89 results on '"Alcaro, Stefano"'
Search Results
2. A chromatographic and computational study on the driving force operating in the exceptionally large enantioseparation of N-thiocarbamoyl-3-(4′-biphenyl)-5-phenyl-4,5-dihydro-(1H) pyrazole on a 4-methylbenzoate cellulose-based chiral stationary phase
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Ortuso, Francesco, Alcaro, Stefano, Menta, Sergio, Fioravanti, Rossella, and Cirilli, Roberto
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- 2014
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3. A chromatographic study on the exceptional enantioselectivity of cellulose tris(4-methylbenzoate) towards C5-chiral 4,5-dihydro-(1 H)-pyrazole derivatives
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Cirilli, Roberto, Alcaro, Stefano, Fioravanti, Rossella, Ferretti, Rosella, Bolasco, Adriana, Gallinella, Bruno, and Faggi, Cristina
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- 2011
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4. Unusually high enantioselectivity in high-performance liquid chromatography using cellulose tris(4-methylbenzoate) as a chiral stationary phase
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Cirilli, Roberto, Alcaro, Stefano, Fioravanti, Rossella, Secci, Daniela, Fiore, Stefano, La Torre, Francesco, and Ortuso, Francesco
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- 2009
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5. Enantioselective recognition of 2,3-benzodiazepin-4-one derivatives with anticonvulsant activity on several polysaccharide chiral stationary phases
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Calabrò, Maria Luisa, Raneri, Daniela, Tommasini, Silvana, Ficarra, Rita, Alcaro, Stefano, Gallelli, Andrea, Micale, Nicola, Zappalà, Maria, and Ficarra, Paola
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- 2006
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6. Modeling and biological evaluation of 3,3′-(1,2-ethanediyl)bis[2-(4-methoxyphenyl)-thiazolidin-4-one], a new synthetic cyclooxygenase-2 inhibitor
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Ottaná, Rosaria, Mazzon, Emanuela, Dugo, Laura, Monforte, Francesca, Maccari, Rosanna, Sautebin, Lidia, De Luca, Grazia, Vigorita, Maria Gabriella, Alcaro, Stefano, Ortuso, Francesco, Caputi, Achille P, and Cuzzocrea, Salvatore
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- 2002
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7. Joining European Scientific Forces to Face Pandemics.
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Vasconcelos, M. Helena, Alcaro, Stefano, Arechavala-Gomeza, Virginia, Baumbach, Jan, Borges, Fernanda, Brevini, Tiziana A.L., Rivas, Javier De Las, Devaux, Yvan, Hozak, Pavel, Keinänen-Toivola, Minna M., Lattanzi, Giovanna, Mohr, Thomas, Murovska, Modra, Prusty, Bhupesh K., Quinlan, Roy A., Pérez-Sala, Dolores, Scheibenbogen, Carmen, Schmidt, Harald H.H.W., Silveira, Isabel, and Tieri, Paolo
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COVID-19 , *PANDEMICS , *EUROPEAN communities , *GUIDELINES , *SCIENTIFIC community - Abstract
Despite the international guidelines on the containment of the coronavirus disease 2019 (COVID-19) pandemic, the European scientific community was not sufficiently prepared to coordinate scientific efforts. To improve preparedness for future pandemics, we have initiated a network of nine European-funded Cooperation in Science and Technology (COST) Actions that can help facilitate inter-, multi-, and trans-disciplinary communication and collaboration. [ABSTRACT FROM AUTHOR]
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- 2021
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8. The mechanisms of pharmacokinetic food-drug interactions – A perspective from the UNGAP group.
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Koziolek, Mirko, Alcaro, Stefano, Augustijns, Patrick, Basit, Abdul W., Grimm, Michael, Hens, Bart, Hoad, Caroline L., Jedamzik, Philipp, Madla, Christine M., Maliepaard, Marc, Marciani, Luca, Maruca, Annalisa, Parrott, Neil, Pávek, Petr, Porter, Christopher J.H., Reppas, Christos, van Riet-Nales, Diana, Rubbens, Jari, Statelova, Marina, and Trevaskis, Natalie L.
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DRUG-food interactions , *ORAL medication , *DRUG absorption , *DIETARY supplements , *GRAPEFRUIT , *PHARMACOKINETICS , *PHARMACODYNAMICS - Abstract
The simultaneous intake of food and drugs can have a strong impact on drug release, absorption, distribution, metabolism and/or elimination and consequently, on the efficacy and safety of pharmacotherapy. As such, food-drug interactions are one of the main challenges in oral drug administration. Whereas pharmacokinetic (PK) food-drug interactions can have a variety of causes, pharmacodynamic (PD) food-drug interactions occur due to specific pharmacological interactions between a drug and particular drinks or food. In recent years, extensive efforts were made to elucidate the mechanisms that drive pharmacokinetic food-drug interactions. Their occurrence depends mainly on the properties of the drug substance, the formulation and a multitude of physiological factors. Every intake of food or drink changes the physiological conditions in the human gastrointestinal tract. Therefore, a precise understanding of how different foods and drinks affect the processes of drug absorption, distribution, metabolism and/or elimination as well as formulation performance is important in order to be able to predict and avoid such interactions. Furthermore, it must be considered that beverages such as milk, grapefruit juice and alcohol can also lead to specific food-drug interactions. In this regard, the growing use of food supplements and functional food requires urgent attention in oral pharmacotherapy. Recently, a new consortium in Understanding Gastrointestinal Absorption-related Processes (UNGAP) was established through COST, a funding organisation of the European Union supporting translational research across Europe. In this review of the UNGAP Working group "Food-Drug Interface", the different mechanisms that can lead to pharmacokinetic food-drug interactions are discussed and summarised from different expert perspectives. Unlabelled Image [ABSTRACT FROM AUTHOR]
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- 2019
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9. Conformational studies and solvent-accessible surface area analysis of known selective DNA G-Quadruplex binders
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Alcaro, Stefano, Artese, Anna, Costa, Giosuè, Distinto, Simona, Ortuso, Francesco, and Parrotta, Lucia
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PROTEIN conformation , *QUADRUPLEX nucleic acids , *DNA , *LIGANDS (Biochemistry) , *TELOMERASE , *DRUG design - Abstract
Abstract: Human telomeres are comprised of d(TTAGGG) repeats involved in the formation of G-quadruplex DNA structures. Ligands that stabilize these G-quadruplex DNA structures are potential inhibitors of the cancer cell-associated enzyme telomerase. In human cells, telomerase adds multiple copies of the 5′-GGTTAG-3′ motif to the end of the G-strand of the telomere and in the majority of tumor cells it results over-expressed. Several structural studies have revealed a diversity of topologies for telomeric quadruplexes, as confirmed by the different conformations deposited in the Protein Data Bank. In recent years an increasing number of chemically diverse telomerase inhibitors have been identified, including both natural and synthetic compounds. Thus telomerase has been regarded as one of the most attractive targets in cancer treatment. In this manuscript, with the aim to rationalize the different experimental activities of known telomerase inhibitors, a computational study was carried out to investigate their conformational properties and the relationships between the target affinity and the ligands solvent-accessible surface area. Among the analyzed different scaffolds of G-quadruplex binders, such a descriptor provided helpful preliminary information to discriminate end-stacking ligand binding affinities, revealing itself as a useful predictive tool in drug design and lead optimization processes. [Copyright &y& Elsevier]
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- 2011
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10. Molecular and structural aspects of clinically relevant mutations related to the approved non-nucleoside inhibitors of HIV-1 reverse transcriptase.
