Alcaro S

References (18)

Title : Novel multifunctional tacrine-donepezil hybrids against Alzheimer's disease: Design synthesis and bioactivity studies - Bayraktar_2024_Arch.Pharm.(Weinheim)__e2300575
Author(s) : Bayraktar G , Bartolini M , Bolognesi ML , Erdogan MA , Armagan G , Bayir E , Sendemir A , Bagetta D , Alcaro S , Alptuzun V
Ref : Arch Pharm (Weinheim) , :e2300575 , 2024
Abstract : A series of tacrine-donepezil hybrids were synthesized as potential multifunctional anti-Alzheimer's disease (AD) compounds. For this purpose, tacrine and the benzylpiperidine moiety of donepezil were fused with a hydrazone group to achieve a small library of tacrine-donepezil hybrids. In agreement with the design, all compounds showed inhibitory activity toward both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC(50) values in the low micromolar range. Kinetic studies on the most potent cholinesterase (ChE) inhibitors within the series showed a mixed-type inhibition mechanism on both enzymes. Also, the docking studies indicated that the compounds inhibit ChEs by dual binding site (DBS) interactions. Notably, tacrine-donepezil hybrids also exhibited significant neuroprotection against H(2)O(2)-induced cell death in a differentiated human neuroblastoma (SH-SY5Y) cell line at concentrations close to their IC(50) values on ChEs and showed high to medium blood-brain barrier (BBB) permeability on human cerebral microvascular endothelial cells (HBEC-5i). Besides, the compounds do not cause remarkable toxicity in a human hepatocellular carcinoma cell line (HepG2) and SH-SY5Y cells. Additionally, the compounds were predicted to also have good bioavailability. Among the tested compounds, H4, H16, H17, and H24 stand out with their biological profile. Taken together, the proposed novel tacrine-donepezil scaffold represents a promising starting point for the development of novel anti-ChE multifunctional agents against AD.
ESTHER : Bayraktar_2024_Arch.Pharm.(Weinheim)__e2300575
PubMedSearch : Bayraktar_2024_Arch.Pharm.(Weinheim)__e2300575
PubMedID: 38593283

Title : Design, Synthesis, and In Vitro, In Silico and In Cellulo Evaluation of New Pyrimidine and Pyridine Amide and Carbamate Derivatives as Multi-Functional Cholinesterase Inhibitors - Bortolami_2022_Pharmaceuticals.(Basel)_15_
Author(s) : Bortolami M , Pandolfi F , Tudino V , Messore A , Madia VN , De Vita D , Di Santo R , Costi R , Romeo I , Alcaro S , Colone M , Stringaro A , Espargaro A , Sabate R , Scipione L
Ref : Pharmaceuticals (Basel) , 15 : , 2022
Abstract : Alzheimer disease is an age-linked neurodegenerative disorder representing one of the greatest medical care challenges of our century. Several drugs are useful in ameliorating the symptoms, even if none could stop or reverse disease progression. The standard approach is represented by the cholinesterase inhibitors (ChEIs) that restore the levels of acetylcholine (ACh) by inhibiting the acetylcholinesterase (AChE). Still, their limited efficacy has prompted researchers to develop new ChEIs that could also reduce the oxidative stress by exhibiting antioxidant properties and by chelating the main metals involved in the disease. Recently, we developed some derivatives constituted by a 2-amino-pyrimidine or a 2-amino-pyridine moiety connected to various aromatic groups by a flexible amino-alkyl linker as new dual inhibitors of AChE and butyrylcholinesterase (BChE). Following our previous studies, in this work we explored the role of the flexible linker by replacing the amino group with an amide or a carbamic group. The most potent compounds showed higher selectivity against BChE in respect to AChE, proving also to possess a weak anti-aggregating activity toward Abeta(42) and tau and to be able to chelate Cu(2+) and Fe(3+) ions. Molecular docking and molecular dynamic studies proposed possible binding modes with the enzymes. It is noteworthy that these compounds were predicted as BBB-permeable and showed low cytotoxicity on the human brain cell line.
ESTHER : Bortolami_2022_Pharmaceuticals.(Basel)_15_
PubMedSearch : Bortolami_2022_Pharmaceuticals.(Basel)_15_
PubMedID: 35745594

