene_locus related to this paper: human-BCHE

Title : N-Hydroxy-N-Propargylamide Derivatives of Ferulic Acid: Inhibitors of Cholinesterases and Monoamine Oxidases - Bautista-Aguilera_2022_Molecules_27_
Author(s) : Bautista-Aguilera M , Alonso JM , Catto M , Iriepa I , Knez D , Gobec S , Marco-Contelles J
Ref : Molecules , 27 : , 2022
Abstract : Alzheimer's disease (AD) is a complex disorder characterized by impaired neurotransmission in cholinergic and monoaminergic neurons, which, in combination with the accumulation of misfolded proteins and increased oxidative stress, leads to the typical features of the disease at the biomolecular level. Given the limited therapeutic success of approved drugs, it is imperative to explore rationally supported therapeutic approaches to combat this disease. The search for novel scaffolds that bind to different receptors and inhibit AD disease-related enzymes could lead to new therapeutic solutions. Here, we describe N-hydroxy-N-propargylamide hybrids 1-6, which were designed by combining the structures of Contilisant-a multifunctional anti-AD ligand-and ferulic acid, a natural antioxidant with various other biological activities. Among the synthesized compounds, we identified compound 4 as a micromolar inhibitor of hAChE with a potent radical-scavenging capacity comparable to resveratrol and Trolox. In addition, compound 4 chelated copper(II) ions associated with amyloid pathology, mitochondrial dysfunction, and oxidative stress. The promising in vitro activity combined with favorable drug-like properties and predicted blood-brain barrier permeability make compound 4 a multifunctional ligand that merits further studies at the biochemical and cellular levels.
ESTHER : Bautista-Aguilera_2022_Molecules_27_
PubMedSearch : Bautista-Aguilera_2022_Molecules_27_
PubMedID: 36364263

Title : Polyfunctionalized alpha-Phenyl-tert-butyl(benzyl)nitrones: Multifunctional Antioxidants for Stroke Treatment - Diez-Iriepa_2022_Antioxidants.(Basel)_11_
Author(s) : Diez-Iriepa D , Knez D , Gobec S , Iriepa I , de los Rios C , Bravo I , Lopez-Munoz F , Marco-Contelles J , Hadjipavlou-Litina D
Ref : Antioxidants (Basel) , 11 : , 2022
Abstract : Nowadays, most stroke patients are treated exclusively with recombinant tissue plasminogen activator, a drug with serious side effects and limited therapeutic window. For this reason, and because of the known effects of oxidative stress on stroke, a more tolerable and efficient therapy for stroke is being sought that focuses on the control and scavenging of highly toxic reactive oxygen species by appropriate small molecules, such as nitrones with antioxidant properties. In this context, herein we report here the synthesis, antioxidant, and neuroprotective properties of twelve novel polyfunctionalized alpha-phenyl-tert-butyl(benzyl)nitrones. The antioxidant capacity of these nitrones was investigated by various assays, including the inhibition of lipid peroxidation induced by AAPH, hydroxyl radical scavenging assay, ABTS(+)-decoloration assay, DPPH scavenging assay, and inhibition of soybean lipoxygenase. The inhibitory effect on monoamine oxidases and cholinesterases and inhibition of beta-amyloid aggregation were also investigated. As a result, (Z)-N-benzyl-1-(2-(3-(piperidin-1-yl)propoxy)phenyl)methanimine oxide (5) was found to be one of the most potent antioxidants, with high ABTS(+) scavenging activity (19%), and potent lipoxygenase inhibitory capacity (IC(50) = 10 microM), selectively inhibiting butyrylcholinesterase (IC(50) = 3.46 +/- 0.27 microM), and exhibited neuroprotective profile against the neurotoxicant okadaic acid in a neuronal damage model. Overall, these results pave the way for the further in-depth analysis of the neuroprotection of nitrone 5 in in vitro and in vivo models of stroke and possibly other neurodegenerative diseases in which oxidative stress is identified as a critical player.
ESTHER : Diez-Iriepa_2022_Antioxidants.(Basel)_11_
PubMedSearch : Diez-Iriepa_2022_Antioxidants.(Basel)_11_
PubMedID: 36139811

Title : Discovery of 1-(phenylsulfonyl)-1H-indole-based multifunctional ligands targeting cholinesterases and 5-HT(6) receptor with anti-aggregation properties against amyloid-beta and tau - Wichur_2021_Eur.J.Med.Chem_225_113783
Author(s) : Wichur T , Pasieka A , Godyn J , Panek D , Goral I , Latacz G , Honkisz-Orzechowska E , Bucki A , Siwek A , Gluch-Lutwin M , Knez D , Brazzolotto X , Gobec S , Kolaczkowski M , Sabate R , Malawska B , Wieckowska A
Ref : Eur Journal of Medicinal Chemistry , 225 :113783 , 2021
Abstract : Multifunctional ligands as an essential variant of polypharmacology are promising candidates for the treatment of multi-factorial diseases like Alzheimer's disease. Based on clinical evidence and following the paradigm of multifunctional ligands we have rationally designed and synthesized a series of compounds targeting processes involved in the development of the disease. The biological evaluation led to the discovery of two compounds with favorable pharmacological characteristics and ADMET profile. Compounds 17 and 35 are 5-HT(6)R antagonists (K(i) = 13 nM and K(i) = 15 nM respectively) and cholinesterase inhibitors with distinct mechanisms of enzyme inhibition. Compound 17, a tacrine derivative is a reversible inhibitor of acetyl- and butyrylcholinesterase (IC(50) = 8 nM and IC(50) = 24 nM respectively), while compound 35 with rivastigmine-derived phenyl N-ethyl-N-methylcarbamate fragment is a selective, pseudo-irreversible inhibitor of butyrylcholinesterase (IC(50) = 455 nM). Both compounds inhibit aggregation of amyloid beta in vitro (75% for compound 17 and 68% for 35 at 10 microM) moreover, compound 35 is a potent tau aggregation inhibitor in cellulo (79%). In ADMET in vitro studies both compounds showed acceptable metabolic stability on mouse liver microsomes (28% and 60% for compound 17 and 35 respectively), no or little effect on CYP3A4 and 2D6 up to a concentration of 10 microM and lack of toxicity on HepG2 cell line (IC(50) values of 80 and 21 microM, for 17 and 35 respectively). Based on the pharmacological characteristics and favorable pharmacokinetic properties, we propose compounds 17 and 35 as an excellent starting point for further optimization and in-depth biological studies.
ESTHER : Wichur_2021_Eur.J.Med.Chem_225_113783
PubMedSearch : Wichur_2021_Eur.J.Med.Chem_225_113783
PubMedID: 34461507

