Monti B

References (13)

Title : Coumarin-azasugar-benzyl conjugates as non-neurotoxic dual inhibitors of butyrylcholinesterase and cancer cell growth - Vaaland_2024_Org.Biomol.Chem__
Author(s) : Vaaland Holmgard IC , Gonzalez-Bakker A , Poeta E , Puerta A , Fernandes MX , Monti B , Fernandez-Bolanos JG , Padron JM , Lopez O , Lindback E
Ref : Org Biomol Chem , : , 2024
Abstract : We have applied the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction to prepare a library of ten coumarin-azasugar-benzyl conjugates and two phthalimide-azasugar-benzyl conjugates with potential anti-Alzheimer and anti-cancer properties. The compounds were evaluated as cholinesterase inhibitors, demonstrating a general preference, of up to 676-fold, for the inhibition of butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE). Nine of the compounds behaved as stronger BuChE inhibitors than galantamine, one of the few drugs in clinical use against Alzheimer's disease. The most potent BuChE inhibitor (IC(50) = 74 nM) was found to exhibit dual activities, as it also showed high activity (GI(50) = 5.6 +/- 1.1 microM) for inhibiting the growth of WiDr (colon cancer cells). In vitro studies on this dual-activity compound on Cerebellar Granule Neurons (CGNs) demonstrated that it displays no neurotoxicity.
ESTHER : Vaaland_2024_Org.Biomol.Chem__
PubMedSearch : Vaaland_2024_Org.Biomol.Chem__
PubMedID: 38590227

Title : Dual-Acting Small Molecules: Subtype-Selective Cannabinoid Receptor 2 Agonist\/Butyrylcholinesterase Inhibitor Hybrids Show Neuroprotection in an Alzheimer's Disease Mouse Model - Spatz_2023_J.Med.Chem__
Author(s) : Spatz P , Steinmuller SAM , Tutov A , Poeta E , Morilleau A , Carles A , Deventer MH , Hofmann J , Stove CP , Monti B , Maurice T , Decker M
Ref : Journal of Medicinal Chemistry , : , 2023
Abstract : We present the synthesis and characterization of merged human butyrylcholinesterase (hBChE) inhibitor/cannabinoid receptor 2 (hCB(2)R) ligands for the treatment of neurodegeneration. In total, 15 benzimidazole carbamates were synthesized and tested for their inhibition of human cholinesterases, also with regard to their pseudoirreversible binding mode and affinity toward both cannabinoid receptors in radioligand binding studies. After evaluation in a calcium mobilization assay as well as a beta-arrestin 2 (betaarr2) recruitment assay, two compounds with balanced activities on both targets were tested for their immunomodulatory effect on microglia activation and regarding their pharmacokinetic properties and blood-brain barrier penetration. Compound 15d, containing a dimethyl carbamate motif, was further evaluated in vivo, showing prevention of Abeta(25-35)-induced learning impairments in a pharmacological mouse model of Alzheimer's disease for both short- and long-term memory responses. Additional combination studies proved a synergic effect of BChE inhibition and CB(2)R activation in vivo.
ESTHER : Spatz_2023_J.Med.Chem__
PubMedSearch : Spatz_2023_J.Med.Chem__
PubMedID: 37127287

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 : Phenothiazine-Tacrine Heterodimers: Pursuing Multitarget Directed Approach in Alzheimer's Disease - Gorecki_2021_ACS.Chem.Neurosci__
Author(s) : Gorecki L , Uliassi E , Bartolini M , Janockova J , Hrabinova M , Hepnarova V , Prchal L , Muckova L , Pejchal J , Karasova JZ , Mezeiova E , Benkova M , Kobrlova T , Soukup O , Petralla S , Monti B , Korabecny J , Bolognesi ML
Ref : ACS Chem Neurosci , : , 2021
Abstract : Since 2002, no clinical candidate against Alzheimer's disease has reached the market; hence, an effective therapy is urgently needed. We followed the so-called "multitarget directed ligand" approach and designed 36 novel tacrine-phenothiazine heterodimers which were in vitro evaluated for their anticholinesterase properties. The assessment of the structure-activity relationships of such derivatives highlighted compound 1dC as a potent and selective acetylcholinesterase inhibitor with IC(50) = 8 nM and 1aA as a potent butyrylcholinesterase inhibitor with IC(50) = 15 nM. Selected hybrids, namely, 1aC, 1bC, 1cC, 1dC, and 2dC, showed a significant inhibitory activity toward tau((306-336)) peptide aggregation with percent inhibition ranging from 50.5 to 62.1%. Likewise, 1dC and 2dC exerted a remarkable ability to inhibit self-induced Abeta(1-42) aggregation. Notwithstanding, in vitro studies displayed cytotoxicity toward HepG2 cells and cerebellar granule neurons; no pathophysiological abnormality was observed when 1dC was administered to mice at 14 mg/kg (i.p.). 1dC was also able to permeate to the CNS as shown by in vitro and in vivo models. The maximum brain concentration was close to the IC(50) value for acetylcholinesterase inhibition with a relatively slow elimination half-time. 1dC showed an acceptable safety and good pharmacokinetic properties and a multifunctional biological profile.
ESTHER : Gorecki_2021_ACS.Chem.Neurosci__
PubMedSearch : Gorecki_2021_ACS.Chem.Neurosci__
PubMedID: 33852284