Title : Evaluation of chromane derivatives: Promising privileged scaffolds for lead discovery within Alzheimer's disease - Moutayakine_2022_Bioorg.Med.Chem_68_116807
Author(s) : Moutayakine A , Marques C , Lopez O , Bagetta D , Leitzbach L , Hagenow S , Carreiro EP , Stark H , Alcaro S , Fernandez-Bolanos JG , Burke AJ
Ref : Bioorganic & Medicinal Chemistry , 68 :116807 , 2022
Abstract : The chromane ring system is widely distributed in nature and has proven to be a highly potent pharmacophore in medicinal chemistry, which includes the area of Alzheimer's and Parkinson's diseases. We report on the development of a gem-dimethylchroman-4-ol family that was shown to give good inhibition of equine serum butyrylcholinesterase (eqBuChE) (in the range 2.9 - 7.3 microM) and in the same range of currently used drugs. We also synthesized a small library of gem-dimethylchroman-4-amine compounds, via a simple reductive amination of the corresponding chromanone precursor, that were also selective for eqBuChE presenting inhibitions in the range 7.6 - 67 microM. Kinetic studies revealed that they were mixed inhibitors. Insights into their mechanism of action were obtained through molecular docking and STD-NMR experiments, and the most active examples showed excellent drug-likeness and pharmacological properties predicted using Swiss-ADME. We also prepared a set of propargyl gem-dimethylchromanamines, for monoamine oxidase (MAO) inhibition but they were only moderately active (the best being 28% inhibition at 1 microM on MAO-B). Overall, our compounds were found to be best suited as inhibitors for BuChE.
ESTHER : Moutayakine_2022_Bioorg.Med.Chem_68_116807
PubMedSearch : Moutayakine_2022_Bioorg.Med.Chem_68_116807
PubMedID: 35653868

Title : New Pyrimidine and Pyridine Derivatives as Multitarget Cholinesterase Inhibitors: Design, Synthesis, and In Vitro and In Cellulo Evaluation - Bortolami_2021_ACS.Chem.Neurosci__
Author(s) : Bortolami M , Pandolfi F , Tudino V , Messore A , Madia VN , De Vita D , Di Santo R , Costi R , Romeo I , Alcaro S , Colone M , Stringaro A , Espargaro A , Sabate R , Scipione L
Ref : ACS Chem Neurosci , : , 2021
Abstract : A new series of pyrimidine and pyridine diamines was designed as dual binding site inhibitors of cholinesterases (ChEs), characterized by two small aromatic moieties separated by a diaminoalkyl flexible linker. Many compounds are mixed or uncompetitive acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE) nanomolar inhibitors, with compound 9 being the most active on Electrophorus electricus AChE (EeAChE) (K(i) = 0.312 microM) and compound 22 on equine BChE (eqBChE) (K(i) = 0.099 microM). Molecular docking and molecular dynamic studies confirmed the interaction mode of our compounds with the enzymatic active site. UV-vis spectroscopic studies showed that these compounds can form complexes with Cu(2+) and Fe(3+) and that compounds 18, 20, and 30 have antioxidant properties. Interestingly, some compounds were also able to reduce Abeta(42) and tau aggregation, with compound 28 being the most potent (22.3 and 17.0% inhibition at 100 microM on Abeta(42) and tau, respectively). Moreover, the most active compounds showed low cytotoxicity on a human brain cell line and they were predicted as BBB-permeable.
ESTHER : Bortolami_2021_ACS.Chem.Neurosci__
PubMedSearch : Bortolami_2021_ACS.Chem.Neurosci__
PubMedID: 34652128