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Alcaro, Stefano, Alteri, Claudia, Artese, Anna, Ceccherini-Silberstein, Francesca, Costa, Giosuè, Ortuso, Francesco, Parrotta, Lucia, Perno, Carlo Federico, and Svicher, Valentina
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MOLECULAR structure ,GENETIC mutation ,NON-nucleoside reverse transcriptase inhibitors ,HIV infections ,MORTALITY ,ANTIRETROVIRAL agents ,DRUG resistance ,HEALTH outcome assessment - Abstract
Abstract: In recent years relevant progress has been made in the treatment of HIV-1 with a consequent decrease in mortality. The availability of potent antiretroviral drugs and the ability of viral load assays that accurately evaluate the true level of viral replication, have led to a better understanding of pathogenesis of the disease and how to obtain improved therapeutic profiles. The highly active antiretroviral therapy (HAART), based on a combination of three or more antiretroviral drugs, has radically changed the clinical outcome of HIV. In particular, reverse transcriptase non-nucleoside inhibitors (NNRTIs) play an essential role in most protocols and are often used in first line treatment. The high specificity of these inhibitors towards HIV-1 has increased the number of structural and molecular modeling studies of enzyme complexes and that have led to chemical syntheses of more selective second and third-generation NNRTIs. However, a considerable percentage of new HIV-1 infections are caused by the emergence of drug-resistant mutant viruses that complicate treatment strategies. In this review we discuss relevant clinical and structural aspects for the management of antiretroviral drug resistance, with detailed explanations of mechanisms and mutation patterns useful to better understand the relation between drug resistance and therapy failure. [Copyright &y& Elsevier]
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- 2011
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11. Chromone-2- and -3-carboxylic acids inhibit differently monoamine oxidases A and B
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Alcaro, Stefano, Gaspar, Alexandra, Ortuso, Francesco, Milhazes, Nuno, Orallo, Francisco, Uriarte, Eugenio, Yáñez, Matilde, and Borges, Fernanda
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CARBOXYLIC acids , *MONOAMINE oxidase inhibitors , *COUMARINS , *DATA analysis , *ENZYME activation - Abstract
Abstract: Chromone carboxylic acids were evaluated as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. The biological data indicated that only chromone-3-carboxylic acid is a potent hMAO-B inhibitor, with a high degree of selectivity for hMAO-B compared to hMAO-A. Conversely the chromone-2-carboxylic acid resulted almost inactive against both MAO isoforms. Docking experiments were performed to elucidate the reasons of the different MAO IC50 data and to explain the absence of activity versus selectivity, respectively. [Copyright &y& Elsevier]
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- 2010
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12. Tetraplex DNA specific ligands based on the fluorenone-carboxamide scaffold
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Alcaro, Stefano, Artese, Anna, Iley, James N., Maccari, Rosanna, Missailidis, Sotiris, Ortuso, Francesco, Ottanà, Rosaria, Ragazzon, Patricia, and Vigorita, Maria Gabriella
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DNA , *LIGANDS (Biochemistry) , *KETONES , *SPECTRUM analysis - Abstract
Abstract: A series of fluorenone-carboxamide compounds was analyzed with regard to DNA binding properties by UV spectroscopy and competition dialysis methods. The morpholino derivative 10 provided interesting results in terms of affinity and specificity toward the DNA G-tetraplex structures. Interactions against this target were evaluated by a comparative molecular modeling study in agreement with the experimental data, proposing a model for the rational design of new agents with potent and selective DNA tetraplex binding properties. [Copyright &y& Elsevier]
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- 2007
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13. Biocatalysed synthesis of β-O-glucosides from 9-fluorenon-2-carbohydroxyesters. Part 3: IFN-inducing and anti-HSV-2 properties
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Alcaro, Stefano, Arena, Adriana, Di Bella, Rosaria, Neri, Simonetta, Ottanà, Rosaria, Ortuso, Francesco, Pavone, Bernadette, Trincone, Antonio, and Vigorita, Maria Gabriella
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GLYCOPROTEINS , *ANTINEOPLASTIC agents , *INTERFERONS , *CELLS - Abstract
Abstract: In pursuing research on the antiviral, interferon (IFN)-inducing tilorone congeners, a new series of fluoren-carboxyhydroxyesters has been prepared and biologically explored. These esters have subsequently been used as sugar acceptors in the enzymatic transglycosylation reaction using the ‘retaining’ β-glycosidase from the archaeon Sulfolobus solfataricus (Ssβ-Gly). Both aglycones (1–6) and corresponding β-glucosides (β-glu 1–β-glu 6) have been screened for cytotoxicity, interferon-stimulating and antiviral properties against HSV-2. It was found that the addition of compounds β-glu 5, β-glu 6 and β-glu 4 to HSV-2 infected U937 cells downregulates viral replication and triggers cells to release IFN-α/β. Taken together, the results showed improved pharmacological profiles as a consequence of glycosylation. A molecular modelling study carried out on this series of compounds completed the structural characterisation of the novel compounds. [Copyright &y& Elsevier]
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- 2005
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14. New conformationally locked bicyclic N,O-nucleoside analogues of antiviral drugs
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Procopio, Antonio, Alcaro, Stefano, De Nino, Antonio, Maiuolo, Loredana, Ortuso, Francesco, and Sindona, Giovanni
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- 2005
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15. Conformational search of antisense nucleotides. Part 2
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Alcaro, Stefano, Ortuso, Francesco, Gallelli, Andrea, Battaglia, Danilo, Tafi, Andrea, and Botta, Maurizio
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NUCLEOTIDES , *ANTISENSE nucleic acids , *NUCLEIC acids , *MONTE Carlo method , *NUMERICAL analysis , *MOLECULAR dynamics - Abstract
In this study is presented the phosphorotioate nucleotide compound (1) possessing an unusual moiety with a chiral P and a Se atoms double bonded. It required a force field parameterization for carrying out standard molecular mechanics calculations. A new set of MMFF parameters was developed and applied for the complete conformational search of the diastereoisomers, using both Monte Carlo and molecular dynamics, with the purpose to validate them by the comparison between calculated structural properties and NMR measurements. [Copyright &y& Elsevier]
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- 2004
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16. Docking experiments showing similar recognition patterns of paclitaxel when interacting with different macromolecular targets
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Alcaro, Stefano, Battaglia, Danilo, and Ortuso, Francesco
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PACLITAXEL , *ANTINEOPLASTIC agents , *TUBULINS , *PROTEINS , *MACROMOLECULES - Abstract
