Scheiner M

References (10)

Title : Photoswitchable Pseudoirreversible Butyrylcholinesterase Inhibitors Allow Optical Control of Inhibition in Vitro and Enable Restoration of Cognition in an Alzheimer's Disease Mouse Model upon Irradiation - Scheiner_2022_J.Am.Chem.Soc__
Author(s) : Scheiner M , Sink A , Hoffmann M , Vrigneau C , Endres E , Carles A , Sotriffer C , Maurice T , Decker M
Ref : Journal of the American Chemical Society , : , 2022
Abstract : To develop tools to investigate the biological functions of butyrylcholinesterase (BChE) and the mechanisms by which BChE affects Alzheimer's disease (AD), we synthesized several selective, nanomolar active, pseudoirreversible photoswitchable BChE inhibitors. The compounds were able to specifically influence different kinetic parameters of the inhibition process by light. For one compound, a 10-fold difference in the IC(50)-values (44.6 nM cis, 424 nM trans) in vitro was translated to an "all or nothing" response with complete recovery in a murine cognition-deficit AD model at dosages as low as 0.3 mg/kg.
ESTHER : Scheiner_2022_J.Am.Chem.Soc__
PubMedSearch : Scheiner_2022_J.Am.Chem.Soc__
PubMedID: 35138833

Title : Selective Pseudo-irreversible Butyrylcholinesterase Inhibitors Transferring Antioxidant Moieties to the Enzyme Show Pronounced Neuroprotective Efficacy In Vitro and In Vivo in an Alzheimer's Disease Mouse Model - Scheiner_2021_J.Med.Chem_64_9302
Author(s) : Scheiner M , Hoffmann M , He F , Poeta E , Chatonnet A , Monti B , Maurice T , Decker M
Ref : Journal of Medicinal Chemistry , 64(13): :9302 , 2021
Abstract : A series of multitarget-directed ligands (MTDLs) was designed by functionalizing a pseudo-irreversible butyrylcholinesterase (BChE) inhibitor. The obtained hybrids were investigated in vitro regarding their hBChE and hAChE inhibition, their enzyme kinetics, and their antioxidant physicochemical properties (DPPH, ORAC, metal chelating). In addition, in vitro assays were applied to investigate antioxidant effects using murine hippocampal HT22 cells and immunomodulatory effects on the murine microglial N9 cell line. The MTDLs retained their antioxidative properties compared to the parent antioxidant-moieties in vitro and the inhibition of hBChE was maintained in the submicromolar range. Representative compounds were tested in a pharmacological Alzheimer's disease (AD) mouse model and demonstrated very high efficacy at doses as low as 0.1 mg/kg. The most promising compound was also tested in BChE(-/-) mice and showed reduced efficacy. In vivo neuroprotection by BChE inhibition can be effectively enhanced by incorporation of structurally diverse antioxidant moieties.
ESTHER : Scheiner_2021_J.Med.Chem_64_9302
PubMedSearch : Scheiner_2021_J.Med.Chem_64_9302
PubMedID: 34152756

Title : Azobioisosteres of Curcumin with Pronounced Activity against Amyloid Aggregation, Intracellular Oxidative Stress, and Neuroinflammation - Hofmann_2021_Chemistry_27_6015
Author(s) : Hofmann J , Ginex T , Espargaro A , Scheiner M , Gunesch S , Arago M , Stigloher C , Sabate R , Luque FJ , Decker M
Ref : Chemistry , 27 :6015 , 2021
Abstract : Many (poly-)phenolic natural products, for example, curcumin and taxifolin, have been studied for their activity against specific hallmarks of neurodegeneration, such as amyloid-beta 42 (Abeta42) aggregation and neuroinflammation. Due to their drawbacks, arising from poor pharmacokinetics, rapid metabolism, and even instability in aqueous medium, the biological activity of azobenzene compounds carrying a pharmacophoric catechol group, which have been designed as bioisoteres of curcumin has been examined. Molecular simulations reveal the ability of these compounds to form a hydrophobic cluster with Abeta42, which adopts different folds, affecting the propensity to populate fibril-like conformations. Furthermore, the curcumin bioisosteres exceeded the parent compound in activity against Abeta42 aggregation inhibition, glutamate-induced intracellular oxidative stress in HT22 cells, and neuroinflammation in microglial BV-2 cells. The most active compound prevented apoptosis of HT22 cells at a concentration of 2.5microm (83 % cell survival), whereas curcumin only showed very low protection at 10microm (21 % cell survival).
ESTHER : Hofmann_2021_Chemistry_27_6015
PubMedSearch : Hofmann_2021_Chemistry_27_6015
PubMedID: 33666306

