Campiani G

References (18)

Title : Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. SARs, Structural Analysis, and Biological Characterization - Butini_2024_J.Med.Chem__
Author(s) : Butini S , Grether U , Jung KM , Ligresti A , Allara M , Postmus AGJ , Maramai S , Brogi S , Papa A , Carullo G , Sykes D , Veprintsev D , Federico S , Grillo A , Di Guglielmo B , Ramunno A , Stevens AF , Heer D , Lamponi S , Gemma S , Benz J , Di Marzo V , van der Stelt M , Piomelli D , Campiani G
Ref : Journal of Medicinal Chemistry , : , 2024
Abstract : New potent, selective monoacylglycerol lipase (MAGL) inhibitors based on the azetidin-2-one scaffold ((+/-)-5a-v, (+/-)-6a-j, and (+/-)-7a-d) were developed as irreversible ligands, as demonstrated by enzymatic and crystallographic studies for (+/-)-5d, (+/-)-5l, and (+/-)-5r. X-ray analyses combined with extensive computational studies allowed us to clarify the binding mode of the compounds. 5v was identified as selective for MAGL when compared with other serine hydrolases. Solubility, in vitro metabolic stability, cytotoxicity, and absence of mutagenicity were determined for selected analogues. The most promising compounds ((+/-)-5c, (+/-)-5d, and (+/-)-5v) were used for in vivo studies in mice, showing a decrease in MAGL activity and increased 2-arachidonoyl-sn-glycerol levels in forebrain tissue. In particular, 5v is characterized by a high eudysmic ratio and (3R,4S)-5v is one of the most potent irreversible inhibitors of h/mMAGL identified thus far. These results suggest that the new MAGL inhibitors have therapeutic potential for different central and peripheral pathologies.
ESTHER : Butini_2024_J.Med.Chem__
PubMedSearch : Butini_2024_J.Med.Chem__
PubMedID: 38241614
Gene_locus related to this paper: human-MGLL

Title : Development of potent and selective FAAH inhibitors with improved drug-like properties as potential tools to treat neuroinflammatory conditions - Papa_2022_Eur.J.Med.Chem_246_114952
Author(s) : Papa A , Pasquini S , Galvani F , Cammarota M , Contri C , Carullo G , Gemma S , Ramunno A , Lamponi S , Gorelli B , Saponara S , Varani K , Mor M , Campiani G , Boscia F , Vincenzi F , Lodola A , Butini S
Ref : Eur Journal of Medicinal Chemistry , 246 :114952 , 2022
Abstract : The neuroprotective performance against neuroinflammation of the endocannabinoid system (ECS) can be remarkably improved by indirect stimulation mediated by the pharmacological inhibition of the key ECS catabolic enzyme fatty acid amide hydrolase (FAAH). Based on our previous works and aiming to discover new selective FAAH inhibitors , we herein reported a new series of carbamate-based FAAH inhibitors (4a-t) which showed improved drug disposition properties compared to the previously reported analogues 2a-b. The introduction of ionizable functions allowed us to obtain new FAAH inhibitors of nanomolar potency characterized by good water solubility and chemical stability at physiological pH. Interesting structure-activity relationships (SARs), deeply analyzed by molecular docking and molecular dynamic (MD) simulations, were obtained. All the newly developed inhibitors showed an excellent selectivity profile evaluated against monoacylglycerol lipase and cannabinoid receptors. The reversible mechanism of action was determined by a rapid dilution assay. Absence of toxicity was confirmed in mouse fibroblasts NIH3T3 (for compounds 4e, 4g, 4n-o, and 4s) and in human astrocytes cell line 1321N1 (for compounds 4e, 4n, and 4s). The absence of undesired cardiac effects was also confirmed for compound 4n. Selected analogues (compounds 4e, 4g, 4n, and 4s) were able to reduce oxidative stress in 1321N1 astrocytes and exhibited notable neuroprotective effects when tested in an ex vivo model of neuroinflammation.
ESTHER : Papa_2022_Eur.J.Med.Chem_246_114952
PubMedSearch : Papa_2022_Eur.J.Med.Chem_246_114952
PubMedID: 36462439