Title : Longitudinal evaluation of a novel BChE PET tracer as an early in vivo biomarker in the brain of a mouse model for Alzheimer disease - Rejc_2021_Theranostics_11_6542
Author(s) : Rejc L , Gomez-Vallejo V , Joya A , Moreno O , Egimendia A , Castellnou P , Rios-Anglada X , Cossio U , Baz Z , Passannante R , Tobalina-Larrea I , Ramos-Cabrer P , Giralt A , Sastre M , Capetillo-Zarate E , Kosak U , Knez D , Gobec S , Marder M , Martin A , Llop J
Ref : Theranostics , 11 :6542 , 2021
Abstract : Purpose: The increase in butyrylcholinesterase (BChE) activity in the brain of Alzheimer disease (AD) patients and animal models of AD position this enzyme as a potential biomarker of the disease. However, the information on the ability of BChE to serve as AD biomarker is contradicting, also due to scarce longitudinal studies of BChE activity abundance. Here, we report (11)C-labeling, in vivo stability, biodistribution, and longitudinal study on BChE abundance in the brains of control and 5xFAD (AD model) animals, using a potent BChE selective inhibitor, [(11)C]4, and positron emission tomography (PET) in combination with computerised tomography (CT). We correlate the results with in vivo amyloid beta (Abeta) deposition, longitudinally assessed by [(18)F]florbetaben-PET imaging. Methods: [(11)C]4 was radiolabelled through (11)C-methylation. Metabolism studies were performed on blood and brain samples of female wild type (WT) mice. Biodistribution studies were performed in female WT mice using dynamic PET-CT imaging. Specific binding was demonstrated by ex vivo and in vivo PET imaging blocking studies in female WT and 5xFAD mice at the age of 7 months. Longitudinal PET imaging of BChE was conducted in female 5xFAD mice at 4, 6, 8, 10 and 12 months of age and compared to age-matched control animals. Additionally, Abeta plaque distribution was assessed in the same mice using [(18)F]florbetaben at the ages of 2, 5, 7 and 11 months. The results were validated by ex vivo staining of BChE at 4, 8, and 12 months and Abeta at 12 months on brain samples. Results: [(11)C]4 was produced in sufficient radiochemical yield and molar activity for the use in PET imaging. Metabolism and biodistribution studies confirmed sufficient stability in vivo, the ability of [(11)C]4 to cross the blood brain barrier (BBB) and rapid washout from the brain. Blocking studies confirmed specificity of the binding. Longitudinal PET studies showed increased levels of BChE in the cerebral cortex, hippocampus, striatum, thalamus, cerebellum and brain stem in aged AD mice compared to WT littermates. [(18)F]Florbetaben-PET imaging showed similar trend of Abeta plaques accumulation in the cerebral cortex and the hippocampus of AD animals as the one observed for BChE at ages 4 to 8 months. Contrarily to the results obtained by ex vivo staining, lower abundance of BChE was observed in vivo at 10 and 12 months than at 8 months of age. Conclusions: The BChE inhibitor [(11)C]4 crosses the BBB and is quickly washed out of the brain of WT mice. Comparison between AD and WT mice shows accumulation of the radiotracer in the AD-affected areas of the brain over time during the early disease progression. The results correspond well with Abeta accumulation, suggesting that BChE is a promising early biomarker for incipient AD.
ESTHER : Rejc_2021_Theranostics_11_6542
PubMedSearch : Rejc_2021_Theranostics_11_6542
PubMedID: 33995675

Title : Synthesis and Initial Characterization of a Reversible, Selective (18)F-Labeled Radiotracer for Human Butyrylcholinesterase - Gentzsch_2021_Mol.Imaging.Biol__
Author(s) : Gentzsch C , Chen X , Spatz P , Kosak U , Knez D , Nose N , Gobec S , Higuchi T , Decker M
Ref : Mol Imaging Biol , : , 2021
Abstract : PURPOSE: A neuropathological hallmark of Alzheimer's disease (AD) is the presence of amyloid-beta (Abeta) plaques in the brain, which are observed in a significant number of cognitively normal, older adults as well. In AD, butyrylcholinesterase (BChE) becomes associated with A(beta) aggregates, making it a promising target for imaging probes to support diagnosis of AD. In this study, we present the synthesis, radiochemistry, in vitro and preliminary ex and in vivo investigations of a selective, reversible BChE inhibitor as PET-tracer for evaluation as an AD diagnostic. PROCEDURES: Radiolabeling of the inhibitor was achieved by fluorination of a respective tosylated precursor using K[(18)F]. IC(50) values of the fluorinated compound were obtained in a colorimetric assay using recombinant, human (h) BChE. Dissociation constants were determined by measuring hBChE activity in the presence of different concentrations of inhibitor. RESULTS: Radiofluorination of the tosylate precursor gave the desired radiotracer in an average radiochemical yield of 20 +/- 3 %. Identity and > 95.5 % radiochemical purity were confirmed by HPLC and TLC autoradiography. The inhibitory potency determined in Ellman's assay gave an IC(50) value of 118.3 +/- 19.6 nM. Dissociation constants measured in kinetic experiments revealed lower affinity of the inhibitor for binding to the acylated enzyme (K(2) = 68.0 nM) in comparison to the free enzyme (K(1) = 32.9 nM). CONCLUSIONS: The reversibly acting, selective radiotracer is synthetically easily accessible and retains promising activity and binding potential on hBChE. Radiosynthesis with (18)F labeling of tosylates was feasible in a reasonable time frame and good radiochemical yield.
ESTHER : Gentzsch_2021_Mol.Imaging.Biol__
PubMedSearch : Gentzsch_2021_Mol.Imaging.Biol__
PubMedID: 33660167

Title : 4-Phenethyl-1-Propargylpiperidine-Derived Dual Inhibitors of Butyrylcholinesterase and Monoamine Oxidase B - Mazej_2021_Molecules_26_
Author(s) : Mazej T , Knez D , Meden A , Gobec S , Sova M
Ref : Molecules , 26 : , 2021
Abstract : 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 (IC(50) of 4.3 microM) and hBChE (IC(50) of 8.5 microM). 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.
ESTHER : Mazej_2021_Molecules_26_
PubMedSearch : Mazej_2021_Molecules_26_
PubMedID: 34299393

Title : Multitarget 2'-hydroxychalcones as potential drugs for the treatment of neurodegenerative disorders and their comorbidities - Kamecki_2021_Neuropharmacol_201_108837
Author(s) : Kamecki F , Knez D , Carvalho D , Marcucci C , Rademacher M , Higgs J , akelj S , Marcos A , de Tezanos Pinto F , Abin-Carriquiry JA , Gobec S , Colettis N , Marder M
Ref : Neuropharmacology , 201 :108837 , 2021
Abstract : The complex nature of neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD) calls for multidirectional treatment. Restoring neurotransmitter levels by combined inhibition of cholinesterases (ChEs) and monoamine oxidases (MAOs, MAO-A and MAO-B), in conjunction with strategies to counteract amyloid beta (Abeta) aggregation, may constitute a therapeutically strong multi-target approach for the treatment of NDDs. Chalcones are a subgroup of flavonoids with a broad spectrum of biological activity. We report here the synthesis of 2'-hydroxychalcones as MAO-A and MAO-B inhibitors. Compounds 5c (IC(50) = 0.031 +/- 0.001 microM), 5a (IC(50) = 0.084 +/- 0.003 microM), 2c (IC(50) = 0.095 +/- 0.019 microM) and 2a (IC(50) = 0.111 +/- 0.006 microM) were the most potent, selective and reversible inhibitors of human (h)MAO-B isoform. hMAO-B inhibitors 1a, 2a and 5a also inhibited murine MAO-B in vivo in mouse brain homogenates. Molecular modelling rationalised the binding mode of 2'-hydroxychalcones in the active site of hMAO-B. Additionally, several derivatives inhibited murine acetylcholinesterase (mAChE) (IC(50) values from 4.37 +/- 0.83 microM to 15.17 +/- 6.03 microM) and reduced the aggregation propensity of Abeta. Moreover, some derivatives bound to the benzodiazepine binding site (BDZ-bs) of the gamma-aminobutyric acid A (GABA(A)) receptors (1a and 2a with K(i) = 4.9 +/- 1.1 microM and 5.0 +/- 1.1 microM, respectively), and exerted sedative and/or anxiolytic like effects on mice. The biological results reported here on 2'-hydroxychalcones provide an extension to previous studies on chalcone scaffold and show them as a potential treatment strategy for NDDs and their associated comorbidities.
ESTHER : Kamecki_2021_Neuropharmacol_201_108837
PubMedSearch : Kamecki_2021_Neuropharmacol_201_108837
PubMedID: 34653442