Title : From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects - Pont_2021_Eur.J.Med.Chem_225_113779
Author(s) : Pont C , Ginex T , Grinan-Ferre C , Scheiner M , Mattellone A , Martinez N , Arce EM , Soriano-Fernandez Y , Naldi M , De Simone A , Barenys M , Gomez-Catalan J , Perez B , Sabate R , Andrisano V , Loza MI , Brea J , Bartolini M , Bolognesi ML , Decker M , Pallas M , Luque FJ , Munoz-Torrero D
Ref : Eur Journal of Medicinal Chemistry , 225 :113779 , 2021
Abstract : Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Abeta42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead.
ESTHER : Pont_2021_Eur.J.Med.Chem_225_113779
PubMedSearch : Pont_2021_Eur.J.Med.Chem_225_113779
PubMedID: 34418785

Title : Photopharmacology on Acetylcholinesterase: Novel Photoswitchable Inhibitors with Improved Pharmacological Profiles - Scheiner_2021_ChemPhotoChem_5_149
Author(s) : Scheiner M , Sink A , Spatz P , Endres E , Decker M
Ref : ChemPhotoChem , 5 :149 , 2021
Abstract : Considerable effort has previously been invested in a light-controlled inhibition of the enzyme acetylcholinesterase (AChE). We found that a novel azobenzene-based bistacrine AChE inhibitor switched faster than the known dithienylethene based bistacrine and inverted the photo-controlled interactions of the photoisomers compared to its dithienylethene congener. Furthermore, we have optimized a previously described light-controlled tacrine-based AChE inhibitor. Isomerization upon irradiation with UV light of the novel inhibitor was observed in aqueous medium and showed no fatigue over several cycles. The cis-enriched form showed an 8.4-fold higher inhibition of hAChE compared with its trans-enriched form and was about 30-fold more active than the reference compound tacrine with a single-digit nanomolar inhibition. We went beyond proof-of-concept to discover photoswitchable AChE inhibitors with pharmacologically desirable nanomolar inhibition, cis-on effect, and pronounces differences between the photoisomers.
ESTHER : Scheiner_2021_ChemPhotoChem_5_149
PubMedSearch : Scheiner_2021_ChemPhotoChem_5_149

Title : Sterubin: Enantioresolution and Configurational Stability, Enantiomeric Purity in Nature, and Neuroprotective Activity in Vitro and in Vivo - Hofmann_2020_Chemistry_26_7299
Author(s) : Hofmann J , Fayez S , Scheiner M , Hoffmann M , Oerter S , Appelt-Menzel A , Maher P , Maurice T , Bringmann G , Decker M
Ref : Chemistry , 26 :7299 , 2020
Abstract : Alzheimer's disease (AD) is a neurological disorder with still no preventive or curative treatment. Flavonoids are phytochemicals with potential therapeutic value. Previous studies described the flavanone sterubin isolated from the Californian plant Eriodictyon californicum as a potent neuroprotectant in several in vitro assays. Herein, the resolution of synthetic racemic sterubin (1) into its two enantiomers, (R)-1 and (S)-1, is described, which has been performed on a chiral chromatographic phase, and their stereochemical assignment online by HPLC-ECD coupling. (R)-1 and (S)-1 showed comparable neuroprotection in vitro with no significant differences. While the pure stereoisomers were configurationally stable in methanol, fast racemization was observed in the presence of culture medium. We also established the occurrence of extracted sterubin as its pure (S)-enantiomer. Moreover, the activity of sterubin (1) was investigated for the first time in vivo, in an AD mouse model. Sterubin (1) showed a significant positive impact on short- and long-term memory at low dosages.
ESTHER : Hofmann_2020_Chemistry_26_7299
PubMedSearch : Hofmann_2020_Chemistry_26_7299
PubMedID: 32358806

Title : Multi-target-directed-ligands acting as enzyme inhibitors and receptor ligands - Rodriguez-Soacha_2019_Eur.J.Med.Chem_180_690
Author(s) : Rodriguez-Soacha DA , Scheiner M , Decker M
Ref : Eur Journal of Medicinal Chemistry , 180 :690 , 2019
Abstract : In this review, we present the latest advances in the field of multi-target-directed ligand (MTDL) design for the treatment of various complex pathologies of multifactorial origin. In particular, latest findings in the field of MTDL design targeting both an enzyme and a receptor are presented for different diseases such as Alzheimer's disease (AD), depression, addiction, glaucoma, non-alcoholic steatohepatitis and pain and inflammation. The ethology of the diseases is briefly described, with special emphasis on how the MTDL can evolve into novel therapies that replace the classic pharmacological dogma "one target one disease". Considering the current needs for therapy adherence improvement, it is exposed as from the medicinal chemistry, different molecular scaffolds are studied. With the use of structure activity relationship studies and molecular optimization, new hybrid molecules are generated with improved biological properties acting at two biologically very distinct targets.
ESTHER : Rodriguez-Soacha_2019_Eur.J.Med.Chem_180_690
PubMedSearch : Rodriguez-Soacha_2019_Eur.J.Med.Chem_180_690
PubMedID: 31401465