Title : Development of a Multiplexed Activity-Based Protein Profiling Assay to Evaluate Activity of Endocannabinoid Hydrolase Inhibitors - Janssen_2018_ACS.Chem.Biol_13_2406
Author(s) : Janssen APA , van der Vliet D , Bakker AT , Jiang M , Grimm SH , Campiani G , Butini S , van der Stelt M
Ref : ACS Chemical Biology , 13 :2406 , 2018
Abstract : Endocannabinoids, an important class of signaling lipids involved in health and disease, are predominantly synthesized and metabolized by enzymes of the serine hydrolase superfamily. Activity-based protein profiling (ABPP) using fluorescent probes, such as fluorophosphonate (FP)-TAMRA and beta-lactone-based MB064, enables drug discovery activities for serine hydrolases. FP-TAMRA and MB064 have distinct, albeit partially overlapping, target profiles but cannot be used in conjunction due to overlapping excitation/emission spectra. We therefore synthesized a novel FP-probe with a green BODIPY as a fluorescent tag and studied its labeling profile in mouse proteomes. Surprisingly, we found that the reporter tag plays an important role in the binding potency and selectivity of the probe. A multiplexed ABPP assay was developed in which a probe cocktail of FP-BODIPY and MB064 visualized most endocannabinoid serine hydrolases in mouse brain proteomes in a single experiment. The multiplexed ABPP assay was employed to profile endocannabinoid hydrolase inhibitor activity and selectivity in the mouse brain.
ESTHER : Janssen_2018_ACS.Chem.Biol_13_2406
PubMedSearch : Janssen_2018_ACS.Chem.Biol_13_2406
PubMedID: 30199617

Title : Multitarget compounds bearing tacrine- and donepezil-like structural and functional motifs for the potential treatment of Alzheimer's disease - Ismaili_2017_Prog.Neurobiol_151_4
Author(s) : Ismaili L , Refouvelet B , Benchekroun M , Brogi S , Brindisi M , Gemma S , Campiani G , Filipic S , Agbaba D , Esteban G , Unzeta M , Nikolic K , Butini S , Marco-Contelles J
Ref : Prog Neurobiol , 151 :4 , 2017
Abstract : Alzheimer's disease is a multifactorial and fatal neurodegenerative disorder characterized by decline of cholinergic function, deregulation of other neurotransmitter systems, beta-amyloid fibril deposition, and beta-amyloid oligomers formation. Based on the involvement of a relevant number of biological systems in Alzheimer's disease progression, multitarget compounds may enable therapeutic efficacy. Accordingly, compounds possessing, besides anticholinergic activity and beta-amyloid aggregation inhibition properties, metal chelating and/or nitric oxide releasing properties with additional antioxidant capacity were developed. Other targets relevant to Alzheimer's disease have also been considered in the last years for producing multitarget compounds such as beta-secretase, monoamino oxidases, serotonin receptors and sigma 1 receptors. The purpose of this review will be to highlight recent reports on the development of multitarget compounds for Alzheimer's disease published within the last years focusing on multifunctional ligands characterized by tacrine-like and donepezil-like structures.
ESTHER : Ismaili_2017_Prog.Neurobiol_151_4
PubMedSearch : Ismaili_2017_Prog.Neurobiol_151_4
PubMedID: 26797191

Title : Donepezil-like multifunctional agents: Design, synthesis, molecular modeling and biological evaluation - Wu_2016_Eur.J.Med.Chem_121_864
Author(s) : Wu MY , Esteban G , Brogi S , Shionoya M , Wang L , Campiani G , Unzeta M , Inokuchi T , Butini S , Marco-Contelles J
Ref : Eur Journal of Medicinal Chemistry , 121 :864 , 2016
Abstract : Currently available drugs against Alzheimer's disease (AD) are only able to ameliorate the disease symptoms resulting in a moderate improvement in memory and cognitive function without any efficacy in preventing and inhibiting the progression of the pathology. In an effort to obtain disease-modifying anti-Alzheimer's drugs (DMAADs) following the multifactorial nature of AD, we have recently developed multifunctional compounds. We herein describe the design, synthesis, molecular modeling and biological evaluation of a new series of donepezil-related compounds possessing metal chelating properties, and being capable of targeting different enzymatic systems related to AD (cholinesterases, ChEs, and monoamine oxidase A, MAO-A). Among this set of analogues compound 5f showed excellent ChEs inhibition potency and a selective MAO-A inhibition (vs MAO-B) coupled to strong complexing properties for zinc and copper ions, both known to be involved in the progression of AD. Moreover, 5f exhibited moderate antioxidant properties as found by in vitro assessment. This compound represents a novel donepezil-hydroxyquinoline hybrid with DMAAD profile paving the way to the development of a novel class of drugs potentially able to treat AD.
ESTHER : Wu_2016_Eur.J.Med.Chem_121_864
PubMedSearch : Wu_2016_Eur.J.Med.Chem_121_864
PubMedID: 26471320