Title : Development and crystallography-aided SAR studies of multifunctional BuChE inhibitors and 5-HT6R antagonists with beta-amyloid anti-aggregation properties - Wichur_2021_Eur.J.Med.Chem_225_113792
Author(s) : Wichur T , Godyn J , Goral I , Latacz G , Bucki A , Siwek A , Gluch-Lutwin M , Mordyl B , Sniecikowska J , Walczak M , Knez D , Jukic M , Salat K , Gobec S , Kolaczkowski M , Malawska B , Brazzolotto X , Wieckowska A
Ref : Eur Journal of Medicinal Chemistry , 225 :113792 , 2021
Abstract : The lack of an effective treatment makes Alzheimer's disease a serious healthcare problem and a challenge for medicinal chemists. Herein we report interdisciplinary research on novel multifunctional ligands targeting proteins and processes involved in the development of the disease: BuChE, 5-HT6 receptors and beta-amyloid aggregation. Structure-activity relationship analyses supported by crystallography and docking studies led to the identification of a fused-type multifunctional ligand 50, with remarkable and balanced potencies against BuChE (IC50 = 90 nM) and 5-HT6R (Ki = 4.8 nM), and inhibitory activity against Abeta aggregation (53% at 10 microM). In in vitro ADME-Tox and in vivo pharmacokinetic studies compound 50 showed good stability in the mouse liver microsomes, favourable safety profile and brain permeability with the brain to plasma ratio of 6.79 after p.o. administration in mice, thus being a promising candidate for in vivo pharmacology studies and a solid foundation for further research on effective anti-AD therapies.
ESTHER : Wichur_2021_Eur.J.Med.Chem_225_113792
PubMedSearch : Wichur_2021_Eur.J.Med.Chem_225_113792
PubMedID: 34530376
Gene_locus related to this paper: human-BCHE

Title : Discovery of multifunctional anti-Alzheimers agents with a unique mechanism of action including inhibition of the enzyme butyrylcholinesterase and gamma-aminobutyric acid transporters - Pasieka_2021_Eur.J.Med.Chem_218_113397
Author(s) : Pasieka A , Panek D , Jonczyk J , Godyn J , Szalaj N , Latacz G , Tabor J , Mezeiova E , Chantegreil F , Dias J , Knez D , Lu J , Pi R , Korabecny J , Brazzolotto X , Gobec S , Hofner G , Wanner K , Wieckowska Q , Malawska B
Ref : Eur Journal of Medicinal Chemistry , 218 :113397 , 2021
Abstract : Looking for an effective anti-Alzheimer's agent is very challenging; however, a multifunctional ligand strategy may be a promising solution for the treatment of this complex disease. We herein present the design, synthesis and biological evaluation of novel hydroxyethylamine derivatives displaying unique, multiple properties that have not been previously reported. The original mechanism of action combines inhibitory activity against disease-modifying targets: beta-secretase enzyme (BACE1) and amyloid beta (Abeta) aggregation, along with an effect on targets associated with symptom relief - inhibition of butyrylcholinesterase (BuChE) and gamma-aminobutyric acid transporters (GATs). Among the obtained molecules, compound 36 exhibited the most balanced and broad activity profile (eeAChE IC50 = 2.86 microM; eqBuChE IC50 = 60 nM; hBuChE IC50 = 20 nM; hBACE1 IC50 = 5.9 microM; inhibition of Abeta aggregation = 57.9% at 10 microM; mGAT1 IC50 = 10.96 microM; and mGAT2 IC50 = 19.05 microM). Moreover, we also identified 31 as the most potent mGAT4 and hGAT3 inhibitor (IC50 = 5.01 microM and IC50 = 2.95 microM, respectively), with high selectivity over other subtypes. Compounds 36 and 31 represent new anti-Alzheimer agents that can ameliorate cognitive decline and modify the progress of disease.
ESTHER : Pasieka_2021_Eur.J.Med.Chem_218_113397
PubMedSearch : Pasieka_2021_Eur.J.Med.Chem_218_113397
PubMedID: 33838585

Title : Structure-activity relationship study of tryptophan-based butyrylcholinesterase inhibitors - Meden_2020_Eur.J.Med.Chem_208_112766
Author(s) : Meden A , Knez D , Malikowska-Racia N , Brazzolotto X , Nachon F , Svete J , Salat K , Groselj U , Gobec S
Ref : Eur Journal of Medicinal Chemistry , 208 :112766 , 2020
Abstract : A series of tryptophan-based selective nanomolar butyrylcholinesterase (BChE) inhibitors was designed and synthesized. Compounds were optimized in terms of potency, selectivity, and synthetic accessibility. The crystal structure of the inhibitor 18 in complex with BChE revealed the molecular basis for its low nanomolar inhibition (IC50 = 2.8 nM). The favourable in vitro results enabled a first-in-animal in vivo efficacy and safety trial, which demonstrated a positive impact on fear-motivated and spatial long-term memory retrieval without any concomitant adverse motor effects. Altogether, this research culminated in a handful of new lead compounds with promising potential for symptomatic treatment of patients with Alzheimers disease.
ESTHER : Meden_2020_Eur.J.Med.Chem_208_112766
PubMedSearch : Meden_2020_Eur.J.Med.Chem_208_112766
PubMedID: 32919297
Gene_locus related to this paper: human-BCHE