Using the Protein Data Bank crystallographic model of paclitaxel with tubulin as reference, a comparative interaction study of the antitumor drug with known macromolecular targets such as β-cyclodextrin and Dickerson''s DNA dodecamer was carried out by molecular modeling techniques. AMBER* united atoms was found to be the most appropriate force field for our study. Conformational search of paclitaxel was performed using a water environment. A large set of conformers was selected for automatic “quasi-flexible” docking calculations performed by the “in-house” software moline. A proper docking protocol was based on a crystallographic model and validated by a remarkable low atomic coordinate deviation. Using this method, a similar pattern via benzamide interaction was established for molecular recognition of paclitaxel cyclodextrin and DNA. The results are supported by our previous observations and other author''s experimental data. [Copyright &y& Elsevier]
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- 2003
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17. Molecular modeling and enzymatic studies of the interaction of a choline analogue and acetylcholinesterase
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Alcaro, Stefano, Scipione, Luigi, Ortuso, Francesco, Posca, Salvatore, Rispoli, Vincenzo, and Rotiroti, Domenicantonio
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ACETYLCHOLINESTERASE , *CHOLINE - 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. [Copyright &y& Elsevier]
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- 2002
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18. Preparation, characterization, molecular modeling and In vitro activity of paclitaxel–cyclodextrin complexes
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Alcaro, Stefano, Ventura, Cinzia Anna, Paolino, Donatella, Battaglia, Danilo, Ortuso, Francesco, Cattel, Luigi, Puglisi, Giovanni, and Fresta, Massimo
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PACLITAXEL , *CYCLODEXTRINS - Abstract
Paclitaxel (PTX) was complexed with β-cyclodextrin (1), 2,6-dimethyl-β-cyclodextrin (2) and 2,3,6-trimethyl-β-cyclodextrin (3). PTX–CYD complexes were characterized both at the solid and liquid states. Experimental findings are in agreement with molecular modeling analysis, which showed different PTX–CYD interaction as a function of macrocyle methylation. The complexation of PTX within the CYD cavity preserved its antitumoral activity. [Copyright &y& Elsevier]
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- 2002
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19. Enantioselective semi-preparative HPLC of two 2-arylpropionic acids on glycopeptides containing chiral stationary phases
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Alcaro, Stefano, D'Acquarica, Ilaria, Gasparrini, Francesco, Misiti, Domenico, Pierini, Marco, and Villani, Claudio
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GLYCOPEPTIDES , *HIGH performance liquid chromatography - Abstract
We describe a new enantioselective HPLC procedure for the direct semi-preparative resolution of two unmodified 2-arylpropionic acids. The method is based on the use of novel laboratory-made chiral stationary phases (CSPs) containing macrocyclic glycopeptide antibiotics, such as teicoplanin and A-40,926, covalently bonded to silica gel microparticles. The new CSPs showed high enantioselectivities and broad applicabilities for separations on a semi-preparative scale. [Copyright &y& Elsevier]
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- 2002
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20. Identification of HIV-1 Reverse Transcriptase Dual Inhibitors by a Combined Shape-, 2D-Fingerprint- and Pharmacophore-based Virtual Screening Approach
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Distinto, Simona, Esposito, Francesca, Kirchmair, Johannes, Cardia, Cristina M., Maccioni, Elias, Alcaro, Stefano, Zinzula, Luca, and Tramontano, Enzo
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- 2011
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21. Current status of antivirals and druggable targets of SARS CoV-2 and other human pathogenic coronaviruses.
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Artese, Anna, Svicher, Valentina, Costa, Giosuè, Salpini, Romina, Di Maio, Velia Chiara, Alkhatib, Mohammad, Ambrosio, Francesca Alessandra, Santoro, Maria Mercedes, Assaraf, Yehuda G., Alcaro, Stefano, and Ceccherini-Silberstein, Francesca
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Coronaviridae is a peculiar viral family, with a very large RNA genome and characteristic appearance, endowed with remarkable tendency to transfer from animals to humans. Since the beginning of the 21st century, three highly transmissible and pathogenic coronaviruses have crossed the species barrier and caused deadly pneumonia, inflicting severe outbreaks and causing human health emergencies of inconceivable magnitude. Indeed, in the past two decades, two human coronaviruses emerged causing serious respiratory illness: severe acute respiratory syndrome coronavirus (SARS-CoV-1) and Middle Eastern respiratory syndrome coronavirus (MERS-CoV), causing more than 10,000 cumulative cases, with mortality rates of 10 % for SARS-CoV-1 and 34.4 % for MERS-CoV. More recently, the severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) has emerged in China and has been identified as the etiological agent of the recent COVID-19 pandemic outbreak. It has rapidly spread throughout the world, causing nearly 22 million cases and ∼ 770,000 deaths worldwide, with an estimated mortality rate of ∼3.6 %, hence posing serious challenges for adequate and effective prevention and treatment. Currently, with the exception of the nucleotide analogue prodrug remdesivir, and despite several efforts, there is no known specific, proven, pharmacological treatment capable of efficiently and rapidly inducing viral containment and clearance of SARS-CoV-2 infection as well as no broad-spectrum drug for other human pathogenic coronaviruses. Another confounding factor is the paucity of molecular information regarding the tendency of coronaviruses to acquire drug resistance, a gap that should be filled in order to optimize the efficacy of antiviral drugs. In this light, the present review provides a systematic update on the current knowledge of the marked global efforts towards the development of antiviral strategies aimed at coping with the infection sustained by SARS-CoV-2 and other human pathogenic coronaviruses, displaying drug resistance profiles. The attention has been focused on antiviral drugs mainly targeting viral protease, RNA polymerase and spike glycoprotein, that have been tested in vitro and/or in clinical trials as well as on promising compounds proven to be active against coronaviruses by an in silico drug repurposing approach. In this respect, novel insights on compounds, identified by structure-based virtual screening on the DrugBank database endowed by multi-targeting profile, are also reported. We specifically identified 14 promising compounds characterized by a good in silico binding affinity towards, at least, two of the four studied targets (viral and host proteins). Among which, ceftolozane and NADH showed the best multi-targeting profile, thus potentially reducing the emergence of resistant virus strains. We also focused on potentially novel pharmacological targets for the development of compounds with anti-pan coronavirus activity. Through the analysis of a large set of viral genomic sequences, the current review provides a comprehensive and specific map of conserved regions across human coronavirus proteins which are essential for virus replication and thus with no or very limited tendency to mutate. Hence, these represent key druggable targets for novel compounds against this virus family. In this respect, the identification of highly effective and innovative pharmacological strategies is of paramount importance for the treatment and/or prophylaxis of the current pandemic but potentially also for future and unavoidable outbreaks of human pathogenic coronaviruses. [ABSTRACT FROM AUTHOR]
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- 2020
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22. Multi-target drug discovery: An opportunity for novel and repurposed bioactive compounds.