Title : Novel propargylamine-based inhibitors of cholinesterases and monoamine oxidases: Synthesis, biological evaluation and docking study - Kratky_2021_Bioorg.Chem_116_105301
Author(s) : Kratky M , Vu QA , Stepankova S , Maruca A , Silva TB , Ambroz M , Pflegr V , Rocca R , Svrckova K , Alcaro S , Borges F , Vinsova J
Ref : Bioorg Chem , 116 :105301 , 2021
Abstract : A combination of several pharmacophores in one molecule has been successfully used for multi-target-directed ligands (MTDL) design. New propargylamine substituted derivatives combined with salicylic and cinnamic scaffolds were designed and synthesized as potential cholinesterases and monoamine oxidases (MAOs) inhibitors. They were evaluated invitro for inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE) using Ellman's method. All the compounds act as dual inhibitors. Most of the derivatives are stronger inhibitors of AChE, the best activity showed 5-bromo-N-(prop-2-yn-1-yl)salicylamide 1e (IC(50) = 8.05 microM). Carbamates (4-bromo-2-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2d and 2,4-dibromo-6-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2e were selective and the most active for BuChE (25.10 and 26.09 microM). 4-Bromo-2-[(prop-2-yn-1-ylimino)methyl]phenol 4a was the most potent inhibitor of MAOs (IC(50) of 3.95 and =10 microM for MAO-B and MAO-A, respectively) along with a balanced inhibition of both cholinesterases being a real MTDL. The mechanism of action was proposed, and binding modes of the hits were studied by molecular docking on human enzymes. Some of the derivatives also exhibited antioxidant properties. Insilico prediction of physicochemical parameters affirm that the molecules would be active after oral administration and able to reach brain tissue.
ESTHER : Kratky_2021_Bioorg.Chem_116_105301
PubMedSearch : Kratky_2021_Bioorg.Chem_116_105301
PubMedID: 34492558

Title : New deferiprone derivatives as multi-functional cholinesterase inhibitors: design, synthesis and in vitro evaluation - Bortolami_2020_Eur.J.Med.Chem_198_112350
Author(s) : Bortolami M , Pandolfi F , De Vita D , Carafa C , Messore A , Di Santo R , Feroci M , Costi R , Chiarotto I , Bagetta D , Alcaro S , Colone M , Stringaro A , Scipione L
Ref : Eur Journal of Medicinal Chemistry , 198 :112350 , 2020
Abstract : In order to obtain multi-functional molecules for Alzheimer's disease, a series of deferiprone derivatives has been synthesized and evaluated in vitro with the hypothesis that they can restore the cholinergic tone and attenuate the dyshomeostasis of the metals mainly involved in the pathology. These compounds were designed as dual binding site AChE inhibitors: they possess an arylalkylamine moiety connected via an alkyl chain to a 3-hydroxy-4-pyridone fragment, to allow the simultaneous interaction with catalytic active site (CAS) and peripheral anionic site (PAS) of the enzyme. Deferiprone moiety and 2-aminopyridine, 2-aminopyrimidine or 2,4-diaminopyrimidine groups have been incorporated into these compounds, in order to obtain molecules potentially able to chelate bio-metals colocalized in Abeta plaques and involved in the generation of radical species. Synthesized compounds were tested by enzymatic inhibition studies towards EeAChE and eqBChE using Ellman's method. The most potent EeAChE inhibitor is compound 5a, with a Ki of 788 +/- 51 nM, while the most potent eqBChE inhibitors are compounds 12 and 19, with Ki values of 182 +/- 18 nM and 258 +/- 25 nM respectively. Selected compounds, among the most potent cholinesterases inhibitors, were able to form complex with iron and in some cases with copper and zinc. Moreover, these compounds were characterized by low toxicity on U-87 MG Cell Line from human brain (glioblastoma astrocytoma).
ESTHER : Bortolami_2020_Eur.J.Med.Chem_198_112350
PubMedSearch : Bortolami_2020_Eur.J.Med.Chem_198_112350
PubMedID: 32380385