Title : N-1,2,3-triazole-isatin derivatives for cholinesterase and beta-amyloid aggregation inhibition: A comprehensive bioassay study - Marques_2020_Bioorg.Chem_98_103753
Author(s) : Marques CS , Lopez O , Bagetta D , Carreiro EP , Petralla S , Bartolini M , Hoffmann M , Alcaro S , Monti B , Bolognesi ML , Decker M , Fernandez-Bolanos JG , Burke AJ
Ref : Bioorg Chem , 98 :103753 , 2020
Abstract : Our goal was the evaluation of a series of N-1,2,3-triazole-isatin derivatives for multi-target activity which included cholinesterase (ChE) inhibition and beta-amyloid (Abeta) peptide anti-aggregation. The compounds have shown considerable promise as butyrylcholinesterase (BuChE) inhibitors. Although the inhibition of eel acetylcholinesterase (eeAChE) was weak, the inhibitions against equine BuChE (eqBuChE) and human BuChE (hBuChE) were more significant with a best inhibition against eqBuChE of 0.46 muM. In some cases, these molecules gave better inhibitions for hBuChE than eqBuChE. For greater insights into their mode of action, molecular docking studies were carried out, followed by STD-NMR validation. In addition, some of these compounds showed weak Abeta anti-aggregation activity. Hepatotoxicity studies showed that they were non-hepatoxic and neurotoxicity studies using neurite outgrowth experiments led to the conclusion that these compounds are only weakly neurotoxic.
ESTHER : Marques_2020_Bioorg.Chem_98_103753
PubMedSearch : Marques_2020_Bioorg.Chem_98_103753
PubMedID: 32200328

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 : Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease - Chalupova_2019_Eur.J.Med.Chem_168_491
Author(s) : Chalupova K , Korabecny J , Bartolini M , Monti B , Lamba D , Caliandro R , Pesaresi A , Brazzolotto X , Gastellier AJ , Nachon F , Pejchal J , Jarosova M , Hepnarova V , Jun D , Hrabinova M , Dolezal R , Karasova JZ , Mzik M , Kristofikova Z , Misik J , Muckova L , Jost P , Soukup O , Benkova M , Setnicka V , Habartova L , Chvojkova M , Kleteckova L , Vales K , Mezeiova E , Uliassi E , Valis M , Nepovimova E , Bolognesi ML , Kuca K
Ref : Eur Journal of Medicinal Chemistry , 168 :491 , 2019
Abstract : A combination of tacrine and tryptophan led to the development of a new family of heterodimers as multi-target agents with potential to treat Alzheimer's disease. Based on the in vitro biological profile, compound S-K1035 was found to be the most potent inhibitor of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), demonstrating balanced IC50 values of 6.3 and 9.1nM, respectively. For all the tacrine-tryptophan heterodimers, favorable inhibitory effect on hAChE as well as on hBChE was coined to the optimal spacer length ranging from five to eight carbon atoms between these two pharmacophores. S-K1035 also showed good ability to inhibit Abeta42 self-aggregation (58.6+/-5.1% at 50muM) as well as hAChE-induced Abeta40 aggregation (48.3+/-6.3% at 100muM). The X-ray crystallographic analysis of TcAChE in complex with S-K1035 pinpointed the utility of the hybridization strategy applied and the structures determined with the two K1035 enantiomers in complex with hBChE could explain the higher inhibition potency of S-K1035. Other in vitro evaluations predicted the ability of S-K1035 to cross blood-brain barrier and to exert a moderate inhibition potency against neuronal nitric oxide synthase. Based on the initial promising biochemical data and a safer in vivo toxicity compared to tacrine, S-K1035 was administered to scopolamine-treated rats being able to dose-dependently revert amnesia.
ESTHER : Chalupova_2019_Eur.J.Med.Chem_168_491
PubMedSearch : Chalupova_2019_Eur.J.Med.Chem_168_491
PubMedID: 30851693
Gene_locus related to this paper: torca-ACHE