Title : N-alkylpiperidine carbamates as potential anti-Alzheimer's agents - Kosak_2020_Eur.J.Med.Chem_197_112282
Author(s) : Kosak U , Strasek N , Knez N , Jukic M , Zakelj S , Zahirovic A , Pislar A , Brazzolotto X , Nachon F , Kos J , Gobec S , Knez D
Ref : Eur Journal of Medicinal Chemistry , 197 :112282 , 2020
Abstract : Compounds capable of interacting with single or multiple targets involved in Alzheimer's disease (AD) pathogenesis are potential anti-Alzheimer's agents. In our aim to develop new anti-Alzheimer's agents, a series of 36 new N-alkylpiperidine carbamates was designed, synthesized and evaluated for the inhibition of cholinesterases [acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)] and monoamine oxidases [monoamine oxidase A (MAO-A and monoamine oxidase B (MAO-B)]. Four compounds are very promising: multiple AChE (IC50 = 7.31 muM), BChE (IC50 = 0.56 muM) and MAO-B (IC50 = 26.1 muM) inhibitor 10, dual AChE (IC50 = 2.25 muM) and BChE (IC50 = 0.81 muM) inhibitor 22, selective BChE (IC50 = 0.06 muM) inhibitor 13, and selective MAO-B (IC50 = 0.18 muM) inhibitor 16. Results of enzyme kinetics experiments showed that despite the carbamate group in the structure, compounds 10, 13, and 22 are reversible and non-time-dependent inhibitors of AChE and/or BChE. The resolved crystal structure of the complex of BChE with compound 13 confirmed the non-covalent mechanism of inhibition. Additionally, N-propargylpiperidine 16 is an irreversible and time-dependent inhibitor of MAO-B, while N-benzylpiperidine 10 is reversible. Additionally, compounds 10, 13, 16, and 22 should be able to cross the blood-brain barrier and are not cytotoxic to human neuronal-like SH-SY5Y and liver HepG2 cells. Finally, compounds 10 and 16 also prevent amyloid beta1-42 (Abeta1-42)-induced neuronal cell death. The neuroprotective effects of compound 16 could be the result of its Abeta1-42 anti-aggregation effects.
ESTHER : Kosak_2020_Eur.J.Med.Chem_197_112282
PubMedSearch : Kosak_2020_Eur.J.Med.Chem_197_112282
PubMedID: 32380361
Gene_locus related to this paper: human-BCHE

Title : Development of potent reversible selective inhibitors of butyrylcholinesterase as fluorescent probes - Pajk_2020_J.Enzyme.Inhib.Med.Chem_35_498
Author(s) : Pajk S , Knez D , Kosak U , Zorovic M , Brazzolotto X , Coquelle N , Nachon F , Colletier JP , Zivin M , Stojan J , Gobec S
Ref : J Enzyme Inhib Med Chem , 35 :498 , 2020
Abstract : Brain butyrylcholinesterase (BChE) is an attractive target for drugs designed for the treatment of Alzheimer's disease (AD) in its advanced stages. It also potentially represents a biomarker for progression of this disease. Based on the crystal structure of previously described highly potent, reversible, and selective BChE inhibitors, we have developed the fluorescent probes that are selective towards human BChE. The most promising probes also maintain their inhibition of BChE in the low nanomolar range with high selectivity over acetylcholinesterase. Kinetic studies of probes reveal a reversible mixed inhibition mechanism, with binding of these fluorescent probes to both the free and acylated enzyme. Probes show environment-sensitive emission, and additionally, one of them also shows significant enhancement of fluorescence intensity upon binding to the active site of BChE. Finally, the crystal structures of probes in complex with human BChE are reported, which offer an excellent base for further development of this library of compounds.
ESTHER : Pajk_2020_J.Enzyme.Inhib.Med.Chem_35_498
PubMedSearch : Pajk_2020_J.Enzyme.Inhib.Med.Chem_35_498
PubMedID: 31914836
Gene_locus related to this paper: human-BCHE

Title : 1-Benzylpyrrolidine-3-amine-based BuChE inhibitors with anti-aggregating, antioxidant and metal-chelating properties as multifunctional agents against Alzheimer's disease - Wichur_2019_Eur.J.Med.Chem_187_111916
Author(s) : Wichur T , Wieckowska A , Wieckowski K , Godyn J , Jonczyk J , Valdivieso ADR , Panek D , Pasieka A , Sabate R , Knez D , Gobec S , Malawska B
Ref : Eur Journal of Medicinal Chemistry , 187 :111916 , 2019
Abstract : Complex pathomechanism of Alzheimer's disease (AD) prompts researchers to develop multifunctional molecules in order to find effective therapy against AD. We designed and synthesized novel multifunctional ligands for which we assessed their activities towards butyrylcholinesterase, beta secretase, amyloid beta (Abeta) and tau protein aggregation as well as antioxidant and metal-chelating properties. All compounds showed dual anti-aggregating properties towards Abeta and tau protein in the in cellulo assay in Escherichia coli. Of particular interest are compounds 24b and 25b, which efficiently inhibit aggregation of Abeta and tau protein at 10 muM (24b: 45% for Abeta, 53% for tau; 25b: 49% for Abeta, 54% for tau). They display free radical scavenging capacity and antioxidant activity in ABTS and FRAP assays, respectively, and selectively chelate copper ions. Compounds 24b and 25b are also the most potent inhibitors of BuChE with IC50 of 2.39 muM and 1.94 muM, respectively. Promising in vitro activities of the presented multifunctional ligands as well as their original scaffold are a very interesting starting point for further research towards effective anti-AD treatment.
ESTHER : Wichur_2019_Eur.J.Med.Chem_187_111916
PubMedSearch : Wichur_2019_Eur.J.Med.Chem_187_111916
PubMedID: 31812794

Title : Biological Evaluation of 8-Hydroxyquinolines as Multi-Target Directed Ligands for Treating Alzheimer's Disease - Knez_2019_Curr.Alzheimer.Res_16_801
Author(s) : Knez D , Sosic I , Pislar A , Mitrovic A , Jukic M , Kos J , Gobec S
Ref : Curr Alzheimer Res , 16 :801 , 2019
Abstract : BACKGROUND: Accumulating evidence suggests that multi-target directed ligands have great potential for the treatment of complex diseases such as Alzheimer's Disease (AD). OBJECTIVE: To evaluate novel chimeric 8-hydroxyquinoline ligands with merged pharmacophores as potential multifunctional ligands for AD. METHODS: Nitroxoline, PBT2 and compounds 2-4 were evaluated in-vitro for their inhibitory potencies on cathepsin B, cholinesterases, and monoamine oxidases. Furthermore, chelation, antioxidative properties and the permeability of Blood-Brain Barrier (BBB) were evaluated by spectroscopy-based assays and the inhibition of Amyloid beta (Abeta) aggregation was determined in immunoassay. Cell-based assays were performed to determine cytotoxicity, neuroprotection against toxic Abeta species, and the effects of compound 2 on apoptotic cascade. RESULTS: Compounds 2-4 competitively inhibited cathepsin B beta-secretase activity, chelated metal ions and were weak antioxidants. All of the compounds inhibited Abeta aggregation, whereas only compound 2 had a good BBB permeability according to the parallel artificial membrane permeability assay. Tested ligands 2 and 3 were not cytotoxic to SH-SY5Y and HepG2 cells at 10 muM. Compound 2 exerted neuroprotective effects towards Abeta toxicity, reduced the activation of caspase-3/7 and diminished the apoptosis of cells treated with Abeta1-42. CONCLUSION: Taken together, our data suggest that compound 2 holds a promise to be used as a multifunctional ligand for AD.
ESTHER : Knez_2019_Curr.Alzheimer.Res_16_801
PubMedSearch : Knez_2019_Curr.Alzheimer.Res_16_801
PubMedID: 31660830