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

Title : Benzoic acid-derived nitrones: A new class of potential acetylcholinesterase inhibitors and neuroprotective agents - Oliveira_2019_Eur.J.Med.Chem_174_116
Author(s) : Oliveira C , Bagetta D , Cagide F , Teixeira J , Amorim R , Silva T , Garrido J , Remiao F , Uriarte E , Oliveira PJ , Alcaro S , Ortuso F , Borges F
Ref : Eur Journal of Medicinal Chemistry , 174 :116 , 2019
Abstract : The discovery of new chemical entities endowed with potent and selective acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE) inhibitory activity is still a relevant subject for Alzheimer's disease therapy. Therefore, a small library of benzoic based amide nitrones (compounds 24 to 42) was synthesized and screened toward cholinesterase enzymes. SAR studies showed that the tert-butyl moiety is the most favourable nitrone pattern. In general, tert-butyl derivatives effectively inhibited AChE, being compound 33 the most potent (IC50=8.3+/-0.3muM; Ki 5.2muM). The data pointed to a non-competitive inhibition mechanism of action, which was also observed for the standard donepezil. None of compounds showed BChE inhibitory activity. Molecular modelling studies provided insights into the enzyme-inhibitor interactions and rationalised the experimental data, confirming that the binding mode of nitrones 33 and 38 towards AChE has the most favourable binding free energy. The tert-butylnitrones 33 and 38 were not cytotoxic on different cell lines (SH-SY5Y and HepG2). Moreover, compound 33 was able to prevent t-BHP-induced oxidative stress in SH-SY5Y differentiated cells. Due to its AChE selectivity and promising cytoprotective properties, as well as its appropriate drug-like profile pointing toward blood-brain barrier permeability, compound 33 is proposed as a valid lead for a further optimization step.
ESTHER : Oliveira_2019_Eur.J.Med.Chem_174_116
PubMedSearch : Oliveira_2019_Eur.J.Med.Chem_174_116
PubMedID: 31029943

Title : The chemistry toolbox of multitarget-directed ligands for Alzheimer's disease - Mesiti_2019_Eur.J.Med.Chem_181_111572
Author(s) : Mesiti F , Chavarria D , Gaspar A , Alcaro S , Borges F
Ref : Eur Journal of Medicinal Chemistry , 181 :111572 , 2019
Abstract : The discovery and development of multitarget-directed ligands (MTDLs) is a promising strategy to find new therapeutic solutions for neurodegenerative diseases (NDs), in particular for Alzheimer's disease (AD). Currently approved drugs for the clinical management of AD are based on a single-target strategy and focus on restoring neurotransmitter homeostasis. Finding disease-modifying therapies AD and other NDs remains an urgent unmet clinical need. The growing consensus that AD is a multifactorial disease, with several interconnected and deregulated pathological pathways, boosted an intensive research in the design of MTDLs. Due to this scientific boom, the knowledge behind the development of MTDLs remains diffuse and lacks balanced guidelines. To rationalize the large amount of data obtained in this field, we herein revise the progress made over the last 5 years on the development of MTDLs inspired by drugs approved for AD. Due to their putative therapeutic benefit in AD, MTDLs based on MAO-B inhibitors will also be discussed in this review.
ESTHER : Mesiti_2019_Eur.J.Med.Chem_181_111572
PubMedSearch : Mesiti_2019_Eur.J.Med.Chem_181_111572
PubMedID: 31404859

Title : 4-(3-Nitrophenyl)thiazol-2-ylhydrazone derivatives as antioxidants and selective hMAO-B inhibitors: synthesis, biological activity and computational analysis - Secci_2019_J.Enzyme.Inhib.Med.Chem_34_597
Author(s) : Secci D , Carradori S , Petzer A , Guglielmi P , D'Ascenzio M , Chimenti P , Bagetta D , Alcaro S , Zengin G , Petzer JP , Ortuso F
Ref : J Enzyme Inhib Med Chem , 34 :597 , 2019
Abstract : A new series of 4-(3-nitrophenyl)thiazol-2-ylhydrazone derivatives were designed, synthesised, and evaluated to assess their inhibitory effect on the human monoamine oxidase (hMAO) A and B isoforms. Different (un)substituted (hetero)aromatic substituents were linked to N1 of the hydrazone in order to establish robust structure-activity relationships. The results of the biological testing demonstrated that the presence of the hydrazothiazole nucleus bearing at C4 a phenyl ring functionalised at the meta position with a nitro group represents an important pharmacophoric feature to obtain selective and reversible human MAO-B inhibition for the treatment of neurodegenerative disorders. In addition, the most potent and selective MAO-B inhibitors were evaluated in silico as potential cholinesterase (AChE/BuChE) inhibitors and in vitro for antioxidant activities. The results obtained from molecular modelling studies provided insight into the multiple interactions and structural requirements for the reported MAO inhibitory properties.
ESTHER : Secci_2019_J.Enzyme.Inhib.Med.Chem_34_597
PubMedSearch : Secci_2019_J.Enzyme.Inhib.Med.Chem_34_597
PubMedID: 30727777

