Catto M

References (51)

Title : Novel 6-alkyl-bridged 4-arylalkylpiperazin-1-yl derivatives of azepino[4,3-b]indol-1(2H)-one as potent BChE-selective inhibitors showing protective effects against neurodegenerative insults - Samarelli_2024_Eur.J.Med.Chem_270_116353
Author(s) : Samarelli F , Purgatorio R , Lopopolo G , Deruvo C , Catto M , Andresini M , Carrieri A , Nicolotti O , De Palma A , Miniero DV , de Candia M , Altomare CD
Ref : Eur Journal of Medicinal Chemistry , 270 :116353 , 2024
Abstract : Due to the putative role of butyrylcholinesterase (BChE) in regulation of acetylcholine levels and functions in the late stages of the Alzheimer's disease (AD), the potential of selective inhibitors (BChEIs) has been envisaged as an alternative to administration of acetylcholinesterase inhibitors (AChEIs). Starting from our recent findings, herein the synthesis and in vitro evaluation of cholinesterase (ChE) inhibition of a novel series of some twenty 3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one derivatives, bearing at the indole nitrogen diverse alkyl-bridged 4-arylalkylpiperazin-1-yl chains, are reported. The length of the spacers, as well as the type of arylalkyl group affected the enzyme inhibition potency and BChE/AChE selectivity. Two compounds, namely 14c (IC(50) = 163 nM) and 14d (IC(50) = 65 nM), bearing at the nitrogen atom in position 6 a n-pentyl- or n-heptyl-bridged 4-phenethylpiperazin-1-yl chains, respectively, proved to be highly potent mixed-type inhibitors of both equine and human BChE isoforms, showing more than two order magnitude of selectivity over AChE. The study of binding kinetics through surface plasmon resonance (SPR) highlighted differences in their BChE residence times (8 and 47 s for 14c and 14d, respectively). Moreover, 14c and 14d proved to hit other mechanisms known to trigger neurodegeneration underlying AD and other CNS disorders. Unlike 14c, compound 14d proved also capable of inhibiting by more than 60% the in vitro self-induced aggregation of neurotoxic amyloid-beta (Abeta) peptide at 100 microM concentration. On the other hand, 14c was slightly better than 14d in counteracting, at 1 and 10 microM concentration, glutamate excitotoxicity, due to over-excitation of NMDA receptors, and hydrogen peroxide-induced oxidative stress assessed in neuroblastoma cell line SH-SY5Y. This paper is dedicated to Prof. Marcello Ferappi, former dean of the Faculty of Pharmacy of the University of Bari, in the occasion of his 90th birthday.
ESTHER : Samarelli_2024_Eur.J.Med.Chem_270_116353
PubMedSearch : Samarelli_2024_Eur.J.Med.Chem_270_116353
PubMedID: 38579622

Title : Chemical and Biological Evaluation of Novel 1H-Chromeno[3,2-c]pyridine Derivatives as MAO Inhibitors Endowed with Potential Anticancer Activity - Kulikova_2023_Int.J.Mol.Sci_24_
Author(s) : Kulikova LN , Purgatorio R , Beloglazkin AA , Tafeenko VA , Reza RG , Levickaya DD , Sblano S , Boccarelli A , de Candia M , Catto M , Voskressensky LG , Altomare CD
Ref : Int J Mol Sci , 24 : , 2023
Abstract : About twenty molecules sharing 1H-chromeno[3,2-c]pyridine as the scaffold and differing in the degree of saturation of the pyridine ring, oxidation at C10, 1-phenylethynyl at C1 and 1H-indol-3-yl fragments at C10, as well as a few small substituents at C6 and C8, were synthesized starting from 1,2,3,4-tetrahydro-2-methylchromeno[3,2-c]pyridin-10-ones (1,2,3,4-THCP-10-ones, 1) or 2,3-dihydro-2-methyl-1H-chromeno[3,2-c]pyridines (2,3-DHPCs, 2). The newly synthesized compounds were tested as inhibitors of the human isoforms of monoamine oxidase (MAO A and B) and cholinesterase (AChE and BChE), and the following main SARs were inferred: (i) The 2,3-DHCP derivatives 2 inhibit MAO A (IC(50) about 1 microM) preferentially; (ii) the 1,2,3,4-THCP-10-one 3a, bearing the phenylethynyl fragment at C1, returned as a potent MAO B inhibitor (IC(50) 0.51 microM) and moderate inhibitor of both ChEs (IC(50)s 7-8 microM); (iii) the 1H-indol-3-yl fragment at C10 slightly increases the MAO B inhibition potency, with the analog 6c achieving MAO B IC(50) of 3.51 microM. The MAO B inhibitor 3a deserves further pharmacological studies as a remedy in the symptomatic treatment of Parkinson's disease and neuroprotectant for Alzheimer's disease. Besides the established neuroprotective effects of MAO inhibitors, the role of MAOs in tumor insurgence and progression has been recently reported. Herein, antiproliferative assays with breast (MCF-7), colon (HCT116) and cisplatin-resistant ovarian (SK-OV-3) tumor cells revealed that the 10-indolyl-bearing 2,3,4,10-THCP analog 6c exerts anti-tumor activity with IC(50)s in the range 4.83-11.3 microM.
ESTHER : Kulikova_2023_Int.J.Mol.Sci_24_
PubMedSearch : Kulikova_2023_Int.J.Mol.Sci_24_
PubMedID: 37175433

Title : Thioxanthenone-based derivatives as multitarget therapeutic leads for Alzheimer's disease - Tonelli_2023_Eur.J.Med.Chem_250_115169
Author(s) : Tonelli M , Catto M , Sabate R , Francesconi V , Laurini E , Pricl S , Pisani L , Miniero DV , Liuzzi GM , Gatta E , Relini A , Gavin R , Del Rio JA , Sparatore F , Carotti A
Ref : Eur Journal of Medicinal Chemistry , 250 :115169 , 2023
Abstract : A set of twenty-five thioxanthene-9-one and xanthene-9-one derivatives, that were previously shown to inhibit cholinesterases (ChEs) and amyloid beta (Abeta(40)) aggregation, were evaluated for the inhibition of tau protein aggregation. All compounds exhibited a good activity, and eight of them (5-8, 10, 14, 15 and 20) shared comparable low micromolar inhibitory potency versus Abeta(40) aggregation and human acetylcholinesterase (AChE), while inhibiting human butyrylcholinesterase (BChE) even at submicromolar concentration. Compound 20 showed outstanding biological data, inhibiting tau protein and Abeta(40) aggregation with IC(50) = 1.8 and 1.3 microM, respectively. Moreover, at 0.1-10 microM it also exhibited neuroprotective activity against tau toxicity induced by okadoic acid in human neuroblastoma SH-SY5Y cells, that was comparable to that of estradiol and PD38. In preliminary toxicity studies, these interesting results for compound 20 are somewhat conflicting with a narrow safety window. However, compound 10, although endowed with a little lower potency for tau and Abeta aggregation inhibition additionally demonstrated good inhibition of ChEs and rather low cytotoxicity. Compound 4 is also worth of note for its high potency as hBChE inhibitor (IC(50) = 7 nM) and for the three order of magnitude selectivity versus hAChE. Molecular modelling studies were performed to explain the different behavior of compounds 4 and 20 towards hBChE. The observed balance of the inhibitory potencies versus the relevant targets indicates the thioxanthene-9-one derivatives as potential MTDLs for AD therapy, provided that the safety window will be improved by further structural variations, currently under investigation.
ESTHER : Tonelli_2023_Eur.J.Med.Chem_250_115169
PubMedSearch : Tonelli_2023_Eur.J.Med.Chem_250_115169
PubMedID: 36753881

Title : Investigation on Novel E\/Z 2-Benzylideneindan-1-One-Based Photoswitches with AChE and MAO-B Dual Inhibitory Activity - Paolino_2023_Molecules_28_
Author(s) : Paolino M , de Candia M , Purgatorio R , Catto M , Saletti M , Tondo AR , Nicolotti O , Cappelli A , Brizzi A , Mugnaini C , Corelli F , Altomare CD
Ref : Molecules , 28 : , 2023
Abstract : The multitarget therapeutic strategy, as opposed to the more traditional 'one disease-one target-one drug', may hold promise in treating multifactorial neurodegenerative syndromes, such as Alzheimer's disease (AD) and related dementias. Recently, combining a photopharmacology approach with the multitarget-directed ligand (MTDL) design strategy, we disclosed a novel donepezil-like compound, namely 2-(4-((diethylamino)methyl)benzylidene)-5-methoxy-2,3-dihydro-1H-inden-1-one (1a), which in the E isomeric form (and about tenfold less in the UV-B photo-induced isomer Z) showed the best activity as dual inhibitor of the AD-related targets acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Herein, we investigated further photoisomerizable 2-benzylideneindan-1-one analogs 1b-h with the unconjugated tertiary amino moiety bearing alkyls of different bulkiness and lipophilicity. For each compound, the thermal stable E geometric isomer, along with the E/Z mixture as produced by UV-B light irradiation in the photostationary state (PSS, 75% Z), was investigated for the inhibition of human ChEs and MAOs. The pure E-isomer of the N-benzyl(ethyl)amino analog 1h achieved low nanomolar AChE and high nanomolar MAO-B inhibition potencies (IC(50)s 39 and 355 nM, respectively), whereas photoisomerization to the Z isomer (75% Z in the PSS mixture) resulted in a decrease (about 30%) of AChE inhibitory potency, and not in the MAO-B one. Molecular docking studies were performed to rationalize the different E/Z selectivity of 1h toward the two target enzymes.
ESTHER : Paolino_2023_Molecules_28_
PubMedSearch : Paolino_2023_Molecules_28_
PubMedID: 37570828

Title : Novel benzothiazole derivatives as multitargeted-directed ligands for the treatment of Alzheimer's disease - Hafez_2023_J.Enzyme.Inhib.Med.Chem_38_2175821
Author(s) : Hafez DE , Dubiel M , La Spada G , Catto M , Reiner-Link D , Syu YT , Abdel-Halim M , Hwang TL , Stark H , Abadi AH
Ref : J Enzyme Inhib Med Chem , 38 :2175821 , 2023
Abstract : Neurodegenerative diseases such as Alzheimer's disease (AD) are multifactorial with several different pathologic mechanisms. Therefore, it is assumed that multitargeted-directed ligands (MTDLs) which interact with different biological targets relevant to the diseases, might offer an improved therapeutic alternative than using the traditional "one-target, one-molecule" approach. Herein, we describe new benzothiazole-based derivatives as a privileged scaffold for histamine H(3) receptor ligands (H(3)R). The most affine compound, the 3-(azepan-1-yl)propyloxy-linked benzothiazole derivative 4b, displayed a K(i) value of 0.012 microM. The multitargeting potential of these H(3)R ligands towards AChE, BuChE and MAO-B enzymes was evaluated to yield compound 3s (pyrrolidin-1-yl-(6-((5-(pyrrolidin-1-yl)pentyl)oxy)benzo[d]thiazol-2-yl)methanone) as the most promising MTDL with a K(i) value of 0.036 microM at H(3)R and IC(50) values of 6.7 microM, 2.35 microM, and 1.6 microM towards AChE, BuChE, and MAO-B, respectively. These findings suggest that compound 3s can be a lead structure for developing new multi-targeting anti-AD agents.
ESTHER : Hafez_2023_J.Enzyme.Inhib.Med.Chem_38_2175821
PubMedSearch : Hafez_2023_J.Enzyme.Inhib.Med.Chem_38_2175821
PubMedID: 36789662