Title : Discovery of novel benzofuran-based compounds with neuroprotective and immunomodulatory properties for Alzheimer's disease treatment - Montanari_2019_Eur.J.Med.Chem_178_243
Author(s) : Montanari S , Mahmoud AM , Pruccoli L , Rabbito A , Naldi M , Petralla S , Moraleda I , Bartolini M , Monti B , Iriepa I , Belluti F , Gobbi S , Di Marzo V , Bisi A , Tarozzi A , Ligresti A , Rampa A
Ref : Eur Journal of Medicinal Chemistry , 178 :243 , 2019
Abstract : To address the multifactorial nature of Alzheimer's Disease (AD), a multi-target-directed ligand approach was herein developed. As a follow-up of our previous studies, a small library of newly designed 2-arylbenzofuran derivatives was evaluated towards cholinesterases and cannabinoid receptors. The two most promising compounds, 8 and 10, were then assessed for their neuroprotective activity and for their ability to modulate the microglial phenotype. Compound 8 emerged as able to fight AD from several directions: it restored the cholinergic system by inhibiting butyrylcholinesterase, showed neuroprotective activity against Abeta1-42 oligomers, was a potent and selective CB2 ligand and had immunomodulatory effects, switching microglia from the pro-inflammatory M1 to the neuroprotective M2 phenotype. Derivative 10 was a potent CB2 inverse agonist with promising immunomodulatory properties and could be considered as a tool for investigating the role of CB2 receptors and for developing potential immunomodulating drugs addressing the endocannabinoid system.
ESTHER : Montanari_2019_Eur.J.Med.Chem_178_243
PubMedSearch : Montanari_2019_Eur.J.Med.Chem_178_243
PubMedID: 31185414

Title : Tacrine-resveratrol fused hybrids as multi-target-directed ligands against Alzheimer's disease - Jerabek_2016_Eur.J.Med.Chem_127_250
Author(s) : Jerabek J , Uliassi E , Guidotti L , Korabecny J , Soukup O , Sepsova V , Hrabinova M , Kuca K , Bartolini M , Pena-Altamira LE , Petralla S , Monti B , Roberti M , Bolognesi ML
Ref : Eur Journal of Medicinal Chemistry , 127 :250 , 2016
Abstract : Multi-target drug discovery is one of the most followed approaches in the active central nervous system (CNS) therapeutic area, especially in the search for new drugs against Alzheimer's disease (AD). This is because innovative multi-target-directed ligands (MTDLs) could more adequately address the complexity of this pathological condition. In a continuation of our efforts aimed at a new series of anti-AD MTDLs, we combined the structural features of the cholinesterase inhibitor drug tacrine with that of resveratrol, which is known for its purported antioxidant and anti-neuroinflammatory activities. The most interesting hybrid compounds (5, 8, 9 and 12) inhibited human acetylcholinesterase at micromolar concentrations and effectively modulated Abeta self-aggregation in vitro. In addition, 12 showed intriguing anti-inflammatory and immuno-modulatory properties in neuronal and glial AD cell models. Importantly, the MTDL profile is accompanied by high-predicted blood-brain barrier permeability, and low cytotoxicity on primary neurons.
ESTHER : Jerabek_2016_Eur.J.Med.Chem_127_250
PubMedSearch : Jerabek_2016_Eur.J.Med.Chem_127_250
PubMedID: 28064079

Title : Novel tacrine-grafted ugi adducts as multipotent anti-Alzheimer drugs: a synthetic renewal in tacrine-ferulic Acid hybrids - Benchekroun_2015_ChemMedChem_10_523
Author(s) : Benchekroun M , Bartolini M , Egea J , Romero A , Soriano E , Pudlo M , Luzet V , Andrisano V , Jimeno ML , Lopez MG , Wehle S , Gharbi T , Refouvelet B , de Andres L , Herrera-Arozamena C , Monti B , Bolognesi ML , Rodriguez-Franco MI , Decker M , Marco-Contelles J , Ismaili L
Ref : ChemMedChem , 10 :523 , 2015
Abstract : Herein we describe the design, multicomponent synthesis, and biological, molecular modeling and ADMET studies, as well as in vitro PAMPA-blood-brain barrier (BBB) analysis of new tacrine-ferulic acid hybrids (TFAHs). We identified (E)-3-(hydroxy-3-methoxyphenyl)-N-{8[(7-methoxy-1,2,3,4-tetrahydroacridin-9-yl)am ino]octyl}-N-[2-(naphthalen-2-ylamino)2-oxoethyl]acrylamide (TFAH 10 n) as a particularly interesting multipotent compound that shows moderate and completely selective inhibition of human butyrylcholinesterase (IC50 =68.2 nM), strong antioxidant activity (4.29 equiv trolox in an oxygen radical absorbance capacity (ORAC) assay), and good beta-amyloid (Abeta) anti-aggregation properties (65.6 % at 1:1 ratio); moreover, it is able to permeate central nervous system (CNS) tissues, as determined by PAMPA-BBB assay. Notably, even when tested at very high concentrations, TFAH 10 n easily surpasses the other TFAHs in hepatotoxicity profiling (59.4 % cell viability at 1000 muM), affording good neuroprotection against toxic insults such as Abeta1-40 , Abeta1-42 , H2 O2 , and oligomycin A/rotenone on SH-SY5Y cells, at 1 muM. The results reported herein support the development of new multipotent TFAH derivatives as potential drugs for the treatment of Alzheimer's disease.
ESTHER : Benchekroun_2015_ChemMedChem_10_523
PubMedSearch : Benchekroun_2015_ChemMedChem_10_523
PubMedID: 25537267