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Alcaro, Stefano and Ortuso, Francesco
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BIOACTIVE compounds , *DRUGS , *PHARMACEUTICAL chemistry , *DOSAGE forms of drugs - Published
- 2020
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23. Discovery of pyridoquinoxaline-based new P-gp inhibitors as coadjutant against Multi Drug Resistance in cancer.
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Ibba, Roberta, Sestito, Simona, Ambrosio, Francesca Alessandra, Marchese, Emanuela, Costa, Giosuè, Fiorentino, Francesco Paolo, Fusi, Fabio, Marchesi, Irene, Polini, Beatrice, Chiellini, Grazia, Alcaro, Stefano, Piras, Sandra, and Carta, Antonio
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DRUG resistance in cancer cells , *CANCER relapse , *DRUG absorption , *MULTIDRUG resistance , *GASTROINTESTINAL agents - Abstract
Multi-drug resistance (MDR) is a serious challenge in contemporary clinical practice and is mostly responsible for the failure of cancer medication therapies. Several experimental evidence links MDR to the overexpression of the drug efflux transporter P-gp, therefore, the discovery of novel P-glycoprotein inhibitors is required to treat or prevent MDR and to improve the absorption of chemotherapy drugs via the gastrointestinal system. In this work, we explored a series of novel pyridoquinoxaline-based derivatives designed from parental compounds, previously proved active in enhancing anticancer drugs in MDR nasopharyngeal carcinoma (KB). Among them, derivative 10d showed the most potent and selective inhibition of fluorescent dye efflux, if compared to reference compounds (MK-571, Novobiocin, Verapamil), and the highest MDR reversal activity when co-administered with the chemotherapeutic agents Vincristine and Etoposide, at non-cytotoxic concentrations. Molecular modelling predicted the two compound 10d binding mode in a ratio of 2:1 with the target protein. No cytotoxicity was observed in healthy microglia cells and off-target investigations showed the absence of Ca V 1.2 channel blockade. In summary, our findings indicated that 10d could potentially be a novel therapeutic coadjutant by inhibiting P-gp transport function in vitro , thereby reversing cancer multidrug resistance. [Display omitted] • Multidrug resistance, mostly responsible for failure of cancer treatment is also driven by P-gp overexpression. • Novel quinoxaline-based compounds were screened for efflux inhibition of fluorescent dye. • Novel pyridoquinoxaline-based derivative 10d reversed MDR when co-administered with different anticancer treatments. • The binding mode of compound 10d is predicted to be of high affinity and with a 2:1 ratio. [ABSTRACT FROM AUTHOR]
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- 2024
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24. MAATrica: a measure for assessing consistency and methods in medicinal and nutraceutical chemistry papers.
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Panzarella, Giulia, Gallo, Alessandro, Coecke, Sandra, Querci, Maddalena, Ortuso, Francesco, Hofmann-Apitius, Martin, Veltri, Pierangelo, Bajorath, Jürgen, and Alcaro, Stefano
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PHARMACEUTICAL chemistry , *SEARCH engines , *TEXT mining , *RESEARCH personnel , *DATA mining , *FUNCTIONAL foods - Abstract
The growing number of scientific papers and document sources underscores the need for methods capable of evaluating the quality of publications. Researchers who are looking for relevant papers for their studies need ways to assess the scientific value of these documents. One approach involves using semantic search engines that can automatically extract important knowledge from the growing body of text. In this study, we introduce a new metric called "MAATrica," which serves as the foundation for an innovative method designed to evaluate research papers. MAATrica offers a new way to analyze and categorize text, focusing on the consistency of research documents in the life sciences, particularly in the fields of medicinal and nutraceutical chemistry. This method utilizes semantic descriptions to cover in silico experiments, as well as in vitro and in vivo essays. Created to aid in evaluation processes like peer review, MAATrica uses toolkits and semantic applications to build the proposed measure, identify scientific entities, and gather information. We have applied MAATrica to roughly 90,000 papers and present our findings here. [Display omitted] • MAATrica is a novel metric for assessing the coherence of methodologies in research papers within the fields of medicinal and nutraceutical chemistry. • MAATrica utilizes SciWalker (SW) as semantic search engine and ontologies to automate knowledge extraction and evaluate research papers. • MAATrica metric has been tested and validated using a dataset comprising approximately 90,000 papers within the SW platform. • MAATrica's reliability has undergone testing through comparisons with manual evaluations, revealing strong agreement and potential support for peer review. • MAATrica employs a user-controlled and customizable ontology, enabling personalized analysis of research papers in the fields of medicinal and nutraceutical chemistry. [ABSTRACT FROM AUTHOR]
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- 2024
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25. Theoretical and structural studies on mechanism of the Stec reaction
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Michelini, Maria del Carmen, Russo, Nino, Alcaro, Stefano, and Wozniak, Lucyna A.