Title : In-vitro and in-silico studies of annelated 1,4,7,8-tetrahydroazocine ester derivatives as nanomolar selective inhibitors of human butyrylcholinesterase - de Candia_2023_Chem.Biol.Interact_14ChEPon_110741
Author(s) : de Candia M , Titov AA , Viayna A , Kulikova LN , Purgatorio R , Piergiovanni B , Niso M , Catto M , Voskressensky LG , Luque FJ , Altomare CD
Ref : Chemico-Biological Interactions , :110741 , 2023
Abstract : Based on previous finding showing 2,3,6,11-tetrahydro-1H-azocino[4,5-b]indole as suitable scaffold of novel inhibitors of acetylcholinesterase (AChE), a main target of drugs for the treatment Alzheimer disease and related dementias, herein we investigated diverse newly and previously synthesized beta-enamino esters (and ketones) derivatives of 1,4,7,8-tetrahydroazocines (and some azonines) fused with benzene, 1H-indole, 4H-chromen-4-one and pyrimidin-4(3H)-one. Twenty derivatives of diversely annelated eight-to-nine-membered azaheterocyclic ring, prepared through domino reaction of the respective tetrahydropyridine and azepine with activated alkynes, were assayed for the inhibitory activity against AChE and butyrylcholinesterase (BChE). As a major outcome, compound 7c, an alkylamino derivative of tetrahydropyrimido[4,5-d]azocine, was found to be a highly potent BChE-selective inhibitor, which showed a noncompetitive/mixed-type inhibition mechanism against human BChE with single digit nanomolar inhibition constant (K(i) = 7.8 +/- 0.2 nM). The four-order magnitude BChE-selectivity of 7c clearly reflects the effect of lipophilicity upon binding to the BChE binding cavity. The ChEs' inhibition data, interpreted by chemoinformatic tools and an in-depth in-silico study (molecular docking combined with molecular dynamics calculations), not only highlighted key structural factors enhancing inhibition potency and selectivity toward BChE, but also shed light on subtle differences distinguishing the binding sites of equine BChE from the recombinant human BChE. Compound 7c inhibited P-glycoprotein with IC(50) of 0.27 microM, which may support its ability to permeate blood-brain barrier, and proved to be no cytotoxic in human liver cancer cell line (HepG2) at the BChE bioactive concentrations. Overall, the biological profile allows us to envision 7c as a promising template to improve design and development of BChE-selective ligands of pharmaceutical interest, including inhibitors and fluorogenic probes.
ESTHER : de Candia_2023_Chem.Biol.Interact_14ChEPon_110741
PubMedSearch : de Candia_2023_Chem.Biol.Interact_14ChEPon_110741
PubMedID: 37839515

Title : Novel thienocycloalkylpyridazinones as useful scaffolds for acetylcholinesterase inhibition and serotonin 5-HT(6) receptor interaction - Asproni_2023_Bioorg.Med.Chem_84_117256
Author(s) : Asproni B , Catto M , Loriga G , Murineddu G , Corona P , Purgatorio R , Cichero E , Fossa P , Scarano N , Martinez AL , Brea J , Pinna GA
Ref : Bioorganic & Medicinal Chemistry , 84 :117256 , 2023
Abstract : A library of eighteen thienocycloalkylpyridazinones was synthesized for human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibition and serotonin 5-HT(6) receptor subtype interaction by following a multitarget-directed ligand approach (MTDL), as a suitable strategy for treatment of Alzheimer's disease (AD). The novel compounds featured a tricyclic scaffold, namely thieno[3,2-h]cinnolinone, thienocyclopentapyridazinone and thienocycloheptapyridazinone, connected through alkyl chains of variable length to proper amine moieties, most often represented by N-benzylpiperazine or 1-(phenylsulfonyl)-4-(piperazin-1-ylmethyl)-1H-indole as structural elements addressing AChE and 5-HT(6) interaction, respectively. Our study highlighted the versatility of thienocycloalkylpyridazinones as useful architectures for AChE interaction, with several N-benzylpiperazine-based analogues emerging as potent and selective hAChE inhibitors with IC(50) in the 0.17-1.23 microM range, exhibiting low to poor activity for hBChE (IC(50) = 4.13-9.70 microM). The introduction of 5-HT(6) structural moiety phenylsulfonylindole in place of N-benzylpiperazine, in tandem with a pentamethylene linker, gave potent 5-HT(6) thieno[3,2-h]cinnolinone and thienocyclopentapyridazinone-based ligands both displaying hAChE inhibition in the low micromolar range and unappreciable activity towards hBChE. While docking studies provided a rational structural explanation for AChE/BChE enzyme and 5-HT(6) receptor interaction, in silico prediction of ADME properties of tested compounds suggested further optimization for development of such compounds in the field of MTDL for AD.
ESTHER : Asproni_2023_Bioorg.Med.Chem_84_117256
PubMedSearch : Asproni_2023_Bioorg.Med.Chem_84_117256
PubMedID: 37003157

Title : Structure-based design of novel donepezil-like hybrids for a multi-target approach to the therapy of Alzheimer's disease - Brunetti_2022_Eur.J.Med.Chem_237_114358
Author(s) : Brunetti L , Leuci R , Carrieri A , Catto M , Occhineri S , Vinci G , Gambacorta L , Baltrukevich H , Chaves S , Laghezza A , Altomare CD , Tortorella P , Santos MA , Loiodice F , Piemontese L
Ref : Eur Journal of Medicinal Chemistry , 237 :114358 , 2022
Abstract : Alzheimer's disease (AD) is a widespread multifactorial aging-related pathology, which includes cholinergic deficit among its main causes. Following a multi-target design strategy, the structure of the approved drug donepezil was taken as the starting point for generating some new potential multi-functional compounds. Therefore, a series of twenty molecular hybrids were synthesized and assayed against three different enzymes, namely the well-established targets acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the innovative one fatty acid amide hydrolase (FAAH). In silico studies confirmed the interaction of benzylpiperidine and the benzylpiperazine isostere with the catalytic anionic site (CAS) of AChE, while the aryloxycarbonyl portion appeared to be important for the interaction with the peripheral site (PAS). A QSAR study was carried out on AChE inhibition data, which revealed that the inhibition potency seems to depend upon the length of the spacer and the number of polar atoms. The docking poses of selected compounds within BChE and FAAH were also calculated. Furthermore, pharmacokinetics and drug-likeness properties were assessed by chemoinformatic tools. Several piperidine derivatives (in particular compound 10) showed interesting profiles as multi-target directed agents, while the lead piperazine derivative 12 (SON38) was found to be a more potent and selective AChE inhibitor (IC(50) = 0.8 nM) than donepezil, besides being able to bind bivalent copper cations (pCu = 7.9 at physiological pH). Finally, the selected lead compounds (10 and 12, SON38) did not show significant cytotoxicity on SH-SY5Y and HepG2 cells at the highest tested concentration (100 microM) in a MTT assay.
ESTHER : Brunetti_2022_Eur.J.Med.Chem_237_114358
PubMedSearch : Brunetti_2022_Eur.J.Med.Chem_237_114358
PubMedID: 35462163

Title : Assessing the Role of a Malonamide Linker in the Design of Potent Dual Inhibitors of Factor Xa and Cholinesterases - Purgatorio_2022_Molecules_27_
Author(s) : Purgatorio R , Gambacorta N , Samarelli F , Lopopolo G , de Candia M , Catto M , Nicolotti O , Altomare CD
Ref : Molecules , 27 : , 2022
Abstract : The rational discovery of new peptidomimetic inhibitors of the coagulation factor Xa (fXa) could help set more effective therapeutic options (to prevent atrial fibrillation). In this respect, we explored the conformational impact on the enzyme inhibition potency of the malonamide bridge, compared to the glycinamide one, as a linker connecting the P1 benzamidine anchoring moiety to the P4 aryl group of novel selective fXa inhibitors. We carried out structure-activity relationship (SAR) studies aimed at investigating para- or meta-benzamidine as the P1 basic group as well as diversely decorated aryl moieties as P4 fragments. To this end, twenty-three malonamide derivatives were synthesized and tested as inhibitors of fXa and thrombin (thr); the molecular determinants behind potency and selectivity were also studied by employing molecular docking. The malonamide linker, compared to the glycinamide one, does significantly increase anti-fXa potency and selectivity. The meta-benzamidine (P1) derivatives bearing 2',4'-difluoro-biphenyl as the P4 moiety proved to be highly potent reversible fXa-selective inhibitors, achieving inhibition constants (K(i)) in the low nanomolar range. The most active compounds were also tested against cholinesterase (ChE) isoforms (acetyl- or butyrylcholinesterase, AChE, and BChE), and some of them returned single-digit micromolar inhibition potency against AChE and/or BChE, both being drug targets for symptomatic treatment of mild-to-moderate Alzheimer's disease. Compounds 19h and 22b were selected as selective fXa inhibitors with potential as multimodal neuroprotective agents.
ESTHER : Purgatorio_2022_Molecules_27_
PubMedSearch : Purgatorio_2022_Molecules_27_
PubMedID: 35807514

Title : A New Series of Aryloxyacetic Acids Endowed with Multi-Target Activity towards Peroxisome Proliferator-Activated Receptors (PPARs), Fatty Acid Amide Hydrolase (FAAH), and Acetylcholinesterase (AChE) - Leuci_2022_Molecules_27_
Author(s) : Leuci R , Brunetti L , Laghezza A , Piemontese L , Carrieri A , Pisani L , Tortorella P , Catto M , Loiodice F
Ref : Molecules , 27 : , 2022
Abstract : A new series of aryloxyacetic acids was prepared and tested as peroxisome proliferator-activated receptors (PPARs) agonists and fatty acid amide hydrolase (FAAH) inhibitors. Some compounds exhibited an interesting dual activity that has been recently proposed as a new potential therapeutic strategy for the treatment of Alzheimer's disease (AD). AD is a multifactorial pathology, hence multi-target agents are currently one of the main lines of research for the therapy and prevention of this disease. Given that cholinesterases represent one of the most common targets of recent research, we decided to also evaluate the effects of our compounds on the inhibition of these specific enzymes. Interestingly, two of these compounds, (S)-5 and 6, showed moderate activity against acetylcholinesterase (AChE) and even some activity, although at high concentration, against Abeta peptide aggregation, thus demonstrating, in agreement with the preliminary dockings carried out on the different targets, the feasibility of a simultaneous multi-target activity towards PPARs, FAAH, and AChE. As far as we know, these are the first examples of molecules endowed with this pharmacological profile that might represent a promising line of research for the identification of novel candidates for the treatment of AD.
ESTHER : Leuci_2022_Molecules_27_
PubMedSearch : Leuci_2022_Molecules_27_
PubMedID: 35164223