Title : Dual-Acting Cholinesterase-Human Cannabinoid Receptor 2 Ligands Show Pronounced Neuroprotection in Vitro and Overadditive and Disease-Modifying Neuroprotective Effects in Vivo - Scheiner_2019_J.Med.Chem_62_9078
Author(s) : Scheiner M , Dolles D , Gunesch S , Hoffmann M , Nabissi M , Marinelli O , Naldi M , Bartolini M , Petralla S , Poeta E , Monti B , Falkeis C , Vieth M , Hubner H , Gmeiner P , Maitra R , Maurice T , Decker M
Ref : Journal of Medicinal Chemistry , 62 :9078 , 2019
Abstract : We have designed and synthesized a series of 14 hybrid molecules out of the cholinesterase (ChE) inhibitor tacrine and a benzimidazole-based human cannabinoid receptor subtype 2 (hCB2R) agonist and investigated them in vitro and in vivo. The compounds are potent ChE inhibitors, and for the most promising hybrids, the mechanism of human acetylcholinesterase (hAChE) inhibition as well as their ability to interfere with AChE-induced aggregation of beta-amyloid (Abeta), and Abeta self-aggregation was assessed. All hybrids were evaluated for affinity and selectivity for hCB1R and hCB2R. To ensure that the hybrids retained their agonist character, the expression of cAMP-regulated genes was quantified, and potency and efficacy were determined. Additionally, the effects of the hybrids on microglia activation and neuroprotection on HT-22 cells were investigated. The most promising in vitro hybrids showed pronounced neuroprotection in an Alzheimer's mouse model at low dosage (0.1 mg/kg, i.p.), lacking hepatotoxicity even at high dose (3 mg/kg, i.p.).
ESTHER : Scheiner_2019_J.Med.Chem_62_9078
PubMedSearch : Scheiner_2019_J.Med.Chem_62_9078
PubMedID: 31609608

Title : Highly Selective Butyrylcholinesterase Inhibitors with Tunable Duration of Action by Chemical Modification of Transferable Carbamate Units Exhibit Pronounced Neuroprotective Effect in an Alzheimer's Disease Mouse Model - Hoffmann_2019_J.Med.Chem_62_9116
Author(s) : Hoffmann M , Stiller C , Endres E , Scheiner M , Gunesch S , Sotriffer C , Maurice T , Decker M
Ref : Journal of Medicinal Chemistry , 62 :9116 , 2019
Abstract : In this study, the carbamate structure of pseudo-irreversible butyrylcholinesterase (BChE) inhibitors was optimized with regard to a longer binding to the enzyme. A set of compounds bearing different heterocycles (e.g., morpholine, tetrahydroisoquinoline, benzimidazole, piperidine) and alkylene spacers (2 to 10 methylene groups between carbamate and heterocycle) in the carbamate residue was synthesized and characterized in vitro for their binding affinity, binding kinetics, and carbamate hydrolysis. These novel BChE inhibitors are highly selective for hBChE over human acetycholinesterase (hAChE), yielding short-, medium-, and long-acting nanomolar hBChE inhibitors (with a half-life of the carbamoylated enzyme ranging from 1 to 28 h). The inhibitors show neuroprotective properties in a murine hippocampal cell line and a pharmacological mouse model of Alzheimer's disease (AD), suggesting a significant benefit of BChE inhibition for a disease-modifying treatment of AD.
ESTHER : Hoffmann_2019_J.Med.Chem_62_9116
PubMedSearch : Hoffmann_2019_J.Med.Chem_62_9116
PubMedID: 31609115

Title : Aminobenzimidazoles and Structural Isomers as Templates for Dual-Acting Butyrylcholinesterase Inhibitors and hCB2 R Ligands To Combat Neurodegenerative Disorders - Dolles_2016_ChemMedChem_11_1270
Author(s) : Dolles D , Nimczick M , Scheiner M , Ramler J , Stadtmuller P , Sawatzky E , Drakopoulos A , Sotriffer C , Wittmann HJ , Strasser A , Decker M
Ref : ChemMedChem , 11 :1270 , 2016
Abstract : A pharmacophore model for butyrylcholinesterase (BChE) inhibitors was applied to a human cannabinoid subtype 2 receptor (hCB2 R) agonist and verified it as a first-generation lead for respective dual-acting compounds. The design, synthesis, and pharmacological evaluation of various derivatives led to the identification of aminobenzimidazoles as second-generation leads with micro- or sub-micromolar activities at both targets and excellent selectivity over hCB1 and AChE, respectively. Computational studies of the first- and second-generation lead structures by applying molecular dynamics (MD) on the active hCB2 R model, along with docking and MD on hBChE, has enabled an explanation of their binding profiles at the protein levels and opened the way for further optimization. Dual-acting compounds with "balanced" affinities and excellent selectivities could be obtained that represent leads for treatment of both cognitive and pathophysiological impairment occurring in neurodegenerative disorders.
ESTHER : Dolles_2016_ChemMedChem_11_1270
PubMedSearch : Dolles_2016_ChemMedChem_11_1270
PubMedID: 26548365