Title : Tryptophan-derived butyrylcholinesterase inhibitors as promising leads against Alzheimer's disease - Meden_2019_Chem.Commun.(Camb)_55_3765
Author(s) : Meden A , Knez D , Jukic M , Brazzolotto X , Grsic M , Pislar A , Zahirovic A , Kos J , Nachon F , Svete J , Gobec S , Groselj U
Ref : Chem Commun (Camb) , 55 :3765 , 2019
Abstract : We have identified tryptophan-based selective nanomolar butyrylcholinesterase (BChE) inhibitors. They are defined according to their chemical modularity, novel binding mode revealed by five solved crystal structures with human BChE, low cytotoxicity, and predicted permeability of the blood-brain barrier. Altogether, these factors indicate their potential as unique lead compounds for symptomatic therapy against Alzheimer's disease.
ESTHER : Meden_2019_Chem.Commun.(Camb)_55_3765
PubMedSearch : Meden_2019_Chem.Commun.(Camb)_55_3765
PubMedID: 30864579
Gene_locus related to this paper: human-BCHE

Title : Multi-target-directed ligands for treating Alzheimer's disease: Butyrylcholinesterase inhibitors displaying antioxidant and neuroprotective activities - Knez_2018_Eur.J.Med.Chem_156_598
Author(s) : Knez D , Coquelle N , Pislar A , Zakelj S , Jukic M , Sova M , Mravljak J , Nachon F , Brazzolotto X , Kos J , Colletier JP , Gobec S
Ref : Eur Journal of Medicinal Chemistry , 156 :598 , 2018
Abstract : The limited clinical efficacy of current symptomatic treatment and minute effect on progression of Alzheimer's disease has shifted the research focus from single targets towards multi-target-directed ligands. Here, a potent selective inhibitor of human butyrylcholinesterase was used as the starting point to develop a new series of multifunctional ligands. A focused library of derivatives was designed and synthesised that showed both butyrylcholinesterase inhibition and good antioxidant activity as determined by the DPPH assay. The crystal structure of compound 11 in complex with butyrylcholinesterase revealed the molecular basis for its low nanomolar inhibition of butyrylcholinesterase (Ki=1.09+/-0.12nM). In addition, compounds 8 and 11 show metal-chelating properties, and reduce the redox activity of chelated Cu(2+) ions in a Cu-ascorbate redox system. Compounds 8 and 11 decrease intracellular levels of reactive oxygen species, and are not substrates of the active efflux transport system, as determined in Caco2 cells. Compound 11 also protects neuroblastoma SH-SY5Y cells from toxic Abeta1-42 species. These data indicate that compounds 8 and 11 are promising multifunctional lead ligands for treatment of Alzheimer's disease.
ESTHER : Knez_2018_Eur.J.Med.Chem_156_598
PubMedSearch : Knez_2018_Eur.J.Med.Chem_156_598
PubMedID: 30031971
Gene_locus related to this paper: human-BCHE

Title : The Magic of Crystal Structure-Based Inhibitor Optimization: Development of a Butyrylcholinesterase Inhibitor with Picomolar Affinity and in Vivo Activity - Kosak_2018_J.Med.Chem_61_119
Author(s) : Kosak U , Brus B , Knez D , Zakelj S , Trontelj J , Pislar A , Sink R , Jukic M , Zivin M , Podkowa A , Nachon F , Brazzolotto X , Stojan J , Kos J , Coquelle N , Salat K , Colletier JP , Gobec S
Ref : Journal of Medicinal Chemistry , 61 :119 , 2018
Abstract : The enzymatic activity of butyrylcholinesterase (BChE) in the brain increases with the progression of Alzheimer's disease, thus classifying BChE as a promising drug target in advanced Alzheimer's disease. We used structure-based drug discovery approaches to develop potent, selective, and reversible human BChE inhibitors. The most potent, compound 3, had a picomolar inhibition constant versus BChE due to strong cation-pi interactions, as revealed by the solved crystal structure of its complex with human BChE. Additionally, compound 3 inhibits BChE ex vivo and is noncytotoxic. In vitro pharmacokinetic experiments show that compound 3 is highly protein bound, highly permeable, and metabolically stable. Finally, compound 3 crosses the blood-brain barrier, and it improves memory, cognitive functions, and learning abilities of mice in a scopolamine model of dementia. Compound 3 is thus a promising advanced lead compound for the development of drugs for alleviating symptoms of cholinergic hypofunction in patients with advanced Alzheimer's disease.
ESTHER : Kosak_2018_J.Med.Chem_61_119
PubMedSearch : Kosak_2018_J.Med.Chem_61_119
PubMedID: 29227101
Gene_locus related to this paper: human-BCHE

Title : Novel Multitarget-Directed Ligands Aiming at Symptoms and Causes of Alzheimer's Disease - Wieckowska_2018_ACS.Chem.Neurosci_9_1195
Author(s) : Wieckowska A , Wichur T , Godyn J , Bucki A , Marcinkowska M , Siwek A , Wieckowski K , Zareba P , Knez D , Gluch-Lutwin M , Kazek G , Latacz G , Mika K , Kolaczkowski M , Korabecny J , Soukup O , Benkova M , Kiec-Kononowicz K , Gobec S , Malawska B
Ref : ACS Chem Neurosci , 9 :1195 , 2018
Abstract : Alzheimer's disease (AD) is a major public health problem, which is due to its increasing prevalence and lack of effective therapy or diagnostics. The complexity of the AD pathomechanism requires complex treatment, e.g. multifunctional ligands targeting both the causes and symptoms of the disease. Here, we present new multitarget-directed ligands combining pharmacophore fragments that provide a blockade of serotonin 5-HT6 receptors, acetyl/butyrylcholinesterase inhibition, and amyloid beta antiaggregation activity. Compound 12 has displayed balanced activity as an antagonist of 5-HT6 receptors ( Ki = 18 nM) and noncompetitive inhibitor of cholinesterases (IC50 hAChE = 14 nM, IC50 eqBuChE = 22 nM). In further in vitro studies, compound 12 has shown amyloid beta antiaggregation activity (IC50 = 1.27 muM) and ability to permeate through the blood-brain barrier. The presented findings may provide an excellent starting point for further studies and facilitate efforts to develop new effective anti-AD therapy.
ESTHER : Wieckowska_2018_ACS.Chem.Neurosci_9_1195
PubMedSearch : Wieckowska_2018_ACS.Chem.Neurosci_9_1195
PubMedID: 29384656

Title : Design, Synthesis, and Biological Evaluation of 2-(Benzylamino-2-Hydroxyalkyl)Isoindoline-1,3-Diones Derivatives as Potential Disease-Modifying Multifunctional Anti-Alzheimer Agents - Panek_2018_Molecules_23_
Author(s) : Panek D , Wieckowska A , Pasieka A , Godyn J , Jonczyk J , Bajda M , Knez D , Gobec S , Malawska B
Ref : Molecules , 23 : , 2018
Abstract : The complex nature of Alzheimer's disease calls for multidirectional treatment. Consequently, the search for multi-target-directed ligands may lead to potential drug candidates. The aim of the present study is to seek multifunctional compounds with expected activity against disease-modifying and symptomatic targets. A series of 15 drug-like various substituted derivatives of 2-(benzylamino-2-hydroxyalkyl)isoindoline-1,3-diones was designed by modification of cholinesterase inhibitors toward beta-secretase inhibition. All target compounds have been synthesized and tested against eel acetylcholinesterase (eeAChE), equine serum butyrylcholinesterase (eqBuChE), human beta-secretase (hBACE-1), and beta-amyloid (Abeta-aggregation). The most promising compound, 12 (2-(5-(benzylamino)-4-hydroxypentyl)isoindoline-1,3-dione), displayed inhibitory potency against eeAChE (IC50 = 3.33 muM), hBACE-1 (43.7% at 50 muM), and Abeta-aggregation (24.9% at 10 muM). Molecular modeling studies have revealed possible interaction of compound 12 with the active sites of both enzymes-acetylcholinesterase and beta-secretase. IN CONCLUSION: modifications of acetylcholinesterase inhibitors led to the discovery of a multipotent anti-Alzheimer's agent, with moderate and balanced potency, capable of inhibiting acetylcholinesterase, a symptomatic target, and disease-modifying targets: beta-secretase and Abeta-aggregation.
ESTHER : Panek_2018_Molecules_23_
PubMedSearch : Panek_2018_Molecules_23_
PubMedID: 29414887