Title : A twenty-year journey exploring coumarin-based derivatives as bioactive molecules - Pisani_2022_Front.Chem_10_1002547
Author(s) : Pisani L , Catto M , Muncipinto G , Nicolotti O , Carrieri A , Rullo M , Stefanachi A , Leonetti F , Altomare CD
Ref : Front Chem , 10 :1002547 , 2022
Abstract : The coumarin core (i.e., 1-benzopyran-2 (2H)-one) is a structural motif highly recurrent in both natural products and bioactive molecules. Indeed, depending on the substituents and branching positions around the byciclic core, coumarin-containing compounds have shown diverse pharmacological activities, ranging from anticoagulant activities to anti-inflammatory, antimicrobial, anti-HIV and antitumor effects. In this survey, we have reported the main scientific results of the 20-years investigation on the coumarin core, exploited by the research group headed by Prof. Angelo Carotti (Bari, Italy) either as a scaffold or a pharmacophore moiety in designing novel biologically active small molecules.
ESTHER : Pisani_2022_Front.Chem_10_1002547
PubMedSearch : Pisani_2022_Front.Chem_10_1002547
PubMedID: 36300022

Title : Towards Alzheimer's disease-related targets: One-pot Cu(I)- mediated synthesis of new nitroindazolyltriazoles - Eddahmi_2022_Bioorg.Chem_130_106261
Author(s) : Eddahmi M , La Spada G , Hafid A , Khouili M , Catto M , Bouissane L
Ref : Bioorg Chem , 130 :106261 , 2022
Abstract : In this work, we have investigated the one pot strategy for the Cu(I)-mediated synthesis of new triazoles bearing nitroindazole moieties using different copper catalysts. The biological activity of newly synthesized nitroindazolyltriazoles towards Alzheimer's disease-related targets, namely cholinesterases, monoamine oxidases, and amyloid aggregation, were investigated. Predictions of target affinity, physicochemical parameters, gastrointestinal absorption and brain penetration were achieved by means of in silico tools.
ESTHER : Eddahmi_2022_Bioorg.Chem_130_106261
PubMedSearch : Eddahmi_2022_Bioorg.Chem_130_106261
PubMedID: 36399866

Title : Dual Reversible Coumarin Inhibitors Mutually Bound to Monoamine Oxidase B and Acetylcholinesterase Crystal Structures - Ekstrom_2022_ACS.Med.Chem.Lett_13_499
Author(s) : Ekstrom F , Gottinger A , Forsgren N , Catto M , Iacovino LG , Pisani P , Binda C
Ref : ACS Med Chem Lett , 13 :499 , 2022
Abstract : Multitarget directed ligands (MTDLs) represent a promising frontier in tackling the complexity of multifactorial pathologies. The synergistic inhibition of monoamine oxidase B (MAO B) and acetylcholinesterase (AChE) is believed to provide a potentiated effect in the treatment of Alzheimer's disease. Among previously reported micromolar or sub-micromolar coumarin-bearing dual inhibitors, compound 1 returned a tight-binding inhibition of MAO B (Ki = 4.5 microM) and a +5.5 C increase in the enzyme Tm value. Indeed, the X-ray crystal structure revealed that binding of 1 produces unforeseen conformational changes at the MAO B entrance cavity. Interestingly, 1 showed great shape complementarity with the AChE enzymatic gorge, being deeply buried from the catalytic anionic subsite (CAS) to the peripheral anionic subsite (PAS) and causing significant structural changes in the active site. These findings provide structural templates for further development of dual MAO B and AChE inhibitors.
ESTHER : Ekstrom_2022_ACS.Med.Chem.Lett_13_499
PubMedSearch : Ekstrom_2022_ACS.Med.Chem.Lett_13_499
PubMedID: 35300078
Gene_locus related to this paper: mouse-ACHE

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 : Synthesis of Isomeric 3-Benzazecines Decorated with Endocyclic Allene Moiety and Exocyclic Conjugated Double Bond and Evaluation of Their Anticholinesterase Activity - Titov_2022_Molecules_27_
Author(s) : Titov AA , Purgatorio R , Obydennik AY , Listratova AV , Borisova TN , de Candia M , Catto M , Altomare CD , Varlamov AV , Voskressensky LG
Ref : Molecules , 27 : , 2022
Abstract : Transformations of 1-methoxymethylethynyl substituted isoquinolines triggered by terminal alkynes in alcohols were studied and new 3-benzazecine-containing compounds synthesized, such as 6-methoxymethyl-3-benzazecines incorporating an endocyclic C6-C8 allene fragment and the -ylidene derivatives 6-methoxymethylene-3-benzazecines. The reaction mechanisms were investigated and a preliminary in vitro screening of their potential inhibitory activities against human acetyl- and butyrylcholinesterases (AChE and BChE) and monoamine oxidases A and B (MAO-A and MAO-B) showed that the allene compounds were more potent than the corresponding -ylidene ones as selective AChE inhibitors. Among the allenes, 3e (R(3) = CH(2)OMe) was found to be a competitive AChE inhibitor with a low micromolar inhibition constant value (K(i) = 4.9 microM), equipotent with the corresponding 6-phenyl derivative 3n (R(3) = Ph, K(i) = 4.5 microM), but 90-fold more water-soluble.
ESTHER : Titov_2022_Molecules_27_
PubMedSearch : Titov_2022_Molecules_27_
PubMedID: 36234811

Title : Design, synthesis and biological evaluation of light-driven on-off multitarget AChE and MAO-B inhibitors - Paolino_2022_RSC.Med.Chem_13_873
Author(s) : Paolino M , Rullo M , Maramai S , de Candia M , Pisani L , Catto M , Mugnaini C , Brizzi A , Cappelli A , Olivucci M , Corelli F , Altomare CD
Ref : RSC Med Chem , 13 :873 , 2022
Abstract : Neurodegenerative diseases are multifactorial disorders characterized by protein misfolding, oxidative stress, and neuroinflammation, finally resulting in neuronal loss and cognitive dysfunctions. Nowadays, an attractive strategy to improve the classical treatments is the development of multitarget-directed molecules able to synergistically interact with different enzymes and/or receptors. In addition, an interesting tool to refine personalized therapies may arise from the use of bioactive species able to modify their activity as a result of light irradiation. To this aim, we designed and synthesized a small library of cinnamic acid-inspired isomeric compounds with light modulated activity able to inhibit acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B), with remarkable selectivity over butyrylcholinesterase (BChE) and MAO-A, which have been investigated as the enzyme targets related to Alzheimer's disease (AD). The inhibitory activities were evaluated for the pure E-diastereomers and the E/Z-diastereomer mixtures, obtained upon UV irradiation. Molecular docking studies were carried out to rationalize the differences in the inhibition potency of the E and Z diastereomers of the best performing analogue 1c. Our preliminary findings may open-up the way for developing innovative multitarget photo-switch drugs against neurodegenerative diseases.
ESTHER : Paolino_2022_RSC.Med.Chem_13_873
PubMedSearch : Paolino_2022_RSC.Med.Chem_13_873
PubMedID: 35923722

Title : Novel Phenothiazine\/Donepezil-like Hybrids Endowed with Antioxidant Activity for a Multi-Target Approach to the Therapy of Alzheimer's Disease - Carocci_2022_Antioxidants.(Basel)_11_
Author(s) : Carocci A , Barbarossa A , Leuci R , Carrieri A , Brunetti L , Laghezza A , Catto M , Limongelli F , Chaves S , Tortorella P , Altomare CD , Santos MA , Loiodice F , Piemontese L
Ref : Antioxidants (Basel) , 11 : , 2022
Abstract : Alzheimer's disease (AD) is a complex multi-factorial neurodegenerative disorder for which only few drugs (including donepezil, DPZ) are available as symptomatic treatments; thus, researchers are focusing on the development of innovative multi-target directed ligands (MTDLs), which could also alter the course of the disease. Among other pathological factors, oxidative stress has emerged as an important factor in AD that could affect several pathways involved in the onset and progression of the pathology. Herein, we propose a new series of hybrid molecules obtained by linking a phenothiazine moiety, known for its antioxidant properties, with N-benzylpiperidine or N-benzylpiperazine fragments, mimicking the core substructure of DPZ. The investigation of the resulting hybrids showed, in addition to their antioxidant properties, their activity against some AD-related targets, such as the inhibition of cholinesterases (both AChE and BChE) and in vitro Abeta(1-40) aggregation, as well as the inhibition of the innovative target fatty acid amide hydrolase (FAAH). Furthermore, the drug-likeness properties of these compounds were assessed using cheminformatic tools. Compounds 11d and 12d showed the most interesting multi-target profiles, with all the assayed activities in the low micromolar range. In silico docking calculations supported the obtained results. Compound 13, on the other hand, while inactive in the DPPH assay, showed the best results in the in vitro antioxidant cell assays conducted on both HepG2 and SHSY-5Y cell lines. These results, paired with the low or absent cytotoxicity of these compounds at tested concentrations, allow us to aim our future research at the study of novel and effective drugs and pro-drugs with similar structural characteristics.
ESTHER : Carocci_2022_Antioxidants.(Basel)_11_
PubMedSearch : Carocci_2022_Antioxidants.(Basel)_11_
PubMedID: 36139705

Title : Homobivalent Lamellarin-Like Schiff Bases: In Vitro Evaluation of Their Cancer Cell Cytotoxicity and Multitargeting Anti-Alzheimer's Disease Potential - Nevskaya_2021_Molecules_26_
Author(s) : Nevskaya AA , Anikina LV , Purgatorio R , Catto M , Nicolotti O , de Candia M , Pisani L , Borisova TN , Miftyakhova AR , Varlamov AV , Nevskaya EY , Borisov RS , Voskressensky LG , Altomare CD
Ref : Molecules , 26 : , 2021
Abstract : Marine alkaloids belonging to the lamellarins family, which incorporate a 5,6-dihydro-1-phenylpyrrolo[2,1-a]isoquinoline (DHPPIQ) moiety, possess various biological activities, spanning from antiviral and antibiotic activities to cytotoxicity against tumor cells and the reversal of multidrug resistance. Expanding a series of previously reported imino adducts of DHPPIQ 2-carbaldehyde, novel aliphatic and aromatic Schiff bases were synthesized and evaluated herein for their cytotoxicity in five diverse tumor cell lines. Most of the newly synthesized compounds were found noncytotoxic in the low micromolar range (<30 microM). Based on a Multi-fingerprint Similarity Search aLgorithm (MuSSeL), mainly conceived for making protein drug target prediction, some DHPPIQ derivatives, especially bis-DHPPIQ Schiff bases linked by a phenylene bridge, were prioritized as potential hits addressing Alzheimer's disease-related target proteins, such as cholinesterases (ChEs) and monoamine oxidases (MAOs). In agreement with MuSSeL predictions, homobivalent para-phenylene DHPPIQ Schiff base 14 exhibited a noncompetitive/mixed inhibition of human acetylcholinesterase (AChE) with K(i) in the low micromolar range (4.69 microM). Interestingly, besides a certain inhibition of MAO A (50% inhibition of the cell population growth (IC(50)) = 12 microM), the bis-DHPPIQ 14 showed a good inhibitory activity on self-induced beta-amyloid (Abeta)(1-40) aggregation (IC(50) = 13 microM), which resulted 3.5-fold stronger than the respective mono-DHPPIQ Schiff base 9.
ESTHER : Nevskaya_2021_Molecules_26_
PubMedSearch : Nevskaya_2021_Molecules_26_
PubMedID: 33445600