Title : Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain - Brindisi_2016_J.Med.Chem_59_2612
Author(s) : Brindisi M , Maramai S , Gemma S , Brogi S , Grillo A , Di Cesare Mannelli L , Gabellieri E , Lamponi S , Saponara S , Gorelli B , Tedesco D , Bonfiglio T , Landry C , Jung KM , Armirotti A , Luongo L , Ligresti A , Piscitelli F , Bertucci C , Dehouck MP , Campiani G , Maione S , Ghelardini C , Pittaluga A , Piomelli D , Di Marzo V , Butini S
Ref : Journal of Medicinal Chemistry , 59 :2612 , 2016
Abstract : We report the discovery of compound 4a, a potent beta-lactam-based monoacylglycerol lipase (MGL) inhibitor characterized by an irreversible and stereoselective mechanism of action, high membrane permeability, high brain penetration evaluated using a human in vitro blood-brain barrier model, high selectivity in binding and affinity-based proteomic profiling assays, and low in vitro toxicity. Mode-of-action studies demonstrate that 4a, by blocking MGL, increases 2-arachidonoylglycerol and behaves as a cannabinoid (CB1/CB2) receptor indirect agonist. Administration of 4a in mice suffering from experimental autoimmune encephalitis ameliorates the severity of the clinical symptoms in a CB1/CB2-dependent manner. Moreover, 4a produced analgesic effects in a rodent model of acute inflammatory pain, which was antagonized by CB1 and CB2 receptor antagonists/inverse agonists. 4a also relieves the neuropathic hypersensitivity induced by oxaliplatin. Given these evidence, 4a, as MGL selective inhibitor, could represent a valuable lead for the future development of therapeutic options for multiple sclerosis and chronic pain.
ESTHER : Brindisi_2016_J.Med.Chem_59_2612
PubMedSearch : Brindisi_2016_J.Med.Chem_59_2612
PubMedID: 26888301

Title : Endocannabinoid Modulation of Predator Stress-Induced Long-Term Anxiety in Rats - Lim_2016_Neuropsychopharmacology_41_1329
Author(s) : Lim J , Igarashi M , Jung KM , Butini S , Campiani G , Piomelli D
Ref : Neuropsychopharmacology , 41 :1329 , 2016
Abstract : Individuals who experience life-threatening psychological trauma are at risk of developing a series of chronic neuropsychiatric pathologies that include generalized anxiety, depression, and drug addiction. The endocannabinoid system has been implicated in the modulation of these responses by regulating the activity of the amygdala and the hypothalamic-pituitary-adrenal axis. However, the relevance of this signaling complex to the long-term consequences of traumatic events is unclear. Here we use an animal model of predatory stress-induced anxiety-like behavior to investigate the role of the endocannabinoid system in the development of persistent anxiety states. Our main finding is that rats exposed to the fox pheromone 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a life-threatening stimulus for rodents, display a marked and selective increase in the mobilization of the endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG), in the amygdala. This effect lasts for at least 14 days after the stress has occurred. In addition, systemic or local pharmacological inhibition of monoacylglycerol lipase (MGL)-a lipid hydrolase that degrades 2-AG in presynaptic nerve terminals-elevates 2-AG levels and suppresses the anxiety-like behavior elicited by exposure to TMT. The results suggest that predator threat triggers long-term changes in 2-AG-mediated endocannabinoid signaling in the amygdala, and that pharmacological interventions targeting MGL might provide a therapeutic strategy for the treatment of chronic brain disorders initiated by trauma.
ESTHER : Lim_2016_Neuropsychopharmacology_41_1329
PubMedSearch : Lim_2016_Neuropsychopharmacology_41_1329
PubMedID: 26361059