Title : Design, Synthesis, and Biological Evaluation of 1-Benzylamino-2-hydroxyalkyl Derivatives as New Potential Disease-Modifying Multifunctional Anti-Alzheimer's Agents - Panek_2018_ACS.Chem.Neurosci_9_1074
Author(s) : Panek D , Wieckowska A , Jonczyk J , Godyn J , Bajda M , Wichur T , Pasieka A , Knez D , Pislar A , Korabecny J , Soukup O , Sepsova V , Sabate R , Kos J , Gobec S , Malawska B
Ref : ACS Chem Neurosci , 9 :1074 , 2018
Abstract : The multitarget approach is a promising paradigm in drug discovery, potentially leading to new treatment options for complex disorders, such as Alzheimer's disease. Herein, we present the discovery of a unique series of 1-benzylamino-2-hydroxyalkyl derivatives combining inhibitory activity against butyrylcholinesterase, beta-secretase, beta-amyloid, and tau protein aggregation, all related to mechanisms which underpin Alzheimer's disease. Notably, diphenylpropylamine derivative 10 showed balanced activity against both disease-modifying targets, inhibition of beta-secretase (IC50 hBACE-1 = 41.60 muM), inhibition of amyloid beta aggregation (IC50 Abeta = 3.09 muM), inhibition of tau aggregation (55% at 10 muM); as well as against symptomatic targets, butyrylcholinesterase inhibition (IC50 hBuChE = 7.22 muM). It might represent an encouraging starting point for development of multifunctional disease-modifying anti-Alzheimer's agents.
ESTHER : Panek_2018_ACS.Chem.Neurosci_9_1074
PubMedSearch : Panek_2018_ACS.Chem.Neurosci_9_1074
PubMedID: 29345897

Title : Dual inhibitors of cholinesterases and monoamine oxidases for Alzheimer's disease - Knez_2017_Future.Med.Chem_9_811
Author(s) : Knez D , Sova M , Kosak U , Gobec S
Ref : Future Med Chem , 9 :811 , 2017
Abstract : Accumulating evidence indicates a solid relationship between several enzymes and Alzheimer's disease. Cholinesterases and monoamine oxidases are closely associated with the disease symptomatology and progression and have been tackled simultaneously using several multifunctional ligands. This design strategy offers great chances to alter the course of Alzheimer's disease, in addition to alleviation of the symptoms. More than 15 years of research has led to the identification of various dual cholinesterase/monoamine oxidase inhibitors, while some showing positive outcomes in clinical trials, thus giving rise to additional research efforts in the field. The aim of this review is to provide an update on the novel dual inhibitors identified recently and to shed light on their therapeutic potential.
ESTHER : Knez_2017_Future.Med.Chem_9_811
PubMedSearch : Knez_2017_Future.Med.Chem_9_811
PubMedID: 28504893

Title : N-Propargylpiperidines with naphthalene-2-carboxamide or naphthalene-2-sulfonamide moieties: Potential multifunctional anti-Alzheimer's agents - Kosak_2017_Bioorg.Med.Chem_25_633
Author(s) : Kosak U , Knez D , Coquelle N , Brus B , Pislar A , Nachon F , Brazzolotto X , Kos J , Colletier JP , Gobec S
Ref : Bioorganic & Medicinal Chemistry , 25 :633 , 2017
Abstract : In the brains of patients with Alzheimer's disease, the enzymatic activities of butyrylcholinesterase (BChE) and monoamine oxidase B (MAO-B) are increased. While BChE is a viable therapeutic target for alleviation of symptoms caused by cholinergic hypofunction, MAO-B is a potential therapeutic target for prevention of neurodegeneration in Alzheimer's disease. Starting with piperidine-based selective human (h)BChE inhibitors and propargylamine-based MAO inhibitors, we have designed, synthesized and biochemically evaluated a series of N-propargylpiperidines. All of these compounds inhibited hBChE with good selectivity over the related enzyme, acetylcholinesterase, and crossed the blood-brain barrier in a parallel artificial membrane permeation assay. The crystal structure of one of the inhibitors (compound 3) in complex with hBChE revealed its binding mode. Three compounds (4, 5, 6) showed concomitant inhibition of MAO-B. Additionally, the most potent hBChE inhibitor 7 and dual BChE and MAO-B inhibitor 6 were non-cytotoxic and protected neuronal SH-SY5Y cells from toxic amyloid beta-peptide species.
ESTHER : Kosak_2017_Bioorg.Med.Chem_25_633
PubMedSearch : Kosak_2017_Bioorg.Med.Chem_25_633
PubMedID: 27908752
Gene_locus related to this paper: human-BCHE

Title : Design, synthesis and biological evaluation of new phthalimide and saccharin derivatives with alicyclic amines targeting cholinesterases, beta-secretase and amyloid beta aggregation - Panek_2016_Eur.J.Med.Chem_125_676
Author(s) : Panek D , Wieckowska A , Wichur T , Bajda M , Godyn J , Jonczyk J , Mika K , Janockova J , Soukup O , Knez D , Korabecny J , Gobec S , Malawska B
Ref : Eur Journal of Medicinal Chemistry , 125 :676 , 2016
Abstract : The complexity of Alzheimer's disease (AD) calls for search of multifunctional compounds as potential candidates for effective therapy. A series of phthalimide and saccharin derivatives linked by different alicyclic fragments (piperazine, hexahydropyrimidine, 3-aminopyrrolidine or 3-aminopiperidine) with phenylalkyl moieties attached have been designed, synthesized, and evaluated as multifunctional anti-AD agents with cholinesterase, beta-secretase and beta-amyloid inhibitory activities. In vitro studies showed that the majority of saccharin derivatives with piperazine moiety and one phthalimide derivative with 3-aminopiperidine fragment exhibited inhibitory potency toward acetylcholinesterase (AChE) with EeAChE IC50 values ranging from 0.83 muM to 19.18 muM. The target compounds displayed inhibition of human beta-secretase-1 (hBACE1) ranging from 26.71% to 61.42% at 50 muM concentration. Among these compounds, two multifunctional agents (26, [2-(2-(4-benzylpiperazin-1-yl)ethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide] and 52, 2-(2-(3-(3,5-difluorobenzylamino)piperidin-1-yl)ethyl)isoindoline-1,3-dione) have been identified. Compound 26 exhibited the highest inhibitory potency against EeAChE (IC50 = 0.83 muM) and inhibitory activity against hBACE1 (33.61% at 50 muM). Compound 52 is a selective AChE inhibitor (IC50 AChE = 6.47 muM) with BACE1 inhibitory activity (26.3% at 50 muM) and it displays the most significant Abeta anti-aggregating properties among all the obtained compounds (39% at 10 muM). Kinetic and molecular modeling studies indicate that 26 may act as non-competitive AChE inhibitor able to interact with both catalytic and peripheral active site of the enzyme.
ESTHER : Panek_2016_Eur.J.Med.Chem_125_676
PubMedSearch : Panek_2016_Eur.J.Med.Chem_125_676
PubMedID: 27721153