Title : Evaluation of water-soluble Mannich base prodrugs of 2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one as multitarget-directed agents for Alzheimer's disease - Purgatorio_2021_ChemMedChem_16_589
Author(s) : Purgatorio R , de Candia M , Catto M , Rullo M , Pisani L , Denora N , Carrieri A , Nevskaya AA , Voskressensky LG , Altomare CD
Ref : ChemMedChem , 16 :589 , 2021
Abstract : Aiming at addressing the poor aqueous solubility in in vivo assays of the recently disclosed 6-phenetyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (1), human butyrylcholinesterase inhibitor (hBChE, IC50 13 nM) and protective agent in NMDA-induced neurotoxicity, different Mannich base derivatives were studied. The N-(4-methylpiperazin-1-yl)methyl derivative 2c showed a 50-fold increase of solubility in pH 7.4 buffered solution, high stability in serum and pH 7.4 (half-life> 24 h) and rapid (< 3 min) conversion to 1 at acidic pH. Albeit less active than 1, 2c retained moderate hBChE inhibition (IC50 3.35 mM) and a significant protective effect against NMDA-induced neurotoxicity at 0.1 mM. Moreover, 2c resulted a weaker serum albumin binder than 1, a blood-brain barrier permeant, and exerted negligible cytotoxicity on HepG2 cells.These findings suggest that 2c could be a water-soluble prodrug candidate of 1for oral administration or a slow-release injectable derivativein in vivoAD models.
ESTHER : Purgatorio_2021_ChemMedChem_16_589
PubMedSearch : Purgatorio_2021_ChemMedChem_16_589
PubMedID: 33156950

Title : Synthesis of 8-phenyl substituted 3-benzazecines with allene moiety, their thermal rearrangement and evaluation as acetylcholinesterase inhibitors - Kobzev_2021_Mol.Divers__
Author(s) : Kobzev MS , Titov AA , Alexandrova EV , Purgatorio R , Catto M , Sorokina EA , Borisova TN , Varlamov AV , Altomare CD , Voskressensky LG
Ref : Mol Divers , : , 2021
Abstract : Various 4'-R-substituted phenyl azacyclic allenes were synthesized in good yields, and their thermal transformations were studied. For the first time, the obtained rearrangement products-new N-bridged cyclopenta[a]indenes, and the corresponding parent allenes were evaluated as potential inhibitors of acetyl- and butyrylcholinesterase. Among the tested compounds, the allene derivative 2g proved to competitively inhibit human AChE with inhibition constant value (K(i)) in the low micromolar range.
ESTHER : Kobzev_2021_Mol.Divers__
PubMedSearch : Kobzev_2021_Mol.Divers__
PubMedID: 33538985

Title : First-in-Class Isonipecotamide-Based Thrombin and Cholinesterase Dual Inhibitors with Potential for Alzheimer Disease - Purgatorio_2021_Molecules_26_
Author(s) : Purgatorio R , Gambacorta N , de Candia M , Catto M , Rullo M , Pisani L , Nicolotti O , Altomare CD
Ref : Molecules , 26 : , 2021
Abstract : Recently, the direct thrombin (thr) inhibitor dabigatran has proven to be beneficial in animal models of Alzheimer's disease (AD). Aiming at discovering novel multimodal agents addressing thr and AD-related targets, a selection of previously and newly synthesized potent thr and factor Xa (fXa) inhibitors were virtually screened by the Multi-fingerprint Similarity Searching aLgorithm (MuSSeL) web server. The N-phenyl-1-(pyridin-4-yl)piperidine-4-carboxamide derivative 1, which has already been experimentally shown to inhibit thr with a K(i) value of 6 nM, has been flagged by a new, upcoming release of MuSSeL as a binder of cholinesterase (ChE) isoforms (acetyl- and butyrylcholinesterase, AChE and BChE), as well as thr, fXa, and other enzymes and receptors. Interestingly, the inhibition potency of 1 was predicted by the MuSSeL platform to fall within the low-to-submicromolar range and this was confirmed by experimental K(i) values, which were found equal to 0.058 and 6.95 microM for eeAChE and eqBChE, respectively. Thirty analogs of 1 were then assayed as inhibitors of thr, fXa, AChE, and BChE to increase our knowledge of their structure-activity relationships, while the molecular determinants responsible for the multiple activities towards the target enzymes were rationally investigated by molecular cross-docking screening.
ESTHER : Purgatorio_2021_Molecules_26_
PubMedSearch : Purgatorio_2021_Molecules_26_
PubMedID: 34500640

Title : Away from Flatness: Unprecedented Nitrogen-Bridged Cyclopenta[a]indene Derivatives as Novel Anti-Alzheimer Multitarget Agents - Titov_2021_ACS.Chem.Neurosci__
Author(s) : Titov AA , Kobzev MS , Catto M , de Candia M , Gambacorta N , Denora N , Pisani L , Nicolotti O , Borisova TN , Varlamov AV , Voskressensky LG , Altomare CD
Ref : ACS Chem Neurosci , : , 2021
Abstract : Nature-inspired, bridged polycyclic molecules share low similarity with currently available drugs, containing preferentially planar and/or achiral moieties. This "Escape from Flatland" scenario, aimed at exploring pharmacological properties of atypical molecular scaffolds, finds interest in synthetic routes leading to tridimensional-shaped molecules. Herein we report on the synthesis of N-bridged cyclopenta[a]indene derivatives, achieved through microwave-assisted thermal rearrangement of allene 3-benzazecines with high diastereoselectivity. The biological evaluation disclosed selective inhibition of human acetylcholinesterase or butyrylcholinesterase, depending on the substitution around the molecular core, which was rationalized by means of docking simulations. The most potent BChE inhibitor 31 was effective in neuroprotection from glutamatergic excitotoxicity and displayed low intrinsic cytotoxicity and good brain penetration. Overall, compound 31 and its close congeners 34 and 35 acted as multitarget agents addressing different biological events involved in neurodegeneration, particularly in the progression of Alzheimer's disease.
ESTHER : Titov_2021_ACS.Chem.Neurosci__
PubMedSearch : Titov_2021_ACS.Chem.Neurosci__
PubMedID: 33395258

Title : Multitarget Biological Profiling of New Naphthoquinone and Anthraquinone-Based Derivatives for the Treatment of Alzheimer's Disease - Campora_2021_ACS.Chem.Neurosci__
Author(s) : Campora M , Canale C , Gatta E , Tasso B , Laurini E , Relini A , Pricl S , Catto M , Tonelli M
Ref : ACS Chem Neurosci , : , 2021
Abstract : Two series of naphthoquinone and anthraquinone derivatives decorated with an aromatic/heteroaromatic chain have been synthesized and evaluated as potential promiscuous agents capable of targeting different factors playing a key role in Alzheimer's disease (AD) pathogenesis. On the basis of the in vitro biological profiling, most of them exhibited a significant ability to inhibit amyloid aggregation, PHF6 tau sequence aggregation, acetylcholinesterase (AChE), and monoamine oxidase (MAO) B. In particular, naphthoquinone 2 resulted as one of the best performing multitarget-directed ligand (MTDL) experiencing a high potency profile in inhibiting beta-amyloid (Abeta(40)) aggregation (IC(50) = 3.2 microM), PHF6 tau fragment (91% at 10 microM), AChE enzyme (IC(50) = 9.2 microM) jointly with a remarkable inhibitory activity against MAO B (IC(50) = 7.7 nM). Molecular modeling studies explained the structure-activity relationship (SAR) around the binding modes of representative compound 2 in complex with hMAO B and hAChE enzymes, revealing inhibitor/protein key contacts and the likely molecular rationale for enzyme selectivity. Compound 2 was also demonstrated to be a strong inhibitor of Abeta(42) aggregation, with potency comparable to quercetin. Accordingly, atomic force microscopy (AFM) revealed that the most promising naphthoquinones 2 and 5 and anthraquinones 11 and 12 were able to impair Abeta(42) fibrillation, deconstructing the morphologies of its fibrillar aggregates. Moreover, the same compounds exerted a moderate neuroprotective effect against Abeta(42) toxicity in primary cultures of cerebellar granule cells. Therefore, our findings demonstrate that these molecules may represent valuable chemotypes toward the development of promising candidates for AD therapy.
ESTHER : Campora_2021_ACS.Chem.Neurosci__
PubMedSearch : Campora_2021_ACS.Chem.Neurosci__
PubMedID: 33428389

Title : Synthesis and biological evaluation of dantrolene-like hydrazide and hydrazone analogues as multitarget agents for neurodegenerative diseases - Bolognino_2021_ChemMedChem__
Author(s) : Bolognino I , Giangregorio N , Tonazzi A , Martinez AL , Altomare CD , Loza MI , Sablone S , Cellamare S , Catto M
Ref : ChemMedChem , : , 2021
Abstract : Dantrolene, a drug used for the management of malignant hyperthermia, had been recently evaluated for prospective repurposing as multitarget agent for neurodegenerative syndromes, including Alzheimer's disease (AD). Herein, twenty-one novel dantrolene-like hydrazide and hydrazone analogues were synthesized with the aim of exploring structure-activity relationships (SARs) for the inhibition of human monoamine oxidases (MAOs) and acetylcholinesterase (AChE), two well-established target enzymes for anti-AD drugs. With few exceptions, the newly synthesized compounds exhibited selectivity toward MAO B over either MAO A and AChE, with the secondary aldimine 9 and phenylhydrazone 20 attaining IC50 values of 0.68 and 0.81 microM, respectively. While no general SAR trend was observed with lipophilicity descriptors, a molecular simplification strategy allowed the main pharmacophore features to be identified, which are responsible for the inhibitory activity toward MAO B. Finally, further in vitro investigations revealed cell protection from oxidative insult and activation of carnitine/acylcarnitine carrier as concomitant biological activities responsible for neuroprotection by hits 9 and 20 and other promising compounds in the examined series.
ESTHER : Bolognino_2021_ChemMedChem__
PubMedSearch : Bolognino_2021_ChemMedChem__
PubMedID: 34047061

Title : First Synthesis of Racemic Trans Propargylamino-Donepezil, a Pleiotrope Agent Able to Both Inhibit AChE and MAO-B, with Potential Interest against Alzheimer's Disease - Guieu_2020_Molecules_26_
Author(s) : Guieu B , Lecoutey C , Legay R , Davis A , Sopkova de Oliveira Santos J , Altomare CD , Catto M , Rochais C , Dallemagne P
Ref : Molecules , 26 : , 2020
Abstract : Alzheimer's disease (AD) is a multifactorial neurodegenerative disease towards which pleiotropic approach using Multi-Target Directed Ligands is nowadays recognized as probably convenient. Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially if displayed by a sole agent such as ladostigil, currently in clinical trial in AD. Considering these results, we wanted to take benefit of the structural analogy lying in donepezil (DPZ) and rasagiline, two indane derivatives marketed as AChE and MAO-B inhibitors, respectively, and to propose the synthesis and the preliminary in vitro biological characterization of a structural compromise between these two compounds, we called propargylaminodonepezil (PADPZ). The synthesis of racemic trans PADPZ was achieved and its biological evaluation established its inhibitory activities towards both (h)AChE (IC(50) = 0.4 microM) and (h)MAO-B (IC(50) = 6.4 microM).
ESTHER : Guieu_2020_Molecules_26_
PubMedSearch : Guieu_2020_Molecules_26_
PubMedID: 33375412