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CHEMICAL structure , *REACTION mechanisms (Chemistry) , *CHEMICAL reactions , *ANILIDES , *DENSITY functionals , *NUCLEAR magnetic resonance spectroscopy , *LOW temperatures - Abstract
Abstract: The mechanism of the Stec reaction between phosphoroselenanilidate or phosphonoanilidate and CS2, activated by strong bases, has been studied computationally, using DFT methods, and experimentally, by low temperature 31P NMR spectroscopy. From molecular calculations, the reaction pathway of the reaction has been revealed with several transition states and intermediates, including a low energy spirocyclic pentacoordinate transition state and acyclic tetracoordinate intermediates, which eventually were correlated with short living molecules detected by NMR spectroscopy. [Copyright &y& Elsevier]
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- 2012
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26. Synthesis and biological assessment of novel 2-thiazolylhydrazones and computational analysis of their recognition by monoamine oxidase B
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Distinto, Simona, Yáñez, Matilde, Alcaro, Stefano, Cardia, M. Cristina, Gaspari, Marco, Sanna, M. Luisa, Meleddu, Rita, Ortuso, Francesco, Kirchmair, Johannes, Markt, Patrick, Bolasco, Adriana, Wolber, Gerhard, Secci, Daniela, and Maccioni, Elias
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HYDRAZONES , *MONOAMINE oxidase , *TREATMENT of neurodegeneration , *HYDRAZINES , *BACULOVIRUS biotechonology , *INSECT cell biotechnology , *STRUCTURAL bioinformatics , *MOLECULAR dynamics - Abstract
Abstract: Monoamine oxidase B (MAO-B) is a promising target for the treatment of neurodegenerative disorders. We report the synthesis and the biological evaluation of halogenated derivatives of 1-aryliden-2-(4-phenylthiazol-2-yl)hydrazines. The fluorinated series shows interesting activity and great selectivity toward the human recombinant MAO-B isoform expressed in baculovirus infected BTI insect cells. The multiple crystal structures alignment of the enzyme highlighted pronounced induced fit (IF) adaptations with respect to bound ligands. Therefore, IF docking (IFD) experiments and molecular dynamic (MD) simulations were carried out to reveal the putative binding mode and to explain the experimentally observed differences in the activity of 1-(aryliden-2-(4-(4-chlorophenyl)thiazol-2-yl)hydrazines. The importance of water molecules within the binding site was also investigated. These are known to play an important role in the binding site cavity and to mediate protein–ligand interactions. Detailed analyses of the trajectories provide insights on the chemical features required for the activity of this scaffold. In particular it was highlighted the importance of fluorine atom interacting with the water close to the cofactor and the influence of steric bulkiness of substituents in the arylidene moiety. Free energy perturbation (FEP) analysis confirmed experimental data. The information we deduced will help to develop novel high-affinity MAO-B inhibitors. [Copyright &y& Elsevier]
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- 2012
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27. β-Cyclodextrin interactions with three drugs used in inflammatory pathologies: An experimental and theoretical study
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Cairo, Patrizia, Ortuso, Francesco, Alcaro, Stefano, Fontananova, Enrica, Tocci, Elena, and Drioli, Enrico
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CYCLODEXTRINS , *DRUGS , *INFLAMMATION , *DIFLUNISAL - Abstract
Abstract: Complexation of 5-amino salicylic acid (1), sulfasalazine (2) and diflunisal (3), nonsteroid anti-inflammatory drugs with a wide range of actions, with β-cyclodextrin (βCD) have been studied by means of differential scanning calorimetry and UV–vis spectroscopy. The experimental results have shown the formation of stable inclusion complexes. The molecular modeling study has been carried out to elucidate the different inclusion behaviors. A preliminary Monte Carlo (MC) conformational search of the guest molecules followed by docking and multiple minimization procedure with two force fields, Amber ∗ and Pcff, has indicated that drugs forms stable complexes with βCD. The results are in good agreement with the experimental data from measurement of stability constants. [Copyright &y& Elsevier]
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- 2008
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28. Targeting non-coding RNAs: Perspectives and challenges of in-silico approaches.
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Rocca, Roberta, Grillone, Katia, Citriniti, Emanuele Liborio, Gualtieri, Gianmarco, Artese, Anna, Tagliaferri, Pierosandro, Tassone, Pierfrancesco, and Alcaro, Stefano
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NON-coding RNA , *LINCRNA , *HUMAN biology , *SMALL molecules , *RNA - Abstract
The growing information currently available on the central role of non-coding RNAs (ncRNAs) including microRNAs (miRNAS) and long non-coding RNAs (lncRNAs) for chronic and degenerative human diseases makes them attractive therapeutic targets. RNAs carry out different functional roles in human biology and are deeply deregulated in several diseases. So far, different attempts to therapeutically target the 3D RNA structures with small molecules have been reported. In this scenario, the development of computational tools suitable for describing RNA structures and their potential interactions with small molecules is gaining more and more interest. Here, we describe the most suitable strategies to study ncRNAs through computational tools. We focus on methods capable of predicting 2D and 3D ncRNA structures. Furthermore, we describe computational tools to identify, design and optimize small molecule ncRNA binders. This review aims to outline the state of the art and perspectives of computational methods for ncRNAs over the past decade. [Display omitted] • NcRNAs are a crucial target in treating chronic and degenerative human diseases. • Finding compounds targeting ncRNA is the first step for clinical applications. • Computational methods speed up ncRNA-interfering molecules discovery. • Protein targeting strategies were often adapted for optimizing ncRNA ligands. • New computational tools are growing for nucleic acids investigation. [ABSTRACT FROM AUTHOR]
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- 2023
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29. Benzoic acid-derived nitrones: A new class of potential acetylcholinesterase inhibitors and neuroprotective agents.
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Oliveira, Catarina, Bagetta, Donatella, Cagide, Fernando, Teixeira, José, Amorim, Ricardo, Silva, Tiago, Garrido, Jorge, Remião, Fernando, Uriarte, Eugenio, Oliveira, Paulo J., Alcaro, Stefano, Ortuso, Francesco, and Borges, Fernanda
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ACETYLCHOLINESTERASE , *ACETYLCHOLINESTERASE inhibitors , *NITRONES , *NEUROPROTECTIVE agents , *ALZHEIMER'S disease , *BLOOD-brain barrier - 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 (IC 50 = 8.3 ± 0.3 μM; Ki 5.2 μM). 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. Image 1 • A small library of non-cytotoxic benzoic based amide nitrones were obtained. • Only nitrones with tert -butyl moiety effectively and selectively inhibited AChE. • Molecular docking studies provided insights into the enzyme-inhibitor interactions. • Compound 33 is highlighted as a non-competitive toward AChE (IC50 = 8.3 μ0.3 μM; Ki 5.2 μM). • Compound 33 was able to prevent t -BHP-induced oxidative stress in SH-SY5Y differentiated cells. [ABSTRACT FROM AUTHOR]
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- 2019
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30. Novel natural non-nucleoside inhibitors of HIV-1 reverse transcriptase identified by shape- and structure-based virtual screening techniques.