Title : Disease-Modifying Anti-Alzheimer's Drugs: Inhibitors of Human Cholinesterases Interfering with beta-Amyloid Aggregation - Brogi_2014_CNS.Neurosci.Ther_20_624
Author(s) : Brogi S , Butini S , Maramai S , Colombo R , Verga L , Lanni C , De Lorenzi E , Lamponi S , Andreassi M , Bartolini M , Andrisano V , Novellino E , Campiani G , Brindisi M , Gemma S
Ref : CNS Neurosci Ther , 20 :624 , 2014
Abstract : AIMS: We recently described multifunctional tools (2a-c) as potent inhibitors of human Cholinesterases (ChEs) also able to modulate events correlated with Abeta aggregation. We herein propose a thorough biological and computational analysis aiming at understanding their mechanism of action at the molecular level.
METHODS: We determined the inhibitory potency of 2a-c on Abeta1-42 self-aggregation, the interference of 2a with the toxic Abeta oligomeric species and with the postaggregation states by capillary electrophoresis analysis and transmission electron microscopy. The modulation of Abeta toxicity was assessed for 2a and 2b on human neuroblastoma cells. The key interactions of 2a with Abeta and with the Abeta-preformed fibrils were computationally analyzed. 2a-c toxicity profile was also assessed (human hepatocytes and mouse fibroblasts).
RESULTS: Our prototypical pluripotent analogue 2a interferes with Abeta oligomerization process thus reducing Abeta oligomers-mediated toxicity in human neuroblastoma cells. 2a also disrupts preformed fibrils. Computational studies highlighted the bases governing the diversified activities of 2a. CONCLUSION: Converging analytical, biological, and in silico data explained the mechanism of action of 2a on Abeta1-42 oligomers formation and against Abeta-preformed fibrils. This evidence, combined with toxicity data, will orient the future design of safer analogues.
ESTHER : Brogi_2014_CNS.Neurosci.Ther_20_624
PubMedSearch : Brogi_2014_CNS.Neurosci.Ther_20_624
PubMedID: 24935788

Title : Multifunctional cholinesterase and amyloid Beta fibrillization modulators. Synthesis and biological investigation - Butini_2013_ACS.Med.Chem.Lett_4_1178
Author(s) : Butini S , Brindisi M , Brogi S , Maramai S , Guarino E , Panico A , Saxena A , Chauhan V , Colombo R , Verga L , De Lorenzi E , Bartolini M , Andrisano V , Novellino E , Campiani G , Gemma S
Ref : ACS Med Chem Lett , 4 :1178 , 2013
Abstract : In order to identify novel Alzheimer's modifying pharmacological tools, we developed bis-tacrines bearing a peptide moiety for specific interference with surface sites of human acetylcholinesterase (hAChE) binding amyloid-beta (Abeta). Accordingly, compounds 2a-c proved to be inhibitors of hAChE catalytic and noncatalytic functions, binding the catalytic and peripheral sites, interfering with Abeta aggregation and with the Abeta self-oligomerization process (2a). Compounds 2a-c in complex with TcAChE span the gorge with the bis-tacrine system, and the peptide moieties bulge outside the gorge in proximity of the peripheral site. These moieties are likely responsible for the observed reduction of hAChE-induced Abeta aggregation since they physically hamper Abeta binding to the enzyme surface. Moreover, 2a was able to significantly interfere with Abeta self-oligomerization, while 2b,c showed improved inhibition of hAChE-induced Abeta aggregation.
ESTHER : Butini_2013_ACS.Med.Chem.Lett_4_1178
PubMedSearch : Butini_2013_ACS.Med.Chem.Lett_4_1178
PubMedID: 24900626

Title : Exploiting protein fluctuations at the active-site gorge of human cholinesterases: further optimization of the design strategy to develop extremely potent inhibitors - Butini_2008_J.Med.Chem_51_3154
Author(s) : Butini S , Campiani G , Borriello M , Gemma S , Panico A , Persico M , Catalanotti B , Ros S , Brindisi M , Agnusdei M , Fiorini I , Nacci V , Novellino E , Belinskaya T , Saxena A , Fattorusso C
Ref : Journal of Medicinal Chemistry , 51 :3154 , 2008
Abstract : Protein conformational fluctuations are critical for biological functions, although the relationship between protein motion and function has yet to be fully explored. By a thorough bioinformatics analysis of cholinesterases (ChEs), we identified specific hot spots, responsible for protein fluctuations and functions, and those active-site residues that play a role in modulating the cooperative network among the key substructures. This drew the optimization of our design strategy to discover potent and reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase (hAChE and hBuChE) that selectively interact with specific protein substructures. Accordingly, two tricyclic moieties differently spaced by functionalized linkers were investigated as molecular yardsticks to probe the finest interactions with specific hot spots in the hChE gorge. A number of SAR trends were identified, and the multisite inhibitors 3a and 3d were found to be the most potent inhibitors of hBuChE and hAChE known to date.
ESTHER : Butini_2008_J.Med.Chem_51_3154
PubMedSearch : Butini_2008_J.Med.Chem_51_3154
PubMedID: 18479118