Title : Chiral Separation, X-ray Structure, and Biological Evaluation of a Potent and Reversible Dual Binding Site AChE Inhibitor - Catto_2020_ACS.Med.Chem.Lett_11_869
Author(s) : Catto M , Pisani L , De la Mora E , Belviso BD , Mangiatordi GF , Pinto A , Palma A , Denora N , Caliandro R , Colletier JP , Silman I , Nicolotti O , Altomare CD
Ref : ACS Med Chem Lett , 11 :869 , 2020
Abstract : Acetylcholinesterase (AChE) inhibitors (AChEIs) still remain the leading therapeutic options for the symptomatic treatment of cognitive deficits associated with mild-to-moderate Alzheimer's disease. The search for new AChEIs benefits from well-established knowledge of the molecular interactions of selective AChEIs, such as donepezil and related dual binding site inhibitors. Starting from a previously disclosed coumarin-based inhibitor (+/-)-cis-1, active as racemate in the nanomolar range toward AChE, we proceeded on a double track by (i) achieving chiral resolution of the enantiomers of 1 by HPLC and (ii) preparing two close achiral analogues of 1, i.e., compounds 4 and 6. An eudismic ratio as high as 20 was observed for the (-) enantiomer of cis-1. The X-ray crystal structure of the complex between the (-)-cis-1 eutomer (coded as MC1420) and T. californica AChE was determined at 2.8 A, and docking calculation results suggested that the eutomer in (1R,3S) absolute configuration should be energetically more favored in binding the enzyme than the eutomer in (1S,3R) configuration. The achiral analogues 4 and 6 were less effective in inhibiting AChE compared to (+/-)-cis-1, but interestingly butylamide 4 emerged as a potent inhibitor of butyrylcholinesterase (BChE).
ESTHER : Catto_2020_ACS.Med.Chem.Lett_11_869
PubMedSearch : Catto_2020_ACS.Med.Chem.Lett_11_869
PubMedID: 32435398

Title : Scouting around 1,2,3,4-Tetrahydrochromeno[3,2-c]pyridin-10-ones for Single- and Multi-target Ligands Directed towards Relevant Alzheimer's Targets - Purgatorio_2020_ChemMedChem_15_1947
Author(s) : Purgatorio R , Kulikova L , Pisani L , Catto M , de Candia M , Carrieri A , Cellamare S , De Palma A , Beloglazkin A , Raesi GR , Voskressensky L , Altomare CD
Ref : ChemMedChem , 15 :1947 , 2020
Abstract : A number of 1,2,3,4-tetrahydrochromeno[3,2-c]pyridin-10-one derivatives were synthesized and screened against different targets involved in Alzheimer's Disease (AD) onset and progression, such as acetyl- and butyrylcholinesterase (AChE and BChE), monoamine oxidases A and B (MAO A and B), aggregation of beta-amyloid (Abeta) and reactive oxygen species (ROS) production. Thus, compounds showing multifaceted profiles of promising anti-AD features were identified as derivatives 1c, 3b, 4 and 5a, returning well-balanced multi-targeting inhibitory activities. Moreover, compound 1f, a potent and selective human MAO B inhibitor (IC50 = 0.89 muM), proved to be a safe neuroprotectant in human neuroblastoma cell line (SH-SY5Y) by improving viability impaired by Abeta1-42 and pro-oxidant insult. Furthermore, structure-activity relationships (SARs) and docking models were derived in order to assist further hit-to-lead optimization stage.
ESTHER : Purgatorio_2020_ChemMedChem_15_1947
PubMedSearch : Purgatorio_2020_ChemMedChem_15_1947
PubMedID: 32716595

Title : Chasing ChEs-MAO B Multi-Targeting 4-Aminomethyl-7-Benzyloxy-2H-Chromen-2-ones - Rullo_2019_Molecules_24_
Author(s) : Rullo M , Catto M , Carrieri A , de Candia M , Altomare CD , Pisani L
Ref : Molecules , 24 : , 2019
Abstract : A series of 4-aminomethyl-7-benzyloxy-2H-chromen-2-ones was investigated with the aim of identifying multiple inhibitors of cholinesterases (acetyl- and butyryl-, AChE and BChE) and monoamine oxidase B (MAO B) as potential anti-Alzheimer molecules. Starting from a previously reported potent MAO B inhibitor (3), we studied single-point modifications at the benzyloxy or at the basic moiety. The in vitro screening highlighted triple-acting compounds (6, 8, 9, 16, 20) showing nanomolar and selective MAO B inhibition along with IC50 against ChEs at the low micromolar level. Enzyme kinetics analysis toward AChE and docking simulations on the target enzymes were run in order to get insight into the mechanism of action and plausible binding modes.
ESTHER : Rullo_2019_Molecules_24_
PubMedSearch : Rullo_2019_Molecules_24_
PubMedID: 31835376

Title : A Prospective Repurposing of Dantrolene as a Multitarget Agent for Alzheimer's Disease - Bolognino_2019_Molecules_24_
Author(s) : Bolognino I , Giangregorio N , Pisani L , de Candia M , Purgatorio R , Tonazzi A , Altomare CD , Cellamare S , Catto M
Ref : Molecules , 24 : , 2019
Abstract : The orphan drug dantrolene (DAN) is the only therapeutic treatment for malignant hyperthermia (MH), a pharmacogenetic pathology affecting 0.2 over 10,000 people in the EU. It acts by inhibiting ryanodine receptors, which are responsible for calcium recruitment in striatal muscles and brain. Because of its involvement in calcium homeostasis, DAN has been successfully investigated for its potential as neuroprotecting small molecule in several animal models of Alzheimer's disease (AD). Nevertheless, its effects at a molecular level, namely on putative targets involved in neurodegeneration, are still scarcely known. Herein, we present a prospective study on repurposing of DAN involving, besides the well-known calcium antagonism, inhibition of monoamine oxidase B and acetylcholinesterase, cytoprotection from oxidative insult, and activation of carnitine/acylcarnitine carrier, as concurring biological activities responsible for neuroprotection.
ESTHER : Bolognino_2019_Molecules_24_
PubMedSearch : Bolognino_2019_Molecules_24_
PubMedID: 31775359

Title : Design, biological evaluation and X-ray crystallography of nanomolar multifunctional ligands targeting simultaneously acetylcholinesterase and glycogen synthase kinase-3 - Oukoloff_2019_Eur.J.Med.Chem_168_58
Author(s) : Oukoloff K , Coquelle N , Bartolini M , Naldi M , Le Guevel R , Bach S , Josselin B , Ruchaud S , Catto M , Pisani L , Denora N , Iacobazzi RM , Silman I , Sussman JL , Buron F , Colletier JP , Jean L , Routier S , Renard PY
Ref : Eur Journal of Medicinal Chemistry , 168 :58 , 2019
Abstract : Both cholinesterases (AChE and BChE) and kinases, such as GSK-3alpha/beta, are associated with the pathology of Alzheimer's disease. Two scaffolds, targeting AChE (tacrine) and GSK-3alpha/beta (valmerin) simultaneously, were assembled, using copper(I)-catalysed azide alkyne cycloaddition (CuAAC), to generate a new series of multifunctional ligands. A series of eight multi-target directed ligands (MTDLs) was synthesized and evaluated in vitro and in cell cultures. Molecular docking studies, together with the crystal structures of three MTDL/TcAChE complexes, with three tacrine-valmerin hybrids allowed designing an appropriate linker containing a 1,2,3-triazole moiety whose incorporation preserved, and even increased, the original inhibitory potencies of the two selected pharmacophores toward the two targets. Most of the new derivatives exhibited nanomolar affinity for both targets, and the most potent compound of the series displayed inhibitory potencies of 9.5nM for human acetylcholinesterase (hAChE) and 7nM for GSK-3alpha/beta. These novel dual MTDLs may serve as suitable leads for further development, since, in the micromolar range, they exhibited low cytotoxicity on a panel of representative human cell lines including the human neuroblastoma cell line SH-SY5Y. Moreover, these tacrine-valmerin hybrids displayed a good ability to penetrate the blood-brain barrier (BBB) without interacting with efflux pumps such as P-gp.
ESTHER : Oukoloff_2019_Eur.J.Med.Chem_168_58
PubMedSearch : Oukoloff_2019_Eur.J.Med.Chem_168_58
PubMedID: 30798053
Gene_locus related to this paper: torca-ACHE

Title : Investigating 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole as scaffold of butyrylcholinesterase-selective inhibitors with additional neuroprotective activities for Alzheimer's disease - Purgatorio_2019_Eur.J.Med.Chem_177_414
Author(s) : Purgatorio R , de Candia M , Catto M , Carrieri A , Pisani L , De Palma A , Toma M , Ivanova OA , Voskressensky LG , Altomare CD
Ref : Eur Journal of Medicinal Chemistry , 177 :414 , 2019
Abstract : Due to the role of butyrylcholinesterase (BChE) in acetylcholine hydrolysis in the late stages of the Alzheimer's disease (AD), inhibitors of butyrylcholinesterase (BChE) have been recently envisaged, besides acetylcholinesterase (AChE) inhibitors, as candidates for treating mild-to-moderate AD. Herein, synthesis and AChE/BChE inhibition activity of some twenty derivatives of 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (HHAI) is reported. Most of the newly synthesized HHAI derivatives achieved the inhibition of both ChE isoforms with IC50s in the micromolar range, with a structure-dependent selectivity toward BChE. Apparently, molecular volume and lipophilicity do increase selectivity toward BChE, and indeed the N(2)-(4-phenylbutyl) HHAI derivative 15d, which behaves as a mixed-type inhibitor, resulted the most potent (IC50 0.17muM) and selective (>100-fold) inhibitor toward either horse serum and human BChE. Moreover, 15d inhibited in vitro self-induced aggregation of neurotoxic amyloid-beta (Abeta) peptide and displayed neuroprotective effects in neuroblastoma SH-SY5Y cell line, significantly recovering (P<0.001) cell viability when impaired by Abeta1-42 and hydrogen peroxide insults. Overall, this study highlighted HHAI as useful and versatile scaffold for developing new small molecules targeting some enzymes and biochemical pathways involved in the pathogenesis of AD.
ESTHER : Purgatorio_2019_Eur.J.Med.Chem_177_414
PubMedSearch : Purgatorio_2019_Eur.J.Med.Chem_177_414
PubMedID: 31158754