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Costa, Giosuè, Rocca, Roberta, Corona, Angela, Grandi, Nicole, Moraca, Federica, Romeo, Isabella, Talarico, Carmine, Gagliardi, Maria Giovanna, Ambrosio, Francesca Alessandra, Ortuso, Francesco, Alcaro, Stefano, Distinto, Simona, Maccioni, Elias, Tramontano, Enzo, and Artese, Anna
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REVERSE transcriptase inhibitors , *MOLECULAR dynamics , *DNA polymerases , *PYRROLIDINE , *NATURAL products - Abstract
Abstract In this work we report a parallel application of both docking- and shape-based virtual screening (VS) methods, followed by Molecular Dynamics simulations (MDs), for discovering new compounds able to inhibit the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) RNA-dependent DNA polymerase activity. Specifically, we screened more than 143000 natural compounds commercially available in the ZINC database against the best five RT crystallographic models, taking into account the five approved NNRTIs as query compounds. As a result, 20 hit molecules were selected and tested on biochemical assays for the inhibition of the RNA dependent DNA polymerase RT function and, among them, an indoline pyrrolidine (hit 1), an indonyl piperazine (hit 2) and an indolyl indolinone (hit 3) derivatives were identified as novel non-nucleoside RT inhibitors in the low micromolar range. Graphical abstract Image 1 Highlights • Shape-based and docking virtual screening were applied to Reverse Transcriptase. • The NNRTI binding pocket flexibility was considered by using different PDB models. • A database of more than 143000 natural compounds was screened. • 3 hits revealed an RT inhibitory activity in the low micromolar range. • The most interesting scaffold was the indolyl indolinone one. [ABSTRACT FROM AUTHOR]
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- 2019
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31. Multi-target-directed ligands for Alzheimer's disease: Discovery of chromone-based monoamine oxidase/cholinesterase inhibitors.
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Reis, Joana, Cagide, Fernando, Valencia, Martín Estrada, Teixeira, José, Bagetta, Donatella, Pérez, Concepción, Uriarte, Eugenio, Oliveira, Paulo J., Ortuso, Francesco, Alcaro, Stefano, Rodríguez-Franco, María Isabel, and Borges, Fernanda
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ALZHEIMER'S disease treatment , *MONOAMINE oxidase inhibitors , *LIGANDS (Biochemistry) , *CHROMONES , *CELL-mediated cytotoxicity , *THERAPEUTICS - Abstract
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)-4 H -chromen-6-yl)acrylate (9a) and 2-(dimethylamino)ethyl (E)-3-(4-oxo-3-(phenylcarbamoyl)-4 H -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 (IC 50 = 0.21 μM, K i = 0.19 μM) and displayed dual h MAO inhibitory activity (h MAO-A IC 50 = 0.94 μM, K i = 0.057 μM and h MAO-B IC 50 = 3.81 μM, K i = 0.48 μM). Compound 23a acted as a selective IMAO-B (IC 50 = 0.63 μM, K i = 0.34 μM) while still displaying h ChE 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. Graphical abstract Image 1 Highlights • Successfully BBB permeable chromone-based multi-target compounds targeting human ChEs and MAOs were developed. • Compound 9a acted as a bifunctional h AChE inibitor also possessing dual h MAO inhibitory activity. • Compound 23a acted as a selective h MAO-B inhibitor displaying h ChE inhibitory activity in the low micromolar range. • Compounds showed limited cytotoxicity in differentiated SH-SY5Y and HepG2 cells. [ABSTRACT FROM AUTHOR]
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- 2018
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32. Design, synthesis and biochemical evaluation of novel multi-target inhibitors as potential anti-Parkinson agents.
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Carradori, Simone, Bagetta, Donatella, Ortuso, Francesco, Alcaro, Stefano, Petzer, Anél, Petzer, Jacobus P., De Monte, Celeste, Secci, Daniela, De Vita, Daniela, Guglielmi, Paolo, Zengin, Gokhan, and Aktumsek, Abdurrahman
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ACETYLCHOLINESTERASE inhibitors , *MONOAMINE oxidase inhibitors , *ANTIPARKINSONIAN agents , *ANTIOXIDANTS , *DRUG design , *DRUG therapy for Parkinson's disease - 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 . [ABSTRACT FROM AUTHOR]
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- 2018
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33. Identification of pyrrolo[3′,4':3,4]cyclohepta[1,2-d][1,2]oxazoles as promising new candidates for the treatment of lymphomas.
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Barreca, Marilia, Spanò, Virginia, Rocca, Roberta, Bivacqua, Roberta, Gualtieri, Gianmarco, Raimondi, Maria Valeria, Gaudio, Eugenio, Bortolozzi, Roberta, Manfreda, Lorenzo, Bai, Ruoli, Montalbano, Alessandra, Alcaro, Stefano, Hamel, Ernest, Bertoni, Francesco, Viola, Giampietro, and Barraja, Paola
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OXAZOLES , *MOLECULAR dynamics , *CELL cycle , *NON-Hodgkin's lymphoma , *SMALL molecules , *PYRROLE derivatives - Abstract
Unsatisfactory outcomes for relapsed/refractory lymphoma patients prompt continuing efforts to develop new therapeutic strategies. Our previous studies on pyrrole-based anti-lymphoma agents led us to synthesize a new series of twenty-six pyrrolo[3′,4':3,4]cyclohepta[1,2- d ] [1,2]oxazole derivatives and study their antiproliferative effects against a panel of four non-Hodgkin lymphoma cell lines. Several candidates showed significant anti-proliferative effects, with IC 50 's reaching the sub-micromolar range in at least one cell line, with compound 3z demonstrating sub-micromolar growth inhibitory effects towards the entire panel. The VL51 cell line was the most sensitive, with an IC 50 value of 0.10 μM for 3z. Our earlier studies had shown that tubulin was a prominent target of many of our oxazole derivatives. We therefore examined their effects on tubulin assembly and colchicine binding. While 3u and 3z did not appear to target tubulin, good activity was observed with 3d and 3p. Molecular docking and molecular dynamics simulations allowed us to rationalize the binding mode of the synthesized compounds toward tubulin. All ligands exhibited a better affinity for the colchicine site, confirming their specificity for this binding pocket. In particular, a better affinity and free energy of binding was observed for 3d and 3p. This result was confirmed by experimental data, indicating that, although both 3d and 3p significantly affected tubulin assembly, only 3d showed activity comparable to that of combretastatin A-4, while 3p was about 4-fold less active. Cell cycle analysis showed that compounds 3u and especially 3z induced a block in G2/M, a strong decrease in S phase even at low compound concentrations and apoptosis through the mitochondrial pathway. Thus, the mechanism of action of 3u and 3z remains to be elucidated. Very high selectivity toward cancer cells and low toxicity in human peripheral blood lymphocytes were observed, highlighting the good potential of these agents in cancer therapy and encouraging further exploration of this compound class to obtain new small molecules as effective lymphoma treatments. [Display omitted] • 3u and 3z showed IC 50 values at submicromolar level against different lymphoma cells. • 3u and 3z displayed very high selectivity toward cancer cells and low toxicity in PBLs. • 3u and 3z induced cell cycle arrest in G2/M. • 3u and 3z induced apoptosis through the mitochondrial pathway. [ABSTRACT FROM AUTHOR]
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- 2023
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34. Identification of G-quadruplex DNA/RNA binders: Structure-based virtual screening and biophysical characterization.