Title : Tacrine based human cholinesterase inhibitors: synthesis of peptidic-tethered derivatives and their effect on potency and selectivity - Butini_2008_Bioorg.Med.Chem.Lett_18_5213
Author(s) : Butini S , Guarino E , Campiani G , Brindisi M , Coccone SS , Fiorini I , Novellino E , Belinskaya T , Saxena A , Gemma S
Ref : Bioorganic & Medicinal Chemistry Lett , 18 :5213 , 2008
Abstract : Tacrine based reversible inhibitors of cholinesterases (ChEIs) containing peptidic tethers were synthesized to interact with specific regions at the gorge level, and their potency was determined with human (h) acetylcholinesterase and butyrylcholinesterase. Analogues 3i,j and 3l,m were identified as promising hits and may pave the way for the development of a new series of tacrine based enzyme selective hChEIs.
ESTHER : Butini_2008_Bioorg.Med.Chem.Lett_18_5213
PubMedSearch : Butini_2008_Bioorg.Med.Chem.Lett_18_5213
PubMedID: 18786825

Title : Discovery of huperzine A-tacrine hybrids as potent inhibitors of human cholinesterases targeting their midgorge recognition sites - Gemma_2006_J.Med.Chem_49_3421
Author(s) : Gemma S , Gabellieri E , Huleatt P , Fattorusso C , Borriello M , Catalanotti B , Butini S , De Angelis M , Novellino E , Nacci V , Belinskaya T , Saxena A , Campiani G
Ref : Journal of Medicinal Chemistry , 49 :3421 , 2006
Abstract : We describe herein the development of novel huperzine A-tacrine hybrids characterized by 3-methylbicyclo[3.3.1]non-3-ene scaffolds. These compounds were specifically designed to establish tight interactions, through different binding modes, with the midgorge recognition sites of human acetylcholinesterase (hAChE: Y72, D74) and human butyrylcholinesterase (hBuChE: N68, D70) and their catalytic or peripheral sites. Compounds 5a-c show a markedly improved biological profile relative to tacrine and huperzine A.
ESTHER : Gemma_2006_J.Med.Chem_49_3421
PubMedSearch : Gemma_2006_J.Med.Chem_49_3421
PubMedID: 16722663

Title : Conformational flexibility in the peripheral site of Torpedo californica acetylcholinesterase revealed by the complex structure with a bifunctional inhibitor - Colletier_2006_J.Am.Chem.Soc_128_4526
Author(s) : Colletier JP , Sanson B , Nachon F , Gabellieri E , Fattorusso C , Campiani G , Weik M
Ref : Journal of the American Chemical Society , 128 :4526 , 2006
Abstract : The X-ray crystallographic structure of Torpedo californica acetylcholinesterase (TcAChE) in complex with the bifunctional inhibitor NF595, a potentially new anti-Alzheimer drug, has been solved. For the first time in TcAChE, a major conformational change in the peripheral-site tryptophan residue is observed upon complexation. The observed conformational flexibility highlights the dynamic nature of protein structures and is of importance for structure-based drug design.
ESTHER : Colletier_2006_J.Am.Chem.Soc_128_4526
PubMedSearch : Colletier_2006_J.Am.Chem.Soc_128_4526
PubMedID: 16594661
Gene_locus related to this paper: torca-ACHE

Title : Development of molecular probes for the identification of extra interaction sites in the mid-gorge and peripheral sites of butyrylcholinesterase (BuChE). Rational design of novel, selective, and highly potent BuChE inhibitors - Campiani_2005_J.Med.Chem_48_1919
Author(s) : Campiani G , Fattorusso C , Butini S , Gaeta A , Agnusdei M , Gemma S , Persico M , Catalanotti B , Savini L , Nacci V , Novellino E , Holloway HW , Greig NH , Belinskaya T , Fedorko JM , Saxena A
Ref : Journal of Medicinal Chemistry , 48 :1919 , 2005
Abstract : Tacrine heterobivalent ligands were designed as novel and reversible inhibitors of cholinesterases. On the basis of the investigation of the active site gorge topology of butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) and by using flexible docking procedures, molecular modeling studies formulated the hypothesis of extra interaction sites in the active gorge of hBuChE, namely, a mid-gorge interaction site and a peripheral interaction site. The design strategy led to novel BuChE inhibitors, balancing potency and selectivity. Among the compounds identified, the heterobivalent ligand 4m, containing an amide nitrogen and a sulfur atom at the 8-membered tether level, is one of the most potent and selective BuChE inhibitors described to date. The novel inhibitors, bearing postulated key features, validated the hypothesis of the presence of extra interaction sites within the hBuChE active site gorge.
ESTHER : Campiani_2005_J.Med.Chem_48_1919
PubMedSearch : Campiani_2005_J.Med.Chem_48_1919
PubMedID: 15771436