Title : Coumarin: A Natural, Privileged and Versatile Scaffold for Bioactive Compounds - Stefanachi_2018_Molecules_23_
Author(s) : Stefanachi A , Leonetti F , Pisani L , Catto M , Carotti A
Ref : Molecules , 23 : , 2018
Abstract : Many naturally occurring substances, traditionally used in popular medicines around the world, contain the coumarin moiety. Coumarin represents a privileged scaffold for medicinal chemists, because of its peculiar physicochemical features, and the versatile and easy synthetic transformation into a large variety of functionalized coumarins. As a consequence, a huge number of coumarin derivatives have been designed, synthesized, and tested to address many pharmacological targets in a selective way, e.g., selective enzyme inhibitors, and more recently, a number of selected targets (multitarget ligands) involved in multifactorial diseases, such as Alzheimer's and Parkinson's diseases. In this review an overview of the most recent synthetic pathways leading to mono- and polyfunctionalized coumarins will be presented, along with the main biological pathways of their biosynthesis and metabolic transformations. The many existing and recent reviews in the field prompted us to make some drastic selections, and therefore, the review is focused on monoamine oxidase, cholinesterase, and aromatase inhibitors, and on multitarget coumarins acting on selected targets of neurodegenerative diseases.
ESTHER : Stefanachi_2018_Molecules_23_
PubMedSearch : Stefanachi_2018_Molecules_23_
PubMedID: 29382051

Title : Natural Scaffolds with Multi-Target Activity for the Potential Treatment of Alzheimer's Disease - Piemontese_2018_Molecules_23_
Author(s) : Piemontese L , Vitucci G , Catto M , Laghezza A , Perna FM , Rullo M , Loiodice F , Capriati V , Solfrizzo M
Ref : Molecules , 23 : , 2018
Abstract : A few symptomatic drugs are currently available for Alzheimer's Disease (AD) therapy, but these molecules are only able to temporary improve the cognitive capacity of the patients if administered in the first stages of the pathology. Recently, important advances have been achieved about the knowledge of this complex condition, which is now considered a multi-factorial disease. Researchers are, thus, more oriented toward the preparation of molecules being able to contemporaneously act on different pathological features. To date, the inhibition of acetylcholinesterase (AChE) and of beta-amyloid (Abeta) aggregation as well as the antioxidant activity and the removal and/or redistribution of metal ions at the level of the nervous system are the most common investigated targets for the treatment of AD. Since many natural compounds show multiple biological properties, a series of secondary metabolites of plants or fungi with suitable structural characteristics have been selected and assayed in order to evaluate their potential role in the preparation of multi-target agents. Out of six compounds evaluated, 1 showed the best activity as an antioxidant (EC50 = 2.6 +/- 0.2 mumol/micromol of DPPH) while compound 2 proved to be effective in the inhibition of AChE (IC50 = 6.86 +/- 0.67 muM) and Abeta1(-)40 aggregation (IC50 = 74 +/- 1 muM). Furthermore, compound 6 inhibited BChE (IC50 = 1.75 +/- 0.59 muM) with a good selectivity toward AChE (IC50 = 86.0 +/- 15.0 muM). Moreover, preliminary tests on metal chelation suggested a possible interaction between compounds 1, 3 and 4 and copper (II). Molecules with the best multi-target profiles will be used as starting hit compounds to appropriately address future studies of Structure-Activity Relationships (SARs).
ESTHER : Piemontese_2018_Molecules_23_
PubMedSearch : Piemontese_2018_Molecules_23_
PubMedID: 30158491

Title : Investigating alkyl nitrates as nitric oxide releasing precursors of multitarget acetylcholinesterase-monoamine oxidase B inhibitors - Pisani_2018_Eur.J.Med.Chem_161_292
Author(s) : Pisani L , Iacobazzi RM , Catto M , Rullo M , Farina R , Denora N , Cellamare S , Altomare CD
Ref : Eur Journal of Medicinal Chemistry , 161 :292 , 2018
Abstract : Herein we envisaged the possibility of exploiting alkyl nitrates as precursors of alcohol-bearing dual inhibitors targeting acetylcholinesterase (AChE) and monoamine oxidase B (MAO B), key enzymes in neurodegenerative syndromes such as Alzheimer's disease (AD), through biotransformation unmasking an alcoholic function upon nitric oxide (NO) release. The cooperation to neuroprotection of low fluxes of NO and target enzymes' inhibition by the alcohol metabolites might return a multitargeting effect. The in vitro screening towards ChEs and MAOs of a collection of 21 primary alcohols disclosed a subset of dual inhibitors, among which three diverse chemotypes were selected to study the corresponding nitrates. Nitrate 14 proved to be a brain permeant, potent AChE-MAO B inhibitor by itself. Moreover, it protected human SH-SY5Y lines against rotenone and hydrogen peroxide with a poor inherent cytotoxicity and showed a slow conversion profile to its alcohol metabolite 9d that still behaved as bimodal and neuroprotective molecule.
ESTHER : Pisani_2018_Eur.J.Med.Chem_161_292
PubMedSearch : Pisani_2018_Eur.J.Med.Chem_161_292
PubMedID: 30366255

Title : Discovery of Potent Dual Binding Site Acetylcholinesterase Inhibitors via Homo- and Heterodimerization of Coumarin-Based Moieties - Pisani_2017_ChemMedChem_12_1349
Author(s) : Pisani L , Catto M , De Palma A , Farina R , Cellamare S , Altomare CD
Ref : ChemMedChem , 12 :1349 , 2017
Abstract : Acetylcholinesterase (AChE) inhibitors still comprise the majority of the marketed drugs for Alzheimer's disease (AD). The structural arrangement of the enzyme, which features a narrow gorge that separates the catalytic and peripheral anionic subsites (CAS and PAS, respectively), inspired the development of bivalent ligands that are able to bind and block the catalytic activity of the CAS as well as the role of the PAS in beta amyloid (Abeta) fibrillogenesis. With the aim of discovering novel AChE dual binders with improved drug-likeness, homo- and heterodimers containing 2H-chromen-2-one building blocks were developed. By exploring diverse linkages of neutral and protonatable amino moieties through aliphatic spacers of different length, a nanomolar bivalent AChE inhibitor was identified (3-[2-({4-[(dimethylamino)methyl]-2-oxo-2H-chromen-7-yl}oxy)ethoxy]-6,7-dimethoxy -2H-chromen-2-one (6 d), IC50 =59 nm) from originally weakly active fragments. To assess the potential against AD, the disease-related biological properties of 6 d were investigated. It performed mixed-type AChE enzyme kinetics (inhibition constant Ki =68 nm) and inhibited Abeta self-aggregation. Moreover, it displayed an outstanding ability to protect SH-SY5Y cells from Abeta1-42 damage.
ESTHER : Pisani_2017_ChemMedChem_12_1349
PubMedSearch : Pisani_2017_ChemMedChem_12_1349
PubMedID: 28570763

Title : Mannich base approach to 5-methoxyisatin 3-(4-isopropylphenyl)hydrazone: A water-soluble prodrug for a multitarget inhibition of cholinesterases, beta-amyloid fibrillization and oligomer-induced cytotoxicity - Pisani_2017_Eur.J.Pharm.Sci_109_381
Author(s) : Pisani L , De Palma A , Giangregorio N , Miniero DV , Pesce P , Nicolotti O , Campagna F , Altomare CD , Catto M
Ref : Eur J Pharm Sci , 109 :381 , 2017
Abstract : Targeting protein aggregation for the therapy of neurodegenerative diseases remains elusive for medicinal chemists, despite a number of small molecules known to interfere in amyloidogenesis, particularly of amyloid beta (Abeta) protein. Starting from previous findings in the antiaggregating activity of a class of indolin-2-ones inhibiting Abeta fibrillization, 5-methoxyisatin 3-(4-isopropylphenyl)hydrazone 1 was identified as a multitarget inhibitor of Abeta aggregation and cholinesterases with IC50s in the low muM range. With the aim of increasing aqueous solubility, a Mannich-base functionalization led to the synthesis of N-methylpiperazine derivative 2. At acidic pH, an outstanding solubility increase of 2 over the parent compound 1 was proved through a turbidimetric method. HPLC analysis revealed an improved stability of the Mannich base 2 at pH2 along with a rapid release of 1 in human serum as well as an outstanding hydrolytic stability of the parent hydrazone. Coincubation of Abeta1-42 with 2 resulted in the accumulation of low MW oligomers, as detected with PICUP assay. Cell assays on SH-SY5Y cells revealed that 2 exerts strong cytoprotective effects in both cell viability and radical quenching assays, mainly related to its active metabolite 1. These findings show that 2 drives the formation of non-toxic, off-pathway Abeta oligomers unable to trigger the amyloid cascade and toxicity.
ESTHER : Pisani_2017_Eur.J.Pharm.Sci_109_381
PubMedSearch : Pisani_2017_Eur.J.Pharm.Sci_109_381
PubMedID: 28801274

Title : 3,4-Dihydroquinazoline derivatives inhibit the activities of cholinesterase enzymes - Park_2017_Bioorg.Med.Chem.Lett_27_1179
Author(s) : Park B , Nam JH , Kim JH , Kim HJ , Onnis V , Balboni G , Lee KT , Park JH , Catto M , Carotti A , Lee JY
Ref : Bioorganic & Medicinal Chemistry Lett , 27 :1179 , 2017
Abstract : A series of 3,4-dihydroquinazoline derivatives consisting of the selected compounds from our chemical library on the diversity basis and the new synthetic compounds were in vitro tested for their inhibitory activities for both acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum) enzymes. It was discovered that most of the compounds displayed weak AChE and strong BuChE inhibitory activities. In particular, compound 8b and 8d were the most active compounds in the series against BChE with IC50 values of 45nM and 62nM, as well as 146- and 161-fold higher affinity to BChE, respectively. To understand the excellent activity of these compounds, molecular docking simulations were performed to get better insights into the mechanism of binding of 3,4-dihydroquinazoline derivatives. As expected, compound 8b and 8d bind to both catalytic anionic site (CAS) and peripheral site (PS) of BChE with better interaction energy values than AChE, in agreement with our experimental data. Furthermore, the non-competitive/mixed-type inhibitions of both compounds further confirmed their dual binding nature in kinetic studies.
ESTHER : Park_2017_Bioorg.Med.Chem.Lett_27_1179
PubMedSearch : Park_2017_Bioorg.Med.Chem.Lett_27_1179
PubMedID: 28189420

Title : Searching for Multi-Targeting Neurotherapeutics against Alzheimer's: Discovery of Potent AChE-MAO B Inhibitors through the Decoration of the 2H-Chromen-2-one Structural Motif - Pisani_2016_Molecules_21_
Author(s) : Pisani L , Farina R , Soto-Otero R , Denora N , Mangiatordi GF , Nicolotti O , Mendez-Alvarez E , Altomare CD , Catto M , Carotti A
Ref : Molecules , 21 : , 2016
Abstract : The need for developing real disease-modifying drugs against neurodegenerative syndromes, particularly Alzheimer's disease (AD), shifted research towards reliable drug discovery strategies to unveil clinical candidates with higher therapeutic efficacy than single-targeting drugs. By following the multi-target approach, we designed and synthesized a novel class of dual acetylcholinesterase (AChE)-monoamine oxidase B (MAO-B) inhibitors through the decoration of the 2H-chromen-2-one skeleton. Compounds bearing a propargylamine moiety at position 3 displayed the highest in vitro inhibitory activities against MAO-B. Within this series, derivative 3h emerged as the most interesting hit compound, being a moderate AChE inhibitor (IC50 = 8.99 microM) and a potent and selective MAO-B inhibitor (IC50 = 2.8 nM). Preliminary studies in human neuroblastoma SH-SY5Y cell lines demonstrated its low cytotoxicity and disclosed a promising neuroprotective effect at low doses (0.1 microM) under oxidative stress conditions promoted by two mitochondrial toxins (oligomycin-A and rotenone). In a Madin-Darby canine kidney (MDCK)II-MDR1 cell-based transport study, Compound 3h was able to permeate the BBB-mimicking monolayer and did not result in a glycoprotein-p (P-gp) substrate, showing an efflux ratio = 0.96, close to that of diazepam.
ESTHER : Pisani_2016_Molecules_21_
PubMedSearch : Pisani_2016_Molecules_21_
PubMedID: 26999091