Title : Synthesis and Biological Assessment of Racemic Benzochromenopyrimidinimines as Antioxidant, Cholinesterase, and Abeta1-42 Aggregation Inhibitors for Alzheimer's Disease Therapy - Dgachi_2016_ChemMedChem_11_1318
Author(s) : Dgachi Y , Ismaili L , Knez D , Benchekroun M , Martin H , Szalaj N , Wehle S , Bautista-Aguilera OM , Luzet V , Bonnet A , Malawska B , Gobec S , Chioua M , Decker M , Chabchoub F , Marco-Contelles J
Ref : ChemMedChem , 11 :1318 , 2016
Abstract : Given the complex nature of Alzheimer's disease (AD), compounds that are able to simultaneously address two or more AD-associated targets show greater promise for development into drugs for AD therapy. Herein we report an efficient two-step synthesis and biological evaluation of new racemic benzochromene derivatives as antioxidants, inhibitors of cholinesterase and beta-amyloid (Abeta1-42 ) aggregation. Based on the results of the primary screening, we identified 15-(3-methoxyphenyl)-9,11,12,15-tetrahydro-10H,14H-benzo[5,6]chromeno[2,3-d]pyrid o[1,2-a]pyrimidin-14-imine (3 e) and 16-(3-methoxyphenyl)-9,10,11,12,13,16-hexahydro-15H-benzo[5',6']chromeno[2',3':4, 5]pyrimido[1,2-a]azepin-15-imine (3 f) as new potential multitarget-directed ligands for AD therapy. Further in-depth biological analysis showed that compound 3 f is a good human acetylcholinesterase inhibitor [IC50 =(0.36+/-0.02) mum], has strong antioxidant activity (3.61 mumol Trolox equivalents), and moderate Abeta1-42 antiaggregating power (40.3 %).
ESTHER : Dgachi_2016_ChemMedChem_11_1318
PubMedSearch : Dgachi_2016_ChemMedChem_11_1318
PubMedID: 26804623

Title : Novel multi-target-directed ligands for Alzheimer's disease: Combining cholinesterase inhibitors and 5-HT6 receptor antagonists. Design, synthesis and biological evaluation - Wieckowska_2016_Eur.J.Med.Chem_124_63
Author(s) : Wieckowska A , Kolaczkowski M , Bucki A , Godyn J , Marcinkowska M , Wieckowski K , Zareba P , Siwek A , Kazek G , Gluch-Lutwin M , Mierzejewski P , Bienkowski P , Sienkiewicz-Jarosz H , Knez D , Wichur T , Gobec S , Malawska B
Ref : Eur Journal of Medicinal Chemistry , 124 :63 , 2016
Abstract : As currently postulated, a complex treatment may be key to an effective therapy for Alzheimer's disease (AD). Recent clinical trials in patients with moderate AD have shown a superior effect of the combination therapy of donepezil (a selective acetylcholinesterase inhibitor) with idalopirdine (a 5-HT6 receptor antagonist) over monotherapy with donepezil. Here, we present the first report on the design, synthesis and biological evaluation of a novel class of multifunctional ligands that combines a 5-HT6 receptor antagonist with a cholinesterase inhibitor. Novel multi-target-directed ligands (MTDLs) were designed by combining pharmacophores directed against the 5-HT6 receptor (1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole) and cholinesterases (tacrine or N-benzylpiperidine analogues). In vitro evaluation led to the identification of tacrine derivative 12 with well-balanced potencies against the 5-HT6 receptor (Kb = 27 nM), acetylcholinesterase and butyrylcholinesterase (IC50hAChE = 12 nM, IC50hBuChE = 29 nM). The compound also showed good in vitro blood-brain-barrier permeability (PAMPA-BBB assay), which was confirmed in vivo (open field study). Central cholinomimetic activity was confirmed in vivo in rats using a scopolamine-induced hyperlocomotion model. A novel class of multifunctional ligands with compound 12 as the best derivative in a series represents an excellent starting point for the further development of an effective treatment for AD.
ESTHER : Wieckowska_2016_Eur.J.Med.Chem_124_63
PubMedSearch : Wieckowska_2016_Eur.J.Med.Chem_124_63
PubMedID: 27560283

Title : Synthesis and preliminary biological evaluations of (+)-isocampholenic acid-derived amides - Groselj_2016_Mol.Divers_20_667
Author(s) : Groselj U , Golobic A , Knez D , Hrast M , Gobec S , Ricko S , Svete J
Ref : Mol Divers , 20 :667 , 2016
Abstract : The synthesis of two novel (+)-isocampholenic acid-derived amines has been realized starting from commercially available (1S)-(+)-10-camphorsulfonic acid. The novel amines as well as (+)-isocampholenic acid have been used as building blocks in the construction of a library of amides using various aliphatic, aromatic, and amino acid-derived coupling partners using BPC and CDI as activating agents. Amide derivatives have been assayed against several enzymes that hold potential for the development of new drugs to battle bacterial infections and Alzheimer's disease. Compounds 20c and 20e showed promising selective sub-micromolar inhibition of human butyrylcholinesterase [Formula: see text] ([Formula: see text] values [Formula: see text] and [Formula: see text], respectively).
ESTHER : Groselj_2016_Mol.Divers_20_667
PubMedSearch : Groselj_2016_Mol.Divers_20_667
PubMedID: 27017352

Title : Synthesis, Molecular Modelling and Biological Evaluation of Novel Heterodimeric, Multiple Ligands Targeting Cholinesterases and Amyloid Beta - Hebda_2016_Molecules_21_
Author(s) : Hebda M , Bajda M , Wieckowska A , Szalaj N , Pasieka A , Panek D , Godyn J , Wichur T , Knez D , Gobec S , Malawska B
Ref : Molecules , 21 : , 2016
Abstract : Cholinesterases and amyloid beta are one of the major biological targets in the search for a new and efficacious treatment of Alzheimer's disease. The study describes synthesis and pharmacological evaluation of new compounds designed as dual binding site acetylcholinesterase inhibitors. Among the synthesized compounds, two deserve special attention-compounds 42 and 13. The former is a saccharin derivative and the most potent and selective acetylcholinesterase inhibitor (EeAChE IC50 = 70 nM). Isoindoline-1,3-dione derivative 13 displays balanced inhibitory potency against acetyl- and butyrylcholinesterase (BuChE) (EeAChE IC50 = 0.76 muM, EqBuChE IC50 = 0.618 muM), and it inhibits amyloid beta aggregation (35.8% at 10 muM). Kinetic studies show that the developed compounds act as mixed or non-competitive acetylcholinesterase inhibitors. According to molecular modelling studies, they are able to interact with both catalytic and peripheral active sites of the acetylcholinesterase. Their ability to cross the blood-brain barrier (BBB) was confirmed in vitro in the parallel artificial membrane permeability BBB assay. These compounds can be used as a solid starting point for further development of novel multifunctional ligands as potential anti-Alzheimer's agents.
ESTHER : Hebda_2016_Molecules_21_
PubMedSearch : Hebda_2016_Molecules_21_
PubMedID: 27023510