Title : Poster (99) Rational design, synthesis and pharmacological evaluation of novel, selective and highly potent cholinesterase inhibitors -
Author(s) : Gaeta A , Savini L , Fattorusso C , Catalanotti B , Campiani G , Chiasserini L , Pellerano C , McKissic D , Saxena A
Ref : In: Cholinesterases in the Second Millennium: Biomolecular and Pathological Aspects , (Inestrosa NC, Campos EO) P. Universidad Catolica de Chile-FONDAP Biomedicina :372 , 2004
PubMedID:

Title : Specific targeting of acetylcholinesterase and butyrylcholinesterase recognition sites. Rational design of novel, selective, and highly potent cholinesterase inhibitors - Savini_2003_J.Med.Chem_46_1
Author(s) : Savini L , Gaeta A , Fattorusso C , Catalanotti B , Campiani G , Chiasserini L , Pellerano C , Novellino E , McKissic D , Saxena A
Ref : Journal of Medicinal Chemistry , 46 :1 , 2003
Abstract : Tacrine-based AChE and BCHE inhibitors were designed by investigating the topology of the active site gorge of the two enzymes. The homobivalent ligands characterized by a nitrogen-bridged atom at the tether level could be considered among the most potent and selective cholinesterase inhibitors described to date. The nitrogen-containing homobivalent ligands 3e,g and the sulfur-containing 3h validated the hypothesis of extra sites of interaction in the AChE and BCHE active site gorges.
ESTHER : Savini_2003_J.Med.Chem_46_1
PubMedSearch : Savini_2003_J.Med.Chem_46_1
PubMedID: 12502352

Title : Novel and potent tacrine-related hetero- and homobivalent ligands for acetylcholinesterase and butyrylcholinesterase - Savini_2001_Bioorg.Med.Chem.Lett_11_1779
Author(s) : Savini L , Campiani G , Gaeta A , Pellerano C , Fattorusso C , Chiasserini L , Fedorko JM , Saxena A
Ref : Bioorganic & Medicinal Chemistry Lett , 11 :1779 , 2001
Abstract : Based upon synthetic and biochemical results, a novel and potent tacrine analogue and heterobivalent analogues of tacrine, were designed. The role played by the amino groups of homo- and heterobivalent ligands in the interaction with the peripheral and catalytic sites of AChE and BuChE were investigated. The syntheses of these materials together with the results of AChE/BuChE inhibition assays are detailed.
ESTHER : Savini_2001_Bioorg.Med.Chem.Lett_11_1779
PubMedSearch : Savini_2001_Bioorg.Med.Chem.Lett_11_1779
PubMedID: 11425559

Title : Synthesis and anticholinesterase activity of huperzine A analogues containing phenol and catechol replacements for the pyridone ring - Campiani_1998_Bioorg.Med.Chem.Lett_8_1413
Author(s) : Campiani G , Kozikowski AP , Wang S , Ming L , Nacci V , Saxena A , Doctor BP
Ref : Bioorganic & Medicinal Chemistry Lett , 8 :1413 , 1998
Abstract : Based upon modeling results obtained using the crystal structure of huperzine A in complex with acetylcholinesterase (AChE), two novel analogues of this potent AChE inhibitor were designed with phenol or catechol rings replacing the pyridone ring. From the modeling studies, the catechol analogue appeared capable of replacing one of the crystallographic waters bridging huperzine with Tyr 130 and Glu 199 of AChE. The synthesis of these materials by use of a palladium catalyzed bicycloannulation strategy is detailed together with the results of AChE inhibition assays.
ESTHER : Campiani_1998_Bioorg.Med.Chem.Lett_8_1413
PubMedSearch : Campiani_1998_Bioorg.Med.Chem.Lett_8_1413
PubMedID: 9871776