Title : Exploring Basic Tail Modifications of Coumarin-Based Dual Acetylcholinesterase-Monoamine Oxidase B Inhibitors: Identification of Water-Soluble, Brain-Permeant Neuroprotective Multitarget Agents - Pisani_2016_J.Med.Chem_59_6791
Author(s) : Pisani L , Farina R , Catto M , Iacobazzi RM , Nicolotti O , Cellamare S , Mangiatordi GF , Denora N , Soto-Otero R , Siragusa L , Altomare CD , Carotti A
Ref : Journal of Medicinal Chemistry , 59 :6791 , 2016
Abstract : Aiming at modulating two key enzymatic targets for Alzheimer's disease (AD), i.e., acetylcholinesterase (AChE) and monoamine oxidase B (MAO B), a series of multitarget ligands was properly designed by linking the 3,4-dimethylcoumarin scaffold to 1,3- and 1,4-substituted piperidine moieties, thus modulating the basicity to improve the hydrophilic/lipophilic balance. After in vitro enzymatic inhibition assays, multipotent inhibitors showing potencies in the nanomolar and in the low micromolar range for hMAO B and eeAChE, respectively, were prioritized and evaluated in human SH-SY5Y cell-based models for their cytotoxicity and neuroprotective effect against oxidative toxins (H2O2, rotenone, and oligomycin-A). The present study led to the identification of a promising multitarget hit compound (5b) exhibiting high hMAO B inhibitory activity (IC50 = 30 nM) and good MAO B/A selectivity (selectivity index, SI = 94) along with a micromolar eeAChE inhibition (IC50 = 1.03 muM). Moreover, 5b behaves as a water-soluble, brain-permeant neuroprotective agent against oxidative insults without interacting with P-gp efflux system.
ESTHER : Pisani_2016_J.Med.Chem_59_6791
PubMedSearch : Pisani_2016_J.Med.Chem_59_6791
PubMedID: 27347731

Title : Multitarget-directed tricyclic pyridazinones as g protein-coupled receptor ligands and cholinesterase inhibitors - Pau_2015_ChemMedChem_10_1054
Author(s) : Pau A , Catto M , Pinna G , Frau S , Murineddu G , Asproni B , Curzu MM , Pisani L , Leonetti F , Loza MI , Brea J , Pinna GA , Carotti A
Ref : ChemMedChem , 10 :1054 , 2015
Abstract : By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G protein-coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone-based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5-HT1A , adrenergic alpha1A , and dopaminergic D2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5-HT1A because of its involvement in neuronal deficits typical of Alzheimer's and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of alpha1A and 5-HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles.
ESTHER : Pau_2015_ChemMedChem_10_1054
PubMedSearch : Pau_2015_ChemMedChem_10_1054
PubMedID: 25924828

Title : Multitarget Therapeutic Leads for Alzheimer's Disease: Quinolizidinyl Derivatives of Bi- and Tricyclic Systems as Dual Inhibitors of Cholinesterases and beta-Amyloid (Abeta) Aggregation - Tonelli_2015_ChemMedChem_10_1040
Author(s) : Tonelli M , Catto M , Tasso B , Novelli F , Canu C , Iusco G , Pisani L , Stradis AD , Denora N , Sparatore A , Boido V , Carotti A , Sparatore F
Ref : ChemMedChem , 10 :1040 , 2015
Abstract : Multitarget therapeutic leads for Alzheimer's disease were designed on the models of compounds capable of maintaining or restoring cell protein homeostasis and of inhibiting beta-amyloid (Abeta) oligomerization. Thirty-seven thioxanthen-9-one, xanthen-9-one, naphto- and anthraquinone derivatives were tested for the direct inhibition of Abeta(1-40) aggregation and for the inhibition of electric eel acetylcholinesterase (eeAChE) and horse serum butyrylcholinesterase (hsBChE). These compounds are characterized by basic side chains, mainly quinolizidinylalkyl moieties, linked to various bi- and tri-cyclic (hetero)aromatic systems. With very few exceptions, these compounds displayed inhibitory activity on both AChE and BChE and on the spontaneous aggregation of beta-amyloid. In most cases, IC50 values were in the low micromolar and sub-micromolar range, but some compounds even reached nanomolar potency. The time course of amyloid aggregation in the presence of the most active derivative (IC50 =0.84 muM) revealed that these compounds might act as destabilizers of mature fibrils rather than mere inhibitors of fibrillization. Many compounds inhibited one or both cholinesterases and Abeta aggregation with similar potency, a fundamental requisite for the possible development of therapeutics exhibiting a multitarget mechanism of action. The described compounds thus represent interesting leads for the development of multitarget AD therapeutics.
ESTHER : Tonelli_2015_ChemMedChem_10_1040
PubMedSearch : Tonelli_2015_ChemMedChem_10_1040
PubMedID: 25924599

Title : Structure-Based Design and Optimization of Multitarget-Directed 2H-Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases - Farina_2015_J.Med.Chem_58_5561
Author(s) : Farina R , Pisani L , Catto M , Nicolotti O , Gadaleta D , Denora N , Soto-Otero R , Mendez-Alvarez E , Passos CS , Muncipinto G , Altomare CD , Nurisso A , Carrupt PA , Carotti A
Ref : Journal of Medicinal Chemistry , 58 :5561 , 2015
Abstract : The multifactorial nature of Alzheimer's disease calls for the development of multitarget agents addressing key pathogenic processes. To this end, by following a docking-assisted hybridization strategy, a number of aminocoumarins were designed, prepared, and tested as monoamine oxidases (MAOs) and acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitors. Highly flexible N-benzyl-N-alkyloxy coumarins 2-12 showed good inhibitory activities at MAO-B, AChE, and BChE but low selectivity. More rigid inhibitors, bearing meta- and para-xylyl linkers, displayed good inhibitory activities and high MAO-B selectivity. Compounds 21, 24, 37, and 39, the last two featuring an improved hydrophilic/lipophilic balance, exhibited excellent activity profiles with nanomolar inhibitory potency toward hMAO-B, high hMAO-B over hMAO-A selectivity and submicromolar potency at hAChE. Cell-based assays of BBB permeation, neurotoxicity, and neuroprotection supported the potential of compound 37 as a BBB-permeant neuroprotective agent against H2O2-induced oxidative stress with poor interaction as P-gp substrate and very low cytotoxicity.
ESTHER : Farina_2015_J.Med.Chem_58_5561
PubMedSearch : Farina_2015_J.Med.Chem_58_5561
PubMedID: 26107513

Title : Design, synthesis and biological evaluation of coumarin alkylamines as potent and selective dual binding site inhibitors of acetylcholinesterase - Catto_2013_Bioorg.Med.Chem_21_146
Author(s) : Catto M , Pisani L , Leonetti F , Nicolotti O , Pesce P , Stefanachi A , Cellamare S , Carotti A
Ref : Bioorganic & Medicinal Chemistry , 21 :146 , 2013
Abstract : Acetylcholinesterase inhibitors (AChEIs) are currently the drugs of choice, although only symptomatic and palliative, for the treatment of Alzheimer's disease (AD). Donepezil is one of most used AChEIs in AD therapy, acting as a dual binding site, reversible inhibitor of AChE with high selectivity over butyrylcholinesterase (BChE). Through a combined target- and ligand-based approach, a series of coumarin alkylamines matching the structural determinants of donepezil were designed and prepared. 6,7-Dimethoxycoumarin derivatives carrying a protonatable benzylamino group, linked to position 3 by suitable linkers, exhibited fairly good AChE inhibitory activity and a high selectivity over BChE. The inhibitory potency was strongly influenced by the length and shape of the spacer and by the methoxy substituents on the coumarin scaffold. The inhibition mechanism, assessed for the most active compound 13 (IC(50) 7.6nM) resulted in a mixed-type, thus confirming its binding at both the catalytic and peripheral binding sites of AChE.
ESTHER : Catto_2013_Bioorg.Med.Chem_21_146
PubMedSearch : Catto_2013_Bioorg.Med.Chem_21_146
PubMedID: 23199476

Title : Design, synthesis and biological evaluation of benzo[e][1,2,4]triazin-7(1H)-one and [1,2,4]-triazino[5,6,1-jk]carbazol-6-one derivatives as dual inhibitors of beta-amyloid aggregation and acetyl\/butyryl cholinesterase - Catto_2012_Eur.J.Med.Chem_58C_84
Author(s) : Catto M , Berezin AA , Lo Re D , Loizou G , Demetriades M , De Stradis A , Campagna F , Koutentis PA , Carotti A
Ref : Eur Journal of Medicinal Chemistry , 58C :84 , 2012
Abstract : Alzheimer's disease AD onset and progression are associated with the dysregulation of multiple and complex physiological processes and a successful therapeutic approach should therefore address more than one target Two new chemical entities the easily accessible heterocyclic scaffolds 1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one benzotriazinone I and 2-phenyl-6H-[1,2,4]triazino[5,6,1-jk]carbazol-6-one triazafluoranthenone II were explored for their multitarget-directed inhibition of beta-amyloid Abeta fibrillization and acetyl AChE and/or butyryl BChE cholinesterase three valuable targets for AD therapy Introduction of appropriate amine substituents at positions 6 and 5 on scaffold I and II respectively allowed the preparation of a series of compounds that were tested as Abeta(1-40 aggregation and cholinesterase inhibitors Potent inhibitors of Abeta self-aggregation were discovered and among them benzotriazinone 7 exhibited an outstanding IC(50 equal to 0.37 muM Compounds bearing a basic amine linked to the heterocyclic scaffold through a linear alkyl chain of varying length also afforded good ChE inhibitors In particular benzotriazinone 24 and triazafluoranthenone 38 were endowed with an interesting multiple activity the former displaying IC(50 values of 1.4 1.5 and 1.9 muM on Abeta aggregation and AChE and BChE inhibition respectively and the latter showing IC(50 values of 1.4 and an outstanding 0.025 muM in the Abeta aggregation and BChE inhibition respectively Benzotriazinone 24 and triazafluoranthenone 29 selected owing to their suitable aqueous solubility and Abeta aggregation inhibition were submitted to a time course kinetic assay followed with thioflavin T ThT spectrofluorimetry circular dichroism CD and transmission electron microscopy TEM Experimental data indicated that 24 acted at a low concentration ratio 10 muM 24vs 50 muM Abeta stabilizing the unstructured Abeta peptide and inhibiting fibrillogenesis and that 29 also acted as fibrillization inhibitor but likely enhancing and stabilizing the beta-sheet arrangement of Abeta to yield protofibrillar species as detected by TEM.
ESTHER : Catto_2012_Eur.J.Med.Chem_58C_84
PubMedSearch : Catto_2012_Eur.J.Med.Chem_58C_84
PubMedID: 23108363