Title : Multitarget Drug Design Strategy: Quinone-Tacrine Hybrids Designed To Block Amyloid-beta Aggregation and To Exert Anticholinesterase and Antioxidant Effects - Nepovimova_2014_J.Med.Chem_57_8576
Author(s) : Nepovimova E , Uliassi E , Korabecny J , Pena-Altamira LE , Samez S , Pesaresi A , Garcia GE , Bartolini M , Andrisano V , Bergamini C , Fato R , Lamba D , Roberti M , Kuca K , Monti B , Bolognesi ML
Ref : Journal of Medicinal Chemistry , 57 :8576 , 2014
Abstract : We report the identification of multitarget anti-Alzheimer compounds designed by combining a naphthoquinone function and a tacrine fragment. In vitro, 15 compounds displayed excellent acetylcholinesterase (AChE) inhibitory potencies and interesting capabilities to block amyloid-beta (Abeta) aggregation. The X-ray analysis of one of those compounds in complex with AChE allowed rationalizing the outstanding activity data (IC50 = 0.72 nM). Two of the compounds showed negligible toxicity in immortalized mouse cortical neurons Neuro2A and primary rat cerebellar granule neurons. However, only one of them was less hepatotoxic than tacrine in HepG2 cells. In T67 cells, both compounds showed antioxidant activity, following NQO1 induction. Furthermore, in Neuro2A, they were able to completely revert the decrease in viability induced by Abeta. Importantly, they crossed the blood-brain barrier, as demonstrated in ex vivo experiments with rats. When ex vivo results were combined with in vitro studies, these two compounds emerged to be promising multitarget lead candidates worthy of further pursuit.
ESTHER : Nepovimova_2014_J.Med.Chem_57_8576
PubMedSearch : Nepovimova_2014_J.Med.Chem_57_8576
PubMedID: 25259726
Gene_locus related to this paper: torca-ACHE

Title : The Bivalent Ligand Approach as a Tool for Improving the in vitro Anti-Alzheimer Multitarget Profile of Dimebon - Rosini_2013_ChemMedChem_8_1276
Author(s) : Rosini M , Simoni E , Bartolini M , Soriano E , Marco-Contelles J , Andrisano V , Monti B , Windisch M , Hutter-Paier B , McClymont DW , Mellor IR , Bolognesi ML
Ref : ChemMedChem , 8 :1276 , 2013
Abstract : Inspired by the concept of bivalent ligands, we prepared a small set of analogues of the drug candidate dimebon. They were shown to inhibit AChE, Abeta42 aggregation, and NMDA receptor activation to a greater extent than dimebon. Some of these compounds also enhanced the survival of chicken neurons under apoptosis-inducing conditions.
ESTHER : Rosini_2013_ChemMedChem_8_1276
PubMedSearch : Rosini_2013_ChemMedChem_8_1276
PubMedID: 23824986

Title : Memory-enhancing drugs: a molecular perspective - Monti_2009_Mini.Rev.Med.Chem_9_769
Author(s) : Monti B , Contestabile A
Ref : Mini Rev Med Chem , 9 :769 , 2009
Abstract : Neurodegenerative diseases associated with dementia are characterized by cognitive deficits and memory impairment, thus stimulating research for memory enhancing drugs. We survey here the state of the art of research and clinical trials on these drugs from cholinesterase inhibitors and drugs acting on neurotransmitter receptors to drugs acting on gene expression.
ESTHER : Monti_2009_Mini.Rev.Med.Chem_9_769
PubMedSearch : Monti_2009_Mini.Rev.Med.Chem_9_769
PubMedID: 19519502