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Rocca, Roberta, Moraca, Federica, Costa, Giosuè, Nadai, Matteo, Scalabrin, Matteo, Talarico, Carmine, Distinto, Simona, Maccioni, Elias, Ortuso, Francesco, Artese, Anna, Alcaro, Stefano, and Richter, Sara N.
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QUADRUPLEX nucleic acids , *RNA , *NUCLEIC acids , *LIGANDS (Biochemistry) , *TELOMERASE , *TELOMERASE genetics , *MOLECULAR biology - Abstract
Background Recent findings demonstrated that, in mammalian cells, telomere DNA (Tel) is transcribed into telomeric repeat-containing RNA (TERRA), which is involved in fundamental biological processes, thus representing a promising anticancer target. For this reason, the discovery of dual (as well as selective) Tel/TERRA G-quadruplex (G4) binders could represent an innovative strategy to enhance telomerase inhibition. Methods Initially, docking simulations of known Tel and TERRA active ligands were performed on the 3D coordinates of bimolecular G4 Tel DNA (Tel 2 ) and TERRA (TERRA 2 ). Structure-based pharmacophore models were generated on the best complexes and employed for the virtual screening of ~ 257,000 natural compounds. The 20 best candidates were submitted to biophysical assays, which included circular dichroism and mass spectrometry at different K + concentrations. Results Three hits were here identified and characterized by biophysical assays. Compound 7 acts as dual Tel 2 /TERRA 2 G4-ligand at physiological KCl concentration, while hit s 15 and 17 show preferential thermal stabilization for Tel 2 DNA. The different molecular recognition against the two targets was also discussed. Conclusions Our successful results pave the way to further lead optimization to achieve both increased selectivity and stabilizing effect against TERRA and Tel DNA G4s. General significance The current study combines for the first time molecular modelling and biophysical assays applied to bimolecular DNA and RNA G4s, leading to the identification of innovative ligand chemical scaffolds with a promising anticancer profile. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. [ABSTRACT FROM AUTHOR]
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- 2017
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35. Natural product-inspired esters and amides of ferulic and caffeic acid as dual inhibitors of HIV-1 reverse transcriptase.
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Sonar, Vijay P., Corona, Angela, Distinto, Simona, Maccioni, Elias, Meleddu, Rita, Fois, Benedetta, Floris, Costantino, Malpure, Nilesh V., Alcaro, Stefano, Tramontano, Enzo, and Cottiglia, Filippo
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REVERSE transcriptase , *DNA polymerases , *CAFFEIC acid , *HYDROXYCINNAMIC acids , *OCIMUM sanctum - Abstract
Using an HIV-1 Reverse Transcriptase (RT)-associated RNase H inhibition assay as lead, bioguided fractionation of the dichloromethane extract of the Ocimum sanctum leaves led to the isolation of five triterpenes ( 1–5 ) along with three 3-methoxy-4-hydroxy phenyl derivatives ( 6 – 8 ). The structure of this isolates were determined by 1D and 2D NMR experiments as well as ESI-MS. Tetradecyl ferulate ( 8 ) showed an interesting RNase H IC 50 value of 12.4 μM and due to the synthetic accessibility of this secondary metabolite, a structure-activity relationship study was carried out. A series of esters and amides of ferulic and caffeic acids were synthesized and, among all, the most active was N-oleylcaffeamide displaying a strong inhibitory activity towards both RT-associated functions, ribonuclease H and DNA polymerase. Molecular modeling studies together with Yonetani-Theorell analysis, demonstrated that N-oleylcaffeamide is able to bind both two allosteric site located one close to the NNRTI binding pocket and the other close to RNase H catalytic site. [ABSTRACT FROM AUTHOR]
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- 2017
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36. Naphthalene diimide-polyamine hybrids as antiproliferative agents: Focus on the architecture of the polyamine chains.
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Milelli, Andrea, Marchetti, Chiara, Greco, Maria Laura, Moraca, Federica, Costa, Giosuè, Turrini, Eleonora, Catanzaro, Elena, Betari, Nibal, Calcabrini, Cinzia, Sissi, Claudia, Alcaro, Stefano, Fimognari, Carmela, Tumiatti, Vincenzo, and Minarini, Anna
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NAPHTHALENE , *POLYAMINES , *ANTINEOPLASTIC agents , *QUADRUPLEX nucleic acids , *MOLECULAR models - Abstract
Naphthalene diimides (NDIs) have been widely used as scaffold to design DNA-directed agents able to target peculiar DNA secondary arrangements endowed with relevant biochemical roles. Recently, we have reported disubstituted linear- and macrocyclic-NDIs that bind telomeric and non-telomeric G-quadruplex with high degree of affinity and selectivity. Herein, the synthesis, biological evaluation and molecular modelling studies of a series of asymmetrically substituted NDIs are reported. Among these, compound 9 emerges as the most interesting of the series being able to bind telomeric G-quadruplex (ΔTm = 29 °C at 2.5 μM), to inhibit the activity of DNA processing enzymes, such as topoisomerase II and TAQ-polymerase, and to exert antiproliferative effects in the NCI panel of cancer cell lines with GI 50 values in the micro-to nanomolar concentration range ( i.e. SR cell line, GI 50 = 76 nM). Molecular mechanisms of cell death have been investigated and molecular modelling studies have been performed in order to shed light on the antiproliferative and DNA-recognition processes. [ABSTRACT FROM AUTHOR]
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- 2017
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37. Insight into non-nucleoside triazole-based systems as viral polymerases inhibitors.