Title : Development of an in-vivo active reversible butyrylcholinesterase inhibitor - Kosak_2016_Sci.Rep_6_39495
Author(s) : Kosak U , Brus B , Knez D , Sink R , Zakelj S , Trontelj J , Pislar A , Slenc J , Gobec M , Zivin M , Tratnjek L , Perse M , Salat K , Podkowa A , Filipek B , Nachon F , Brazzolotto X , Wieckowska A , Malawska B , Stojan J , Rascan IM , Kos J , Coquelle N , Colletier JP , Gobec S
Ref : Sci Rep , 6 :39495 , 2016
Abstract : Alzheimer's disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with the disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. Potent, selective and reversible human BChE inhibitors were developed. The solved crystal structure of human BChE in complex with the most potent inhibitor reveals its binding mode and provides the molecular basis of its low nanomolar potency. Additionally, this compound is noncytotoxic and has neuroprotective properties. Furthermore, this inhibitor moderately crosses the blood-brain barrier and improves memory, cognitive functions and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic adverse effects. Our study provides an advanced lead compound for developing drugs for alleviating symptoms caused by cholinergic hypofunction in advanced AD.
ESTHER : Kosak_2016_Sci.Rep_6_39495
PubMedSearch : Kosak_2016_Sci.Rep_6_39495
PubMedID: 28000737
Gene_locus related to this paper: human-BCHE

Title : Synthesis and Biological Evaluation of Benzochromenopyrimidinones as Cholinesterase Inhibitors and Potent Antioxidant, Non-Hepatotoxic Agents for Alzheimer's Disease - Dgachi_2016_Molecules_21_
Author(s) : Dgachi Y , Bautista-Aguilera OM , Benchekroun M , Martin H , Bonet A , Knez D , Godyn J , Malawska B , Gobec S , Chioua M , Janockova J , Soukup O , Chabchoub F , Marco-Contelles J , Ismaili L
Ref : Molecules , 21 : , 2016
Abstract : We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 +/- 0.03 muM), good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.
ESTHER : Dgachi_2016_Molecules_21_
PubMedSearch : Dgachi_2016_Molecules_21_
PubMedID: 27187348

Title : LiSiCA: A Software for Ligand-Based Virtual Screening and Its Application for the Discovery of Butyrylcholinesterase Inhibitors - Lesnik_2015_J.Chem.Inf.Model_55_1521
Author(s) : Lesnik S , Stular T , Brus B , Knez D , Gobec S , Janezic D , Konc J
Ref : J Chem Inf Model , 55 :1521 , 2015
Abstract : We developed LiSiCA (ligand similarity using clique algorithm)-ligand-based virtual screening software that uses a fast maximum clique algorithm to find two- and three-dimensional similarities between pairs of molecules and applied it to the discovery of novel potent butyrylcholinesterase inhibitors. LiSiCA, which runs in parallel on multiple processor cores, was successfully tested on the Database of Useful Decoys-Enhanced, to evaluate its ability to discriminate active molecules from decoys. We then applied LiSiCA for the discovery of novel inhibitors of human butyrylcholinesterase, a promising anti-Alzheimer target, using a known inhibitor as the reference compound. We demonstrated that LiSiCA is capable of finding potent nanomolar inhibitors, whose scaffolds differed from the reference compound, thus proving its ability for scaffold hopping and usefulness in drug discovery.
ESTHER : Lesnik_2015_J.Chem.Inf.Model_55_1521
PubMedSearch : Lesnik_2015_J.Chem.Inf.Model_55_1521
PubMedID: 26158767

Title : Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents - Knez_2015_Bioorg.Med.Chem_23_4442
Author(s) : Knez D , Brus B , Coquelle N , Sosic I , Sink R , Brazzolotto X , Mravljak J , Colletier JP , Gobec S
Ref : Bioorganic & Medicinal Chemistry , 23 :4442 , 2015
Abstract : Tremendous efforts have been dedicated to the development of effective therapeutics against Alzheimer's disease, which represents the most common debilitating neurodegenerative disease. Multifunctional agents are molecules designed to have simultaneous effects on different pathological processes. Such compounds represent an emerging strategy for the development of effective treatments against Alzheimer's disease. Here, we report on the synthesis and biological evaluation of a series of nitroxoline-based analogs that were designed by merging the scaffold of 8-hydroxyquinoline with that of a known selective butyrylcholinesterase inhibitor that has promising anti-Alzheimer properties. Most strikingly, compound 8g inhibits self-induced aggregation of the amyloid beta peptide (Abeta1-42), inhibits with sub-micromolar potency butyrylcholinesterase (IC50=215 nM), and also selectively complexes Cu(2+). Our study thus designates this compound as a promising multifunctional agent for therapeutic treatment of Alzheimer's disease. The crystal structure of human butyrylcholinesterase in complex with compound 8g is also solved, which suggests ways to further optimize compounds featuring the 8-hydroxyquinoline scaffold.
ESTHER : Knez_2015_Bioorg.Med.Chem_23_4442
PubMedSearch : Knez_2015_Bioorg.Med.Chem_23_4442
PubMedID: 26116179
Gene_locus related to this paper: human-BCHE

Title : Exploring the aryl esterase catalysis of paraoxonase-1 through solvent kinetic isotope effects and phosphonate-based isosteric analogues of the tetrahedral reaction intermediate - Bavec_2014_Biochimie_106_184
Author(s) : Bavec A , Knez D , Makovec T , Stojan J , Gobec S , Golicnik M
Ref : Biochimie , 106 :184 , 2014
Abstract : Although a recent study of Debord et al. in Biochimie (2014; 97:72-77) described the thermodynamics of the catalysed hydrolysis of phenyl acetate by human paraoxonase-1, the mechanistic details along the reaction route of this enzyme remain unclear. Therefore, we briefly present the solvent kinetic isotope effects on the phenyl acetate esterase activity of paraoxonase-1 and its inhibition with the phenyl methylphosphonate anion, which is a stable isosteric analogue that mimics the high-energy tetrahedral intermediate on the hydroxide-promoted hydrolysis pathway. The data show normal isotope effects, while proton inventory analysis indicates that two protons contribute to the kinetic isotope effect. Coherently, moderate competitive inhibition with the phenyl methylphosphonate anion reveals that the rate-limiting transition state suboptimally resembles the tetrahedral intermediate. The implications of these findings can be attributed to two possible reaction mechanisms that might occur during the paraoxonase-1-catalysed hydrolysis of phenyl acetate.
ESTHER : Bavec_2014_Biochimie_106_184
PubMedSearch : Bavec_2014_Biochimie_106_184
PubMedID: 25180809