Title : Quinolizidinyl derivatives of bi- and tricyclic systems as potent inhibitors of acetyl- and butyrylcholinesterase with potential in Alzheimer's disease - Tasso_2011_Eur.J.Med.Chem_46_2170
Author(s) : Tasso B , Catto M , Nicolotti O , Novelli F , Tonelli M , Giangreco I , Pisani L , Sparatore A , Boido V , Carotti A , Sparatore F
Ref : Eur Journal of Medicinal Chemistry , 46 :2170 , 2011
Abstract : On the pattern of the potent and selective butyrylcholinesterase (BChE) inhibitors ethopropazine and Astra1397, sets of quinolizidinyl derivatives of bi- and tricyclic (hetero)aromatic systems were studied as dual, or BChE-selective inhibitors. All compounds exhibited activity against both cholinesterases, but inhibition of BChE was generally stronger, with submicromolar IC50 values for most of them (e.g. 15: IC50 versus BChE=0.15 muM; SI=47). However, in a subset of quinolizidinyl derivatives of 6-hydroxycoumarin an inverted selectivity for acetylcholinesterase (AChE) was observed (e.g. 46: IC50 versus AChE=0.35 muM; SI=0.06). Docking studies furnished a sound interpretation of the observed different enzyme activity. Several of the studied compounds have shown, in the past, additional pharmacological properties (as antagonism on presynaptic muscarinic autoreceptor; inhibition of enkephaline aminopeptidase and antipsychotic activity) of some relevance in Alzheimer's disease, and may, therefore, represent hits for the development of interesting single-entity multi-target drugs.
ESTHER : Tasso_2011_Eur.J.Med.Chem_46_2170
PubMedSearch : Tasso_2011_Eur.J.Med.Chem_46_2170
PubMedID: 21459491

Title : Targeting monoamine oxidases with multipotent ligands: an emerging strategy in the search of new drugs against neurodegenerative diseases - Pisani_2011_Curr.Med.Chem_18_4568
Author(s) : Pisani L , Catto M , Leonetti F , Nicolotti O , Stefanachi A , Campagna F , Carotti A
Ref : Curr Med Chem , 18 :4568 , 2011
Abstract : The socioeconomic burden of multi-factorial pathologies, such as neurodegenerative diseases (NDs), is enormous worldwide. Unfortunately, no proven disease-modifying therapy is available yet and in most cases (e.g., Alzheimer's and Parkinson's disease) the approved drugs exert only palliative and symptomatic effects. Nowadays, an emerging strategy for the discovery of disease-modifying drugs is based on the multi-target directed ligand (MTDL) design, an innovative shift from the traditional approach one-drug-one-target to the more ambitious one-drug-more-targets goal. Herein, we review the discovery strategy, the mechanism of action and the biopharmacological evaluation of multipotent ligands exhibiting monoamine oxidase (MAO) inhibition as the core activity with a potential for the treatment of NDs. In particular, MAO inhibitors exhibiting additional acetylcholinesterase (AChE) or nitric oxide synthase (NOS) inhibition, or ion chelation/antioxidant-radical scavenging/anti-inflammatory/A2A receptor antagonist/APP processing modulating activities have been thoroughly examined.
ESTHER : Pisani_2011_Curr.Med.Chem_18_4568
PubMedSearch : Pisani_2011_Curr.Med.Chem_18_4568
PubMedID: 21864289

Title : Homodimeric bis-quaternary heterocyclic ammonium salts as potent acetyl- and butyrylcholinesterase inhibitors: a systematic investigation of the influence of linker and cationic heads over affinity and selectivity - Conejo-Garcia_2011_J.Med.Chem_54_2627
Author(s) : Conejo-Garcia A , Pisani L , Nunez Mdel C , Catto M , Nicolotti O , Leonetti F , Campos JM , Gallo MA , Espinosa A , Carotti A
Ref : Journal of Medicinal Chemistry , 54 :2627 , 2011
Abstract : A molecular library of quaternary ammonium salts (QASs), mainly composed of symmetrical bis-quaternary heterocyclic bromides exhibiting choline kinase (ChoK) inhibitory activity, were evaluated for their ability to inhibit acetyl- and butyrylcholinesterase (AChE and BChE, respectively). The molecular framework of QASs consisted of two positively charged heteroaromatic (pyridinium or quinolinium) or sterically hindered aliphatic (quinuclidinium) nitrogen rings kept at an appropriate distance by lipophilic rigid or semirigid linkers. Many homodimeric QASs showed AChE and BChE inhibitory potency in the nanomolar range along with a low enzymatic selectivity. Computational studies on AChE, BChE, and ChoK allowed identification of the key molecular determinants for high affinity and selectivity over either one of the three enzymes and guided the design of a hybrid bis-QAS (56) exhibiting the highest AChE affinity (IC(50) = 15 nM) and selectivity over BChE and ChoK (SI = 50 and 562, respectively) and a promising pharmacological potential in myasthenia gravis and neuromuscular blockade.
ESTHER : Conejo-Garcia_2011_J.Med.Chem_54_2627
PubMedSearch : Conejo-Garcia_2011_J.Med.Chem_54_2627
PubMedID: 21417225

Title : Design, synthesis, and biological evaluation of coumarin derivatives tethered to an edrophonium-like fragment as highly potent and selective dual binding site acetylcholinesterase inhibitors - Pisani_2010_ChemMedChem_5_1616
Author(s) : Pisani L , Catto M , Giangreco I , Leonetti F , Nicolotti O , Stefanachi A , Cellamare S , Carotti A
Ref : ChemMedChem , 5 :1616 , 2010
Abstract : A large series of substituted coumarins linked through an appropriate spacer to 3-hydroxy-N,N-dimethylanilino or 3-hydroxy-N,N,N-trialkylbenzaminium moieties were synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The highest AChE inhibitory potency in the 3-hydroxy-N,N-dimethylanilino series was observed with a 6,7-dimethoxy-3-substituted coumarin derivative, which, along with an outstanding affinity (IC(50)=0.236 nM) exhibits excellent AChE/BChE selectivity (SI>300 000). Most of the synthesized 3-hydroxy-N,N,N-trialkylbenzaminium salts display an AChE affinity in the sub-nanomolar to picomolar range along with excellent AChE/BChE selectivities (SI values up to 138 333). The combined use of docking and molecular dynamics simulations permitted us to shed light on the observed structure-affinity and structure-selectivity relationships, to detect two possible alternative binding modes, and to assess the critical role of pi-pi stacking interactions in the AChE peripheral binding site.
ESTHER : Pisani_2010_ChemMedChem_5_1616
PubMedSearch : Pisani_2010_ChemMedChem_5_1616
PubMedID: 20677317

Title : Homo- and hetero-bivalent edrophonium-like ammonium salts as highly potent, dual binding site AChE inhibitors - Leonetti_2008_Bioorg.Med.Chem_16_7450
Author(s) : Leonetti F , Catto M , Nicolotti O , Pisani L , Cappa A , Stefanachi A , Carotti A
Ref : Bioorganic & Medicinal Chemistry , 16 :7450 , 2008
Abstract : A number of mono- and bis-quaternary ammonium salts, containing edrophonium-like and coumarin moieties tethered by an appropriate linker, proved to be highly potent and selective dual binding site acetylcholinesterase inhibitors with good selectivity over butyrylcholinesterase. Homobivalent bis-quaternary inhibitors 11 and 12, differing by only one methylene unit in the linker, were the most potent and selective inhibitors exhibiting a sub-nanomolar affinity (IC(50)=0.49 and 0.17 nM, respectively) and a high butyryl-/acetylcholinesterase affinity ratio (SI=1465 and 4165, respectively). The corresponding hetero-bivalent coumarinic inhibitors 13 and 14 were also endowed with excellent inhibitory potency but a lower AChE selectivity (IC(50)=2.1 and 1.0 nM, and SI=505 and 708, respectively). Docking simulations enabled clear interpretation of the structure-affinity relationships and detection of key binding interactions at the primary and peripheral AChE binding sites.
ESTHER : Leonetti_2008_Bioorg.Med.Chem_16_7450
PubMedSearch : Leonetti_2008_Bioorg.Med.Chem_16_7450
PubMedID: 18585045

Title : Ester derivatives of annulated tetrahydroazocines: a new class of selective acetylcholinesterase inhibitors - Carotti_2006_Bioorg.Med.Chem_14_7205
Author(s) : Carotti A , de Candia M , Catto M , Borisova TN , Varlamov AV , Mendez-Alvarez E , Soto-Otero R , Voskressensky LG , Altomare CD
Ref : Bioorganic & Medicinal Chemistry , 14 :7205 , 2006
Abstract : A series of ester derivatives of annulated tetrahydroazocines, namely 2,3,6,11-tetrahydro-1H-azocino[4,5-b]indoles (5-10), 2,3,6,7-tetrahydro-1H-azocino[5,4-b]indoles (11-14), and 4,7,8,9-tetrahydro-1H-pyrrolo[2,3-d]azocines (15-18), synthesized through an efficient 6-->8 membered ring expansion procedure, were investigated for their acetylcholinesterase (AChE) inhibitory activities. Most of the compounds acted as AChE inhibitors in vitro, with IC(50) values ranging from 5 to 40 microM. The most potent compounds 11 and 15, both as racemic mixtures, proved selective toward AChE, exhibiting selectivity ratios versus butyrylcholinesterase (BuChE) of ca. 15 and more than 20, respectively. Structure-activity studies highlighted, among other factors, lipophilicity as a property modulating the AChE inhibition potency, as shown by a reasonable parabolic correlation between pIC(50) and experimental 1-octanol/water partition coefficient (logP), which described the prevailing behavior of the examined compounds (r(2)=0.665). Molecular docking simulations using the X-ray crystal structure of AChE from Torpedo californica suggested possible binding modes of the tetrahydroazocine ester derivatives 11 and 15.
ESTHER : Carotti_2006_Bioorg.Med.Chem_14_7205
PubMedSearch : Carotti_2006_Bioorg.Med.Chem_14_7205
PubMedID: 16843666

Title : Coumarins derivatives as dual inhibitors of acetylcholinesterase and monoamine oxidase - Bruhlmann_2001_J.Med.Chem_44_3195
Author(s) : Bruhlmann C , Ooms F , Carrupt PA , Testa B , Catto M , Leonetti F , Altomare CD , Carotti A
Ref : Journal of Medicinal Chemistry , 44 :3195 , 2001
Abstract : A set of 17 coumarin and 2 chromone derivatives with known inhibitory activity toward monoamine oxidase (MAO) A and B were tested as acetylcholinesterase (AChE) inhibitors. All compounds inhibited AChE with values in the micromolar range (3-100 microM). A kinetic study showed that most compounds acted as noncompetitive AChE inhibitors. This finding may be of interest in the context of Alzheimer's disease because recent observations suggest that MAO and AChE inhibition might decrease beta-amyloid deposition.
ESTHER : Bruhlmann_2001_J.Med.Chem_44_3195
PubMedSearch : Bruhlmann_2001_J.Med.Chem_44_3195
PubMedID: 11543689