Title : Multi-target-directed ligands for Alzheimer's disease: Discovery of chromone-based monoamine oxidase\/cholinesterase inhibitors - Reis_2018_Eur.J.Med.Chem_158_781
Author(s) : Reis J , Cagide F , Valencia ME , Teixeira J , Bagetta D , Perez C , Uriarte E , Oliveira PJ , Ortuso F , Alcaro S , Rodriguez-Franco MI , Borges F
Ref : Eur Journal of Medicinal Chemistry , 158 :781 , 2018
Abstract : There has been a substantial research effort to design multi-target ligands for the treatment of Alzheimer's disease (AD), an approach that is moved by the knowledge that AD is a complex and multifactorial disease affecting many linked to pathological pathways. Accordingly, we have devoted efforts to develop multi-target ligands based on the chromone scaffold. As a result, a small library of chromone derivatives was synthesized and screened towards human cholinesterases and monoamine oxidases. Compounds 2-(dimethylamino)ethyl (E)-3-(4-oxo-2-(p-methylphenlcarbamoyl)-4H-chromen-6-yl)acrylate (9a) and 2-(dimethylamino)ethyl (E)-3-(4-oxo-3-(phenylcarbamoyl)-4H-chromen-6-yl)acrylate (23a) were identified as the most promising multi-target inhibitors of the series. Compound 9a acted as a potent, selective and bifunctional AChEI (IC50=0.21muM, Ki=0.19muM) and displayed dual hMAO inhibitory activity (hMAO-A IC50=0.94muM, Ki=0.057muM and hMAO-B IC50=3.81muM, Ki=0.48muM). Compound 23a acted as a selective IMAO-B (IC50=0.63muM, Ki=0.34muM) while still displaying hChE inhibitory and bifunctional activity in the low micromolar range. Overall, these two compounds stand out as reversible multi-target inhibitors with favourable permeability, toxicological and drug-like profiles, thus being valid candidates for subsequent optimization and pre-clinical studies.
ESTHER : Reis_2018_Eur.J.Med.Chem_158_781
PubMedSearch : Reis_2018_Eur.J.Med.Chem_158_781
PubMedID: 30245401

Title : Design, synthesis and biochemical evaluation of novel multi-target inhibitors as potential anti-Parkinson agents - Carradori_2018_Eur.J.Med.Chem_143_1543
Author(s) : Carradori S , Ortuso F , Petzer A , Bagetta D , De Monte C , Secci D , De Vita D , Guglielmi P , Zengin G , Aktumsek A , Alcaro S , Petzer JP
Ref : Eur Journal of Medicinal Chemistry , 143 :1543 , 2018
Abstract : New 4-(3-nitrophenyl)thiazol-2-ylhydrazone derivatives are proposed as dual-target-directed monoamine oxidase B (MAO-B) and acetylcholinesterase (AChE) inhibitors, as well as antioxidant agents, for the treatment of neurodegenerative disorders such as Parkinson's disease. Rational molecular design, target recognition and predicted pharmacokinetic properties have been evaluated by means of molecular modelling. Based on these properties, compounds were synthesized and evaluated in vitro as MAO-B and AChE inhibitors, and compared to the activities at their corresponding isozymes, monoamine oxidase A (MAO-A) and butyrylcholinesterase (BuChE), respectively. Anti-oxidant properties, potentially useful in the treatment of neurodegenerative disorders, have been also investigated in vitro. Among the evaluated compounds, three inhibitors may be considered as promising dual inhibitors of MAO-B and AChE, in vitro. MAO-B inhibition was also shown to be competitive and reversible for compound 19.
ESTHER : Carradori_2018_Eur.J.Med.Chem_143_1543
PubMedSearch : Carradori_2018_Eur.J.Med.Chem_143_1543
PubMedID: 29126727

Title : (Thiazol-2-yl)hydrazone derivatives from acetylpyridines as dual inhibitors of MAO and AChE: synthesis, biological evaluation and molecular modeling studies - D'Ascenzio_2015_J.Enzyme.Inhib.Med.Chem_30_908
Author(s) : D'Ascenzio M , Chimenti P , Gidaro MC , De Monte C , De Vita D , Granese A , Scipione L , Di Santo R , Costa G , Alcaro S , Yanez M , Carradori S
Ref : J Enzyme Inhib Med Chem , 30 :908 , 2015
Abstract : Several (thiazol-2-yl)hydrazone derivatives from 2-, 3- and 4-acetylpyridine were synthesized and tested against human monoamine oxidase (hMAO) A and B enzymes. Most of them had an inhibitory effect in the low micromolar/high nanomolar range, being derivatives of 4-acetylpyridine selective hMAO-B inhibitors also at low nanomolar concentrations. The structure-activity relationship, as confirmed by molecular modeling studies, proved that the pyridine ring linked to the hydrazonic nitrogen and the substituted aryl moiety at C4 of the thiazole conferred the inhibitory effects on hMAO enzymes. Successively, the strongest hMAO-B inhibitors were tested toward acetylcholinesterase (AChE) and the most interesting compound showed activity in the low micromolar range. Our results suggest that this scaffold could be further investigated for its potential multi-targeted role in the discovery of new drugs against the neurodegenerative diseases.
ESTHER : D'Ascenzio_2015_J.Enzyme.Inhib.Med.Chem_30_908
PubMedSearch : D'Ascenzio_2015_J.Enzyme.Inhib.Med.Chem_30_908
PubMedID: 25807300

Title : N-Methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2- yl)methyl)prop-2-yn-1-amine, a new cholinesterase and monoamine oxidase dual inhibitor - Bautista-Aguilera_2014_J.Med.Chem_57_10455
Author(s) : Bautista-Aguilera OM , Samadi A , Chioua M , Nikolic K , Filipic S , Agbaba D , Soriano E , de Andres L , Rodriguez-Franco MI , Alcaro S , Ramsay RR , Ortuso F , Yanez M , Marco-Contelles J
Ref : Journal of Medicinal Chemistry , 57 :10455 , 2014
Abstract : On the basis of N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methyl prop-2-yn-1-amine (II, ASS234) and QSAR predictions, in this work we have designed, synthesized, and evaluated a number of new indole derivatives from which we have identified N-methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2- yl)methyl)prop-2-yn-1-amine (2, MBA236) as a new cholinesterase and monoamine oxidase dual inhibitor.
ESTHER : Bautista-Aguilera_2014_J.Med.Chem_57_10455
PubMedSearch : Bautista-Aguilera_2014_J.Med.Chem_57_10455
PubMedID: 25418133

Title : An approach to address Candida rugosa lipase regioselectivity in the acylation reactions of trytilated glucosides - Palocci_2007_J.Biotechnol_128_908
Author(s) : Palocci C , Falconi M , Alcaro S , Tafi A , Puglisi R , Ortuso F , Botta M , Alberghina L , Cernia E
Ref : J Biotechnol , 128 :908 , 2007
Abstract : Candida rugosa lipase crude preparations (CRL) catalyse the regioselective acylation of methyl 6-O-trytil beta-d-glucopyranoside in organic solvents, using vinyl acetate as acyl donor. The ratio of the two products formed, namely methyl 2-O acetyl 6-O-trytil beta-d-glucopyranoside and methyl 3-O acetyl 6-O-trytil beta-d-glucopyranoside was found to be markedly affected by the nature of the reaction medium. In hydrophobic solvents values up to 80% of the monoacetylated product in position C-3 were obtained compared to less than 30% in solvents with low hydrophobicity. Computational studies were carried out to simulate the interactions between methyl 6-O-trytil beta-d-glucopyranoside and both CRL and the solvents, in order to rationalize the experimental results.
ESTHER : Palocci_2007_J.Biotechnol_128_908
PubMedSearch : Palocci_2007_J.Biotechnol_128_908
PubMedID: 17321623

Title : Molecular modelling and enzymatic studies of acetylcholinesterase and butyrylcholinesterase recognition with paraquat and related compounds - Alcaro_2007_SAR.QSAR.Environ.Res_18_595
Author(s) : Alcaro S , Arcone R , Vecchio I , Ortuso F , Gallelli A , Pasceri R , Procopio A , Iannone M
Ref : SAR QSAR Environ Research , 18 :595 , 2007
Abstract : The potent herbicide paraquat and three other analogues MPP+, MPDP+ and MPTP have a known toxicological profile linked to the ability to damage dopaminergic neurons. Other biological effects were recently addressed to this class of compounds, including the ability to interact with enzymatic targets involved in the Central Nervous System, such as the acetylcholinesterase (AChE) and the butyrylcholinesterase (BuChE). A combined molecular modelling and enzymatic study focusing onto their interaction against the AChE and BuChE is reported. The former study was performed by docking techniques using target known co-crystallographic models. The latter study was carried out by the widely adopted Ellman's method. In both studies the anti-Alzheimer FDA approved drug tacrine was used as reference inhibitor. Our results indicate that paraquat, MPTP, MPDP+ and MPP+ recognize both enzymatic cleft in a similar fashion compared to the reference inhibitor. A structure-activity correlation was found with the net charge of the ligands, indicating a major role of the electrostatic term in the recognition and inhibition of these compounds. Our data completed their enzymatic profile, added new information on the molecular mechanisms underlying their neurotoxicity useful for the rational design of new cholinesterase inhibitors.
ESTHER : Alcaro_2007_SAR.QSAR.Environ.Res_18_595
PubMedSearch : Alcaro_2007_SAR.QSAR.Environ.Res_18_595
PubMedID: 17654339

Title : Further studies on the interaction of the 5-hydroxytryptamine3 (5-HT3) receptor with arylpiperazine ligands. development of a new 5-HT3 receptor ligand showing potent acetylcholinesterase inhibitory properties - Cappelli_2005_J.Med.Chem_48_3564
Author(s) : Cappelli A , Gallelli A , Manini M , Anzini M , Mennuni L , Makovec F , Menziani MC , Alcaro S , Ortuso F , Vomero S
Ref : Journal of Medicinal Chemistry , 48 :3564 , 2005
Abstract : Novel arylpiperazine derivatives bearing lipophilic probes were designed, synthesized, and evaluated for their potential ability to interact with the 5-hydroxytryptamine(3) (5-HT(3)) receptor. Most of the new compounds show subnanomolar 5-HT(3) receptor affinity. Ester 6bc showing a picomolar K(i) value is one of the most potent 5-HT(3) receptor ligands so far synthesized. The structure-affinity relationship study suggests the existence of a certain degree of conformational freedom of the amino acid residues interacting with the substituents in positions 3 and 4 of the quipazine quinoline nucleus. Thus, the tacrine-related heterobivalent ligand 6o was designed in an attempt to capitalize on the evidence of such a steric tolerance. Compound 6o shows a nanomolar potency for both the 5-HT(3) receptor and the human AChE and represents the first example of a rationally designed high-affinity 5-HT(3) receptor ligand showing nanomolar AChE inhibitory activity. Finally, the computational analysis performed on compound 6o allowed the rationalization of the structure-energy determinants for AChE versus BuChE selectivity and revealed the existence of a subsite at the boundary of the 5-HT(3) receptor extracellular domain, which could represent a "peripheral" site similar to that evidenced in the AChE gorge.
ESTHER : Cappelli_2005_J.Med.Chem_48_3564
PubMedSearch : Cappelli_2005_J.Med.Chem_48_3564
PubMedID: 15887964

Title : Molecular modeling and enzymatic studies of the interaction of a choline analogue and acetylcholinesterase - Alcaro_2002_Bioorg.Med.Chem.Lett_12_2899
Author(s) : Alcaro S , Scipione L , Ortuso F , Posca S , Rispoli V , Rotiroti D
Ref : Bioorganic & Medicinal Chemistry Lett , 12 :2899 , 2002
Abstract : Pivaloyl-choline iodide 1 interactions with acetylcholinesterase (AChE) have been studied by theoretical and enzymatic methods. An integrated computational approach has clearly shown a substrate rather than inhibitory profile for 1. Enzymatic experiments have also supported the same theoretical conclusion indicating that AChE was able to hydrolyze 1 to choline.
ESTHER : Alcaro_2002_Bioorg.Med.Chem.Lett_12_2899
PubMedSearch : Alcaro_2002_Bioorg.Med.Chem.Lett_12_2899
PubMedID: 12270172