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Bivacqua, Roberta, Barreca, Marilia, Spanò, Virginia, Raimondi, Maria Valeria, Romeo, Isabella, Alcaro, Stefano, Andrei, Graciela, Barraja, Paola, and Montalbano, Alessandra
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POLYMERASES , *LIFE cycles (Biology) , *ANTIVIRAL agents , *REVERSE transcriptase , *VIRAL transmission , *STRUCTURE-activity relationships - Abstract
Viruses have been recognized as the etiological agents responsible for many pathological conditions ranging from asymptomatic infections to serious diseases, even leading to death. For this reason, many efforts have been made to identify selective viral targets with the aim of developing efficient therapeutic strategies, devoid of drug-resistance issues. Considering their crucial role in the viral life cycle, polymerases are very attractive targets. Among the classes of compounds explored as viral polymerases inhibitors, here we present an overview of non-nucleoside triazole-based compounds identified in the last fifteen years. Furthermore, the structure-activity relationships (SAR) of the different chemical entities are described in order to highlight the key chemical features required for the development of effective antiviral agents. [Display omitted] • Non-nucleoside triazole systems as antiviral agents. • Viral polymerases as valuable target in the control of viral spread. • SAR analysis of triazole based polymerase inhibitors. [ABSTRACT FROM AUTHOR]
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- 2023
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38. 8-Amide and 8-carbamate substitution patterns as modulators of 7-hydroxy-4-methylcoumarin's antidepressant profile: Synthesis, biological evaluation and docking studies.
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Matos, Maria J., Novo, Paula, Mayán, Lucía, Torres, Iria, Uriarte, Eugenio, Yáñez, Matilde, Fontenla, José Ángel, Ortuso, Francesco, Alcaro, Stefano, Procopio, Francesca, Rodríguez-Franco, María Isabel, Val, Cristina, Loza, María I., Brea, José, Borges, Fernanda, and Viña, Dolores
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MOLECULAR docking , *MONOAMINE oxidase , *MENTAL illness , *NEUROLOGICAL disorders , *BLOOD-brain barrier , *ANTIDEPRESSANTS , *FENITROTHION - Abstract
Psychiatric and neurological disorders affect millions of people worldwide. Currently available treatments may help to improve symptoms, but they cannot cure the diseases. Therefore, there is an urgent need for potent and safe therapeutic solutions. 8-Amide and 8-carbamatecoumarins were synthetized and evaluated as human monoamine oxidase A and B (h MAO-A and h MAO-B) inhibitors. Comparison between both scaffolds has been established, and we hypothesized that the introduction of different substituents can modulate h MAO activity and selectivity. N -(7-Hydroxy-4-methylcoumarin-8-yl)-4-methylbenzamide (9) and ethyl N -(7-hydroxy-4-methylcoumarin-8-yl)carbamate (20) proved to be the most active and selective h MAO-A inhibitors (IC 50 = 15.0 nM and IC 50 = 22.0 nM, respectively), being compound 9 an irreversible h MAO-A inhibitor twenty-four times more active in vitro than moclobemide, a drug used in the treatment of depression and anxiety. Based on PAMPA assay results, both compounds proved to be good candidates to cross the blood-brain barrier. In addition, these compounds showed non-significant cytotoxicity on neuronal viability assays. Also, the best compound proved to have a t 1/2 of 6.84 min, an intrinsic clearance of 195.63 μL min−1 mg−1 protein, and to be chemically stable at pH 3.0, 7.4 and 10.0. Docking studies were performed to better understand the binding affinities and selectivity profiles for both h MAO isoforms. Finally, theoretical drug-like properties calculations corroborate the potential of both scaffolds on the search for new therapeutic solutions for psychiatric disorders as depression. [Display omitted] • 8-Amide and 8-carbamatecoumarins have been evaluated as h MAO-A and h MAO-B inhibitors. • Four molecules from the series proved to be h MAO-A inhibitors in the nanomolar range. • Compound 9 is 24 times more active in vitro than moclobemide. • Compounds 9 and 20 proved to be able to cross the BBB. • These compounds proved to be non-cytotoxic on neuronal viability assays. [ABSTRACT FROM AUTHOR]
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- 2023
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39. Development of [1,2]oxazoloisoindoles tubulin polymerization inhibitors: Further chemical modifications and potential therapeutic effects against lymphomas.
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Barreca, Marilia, Spanò, Virginia, Rocca, Roberta, Bivacqua, Roberta, Abel, Anne-Catherine, Maruca, Annalisa, Montalbano, Alessandra, Raimondi, Maria Valeria, Tarantelli, Chiara, Gaudio, Eugenio, Cascione, Luciano, Rinaldi, Andrea, Bai, Ruoli, Steinmetz, Michel O., Prota, Andrea E., Alcaro, Stefano, Hamel, Ernest, Bertoni, Francesco, and Barraja, Paola
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TUBULINS , *CHEMICAL inhibitors , *CHEMICAL potential , *MUCOSA-associated lymphoid tissue lymphoma , *TREATMENT effectiveness , *LYMPHOMAS - Abstract
Lymphomas are among the ten most common cancers, and, although progress has been achieved in increasing survival, there is still an unmet need for more effective therapeutic approaches, including better options for patients with refractory tumors that initially respond but then relapse. The lack of effective alternative treatment options highlights the need to develop new therapeutic strategies capable of improving survival prospects for lymphoma patients. Herein, we describe the identification and exploration of the SAR of a series of [1,2]oxazolo[5,4 -e ]isoindoles as potent small molecules that bind to the colchicine site of tubulin and that have promise for the treatment of refractory lymphomas. Exploration of the chemical space of this class of compounds at the pyrrole moiety and at the [1,2]oxazole ring highlighted two compounds bearing a 3,5-dimethoxybenzyl and a 3,4,5-trimethoxybenzyl group as potent candidates and showed that structural modifications at the isoxazole moiety are generally not favorable for activity. The two best candidates showed efficacy against different lymphoma histotypes and displayed 88 and 80% inhibition of colchicine binding fitting well into the colchicine pocket, as demonstrated by X-ray crystallography T 2 R-TTL–complexes, docking and thermodynamic analysis of the tubulin-colchicine complex structure. These results were confirmed by transcriptome data, thus indicating [1,2]oxazolo[5,4 -e ]isoindoles are promising candidates as antitubulin agents for the treatment of refractory lymphomas. [Display omitted] • 14k , 15k , 17i and 17j exhibited high antiproliferative activity against the NCI panel. • 17i and 17j demonstrated high selectivity against one marginal zone lymphoma cell line. • 2e and 2f showed efficacy against different lymphoma histotypes at nanomolar level. • 2e and 2f displayed 88 and 80% inhibition of colchicine binding, respectively. • Crystal structure of tubulin- 2e complex confirmed the binding at the intradimer interface. [ABSTRACT FROM AUTHOR]
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- 2022
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40. (E)-3-Heteroarylidenechroman-4-ones as potent and selective monoamine oxidase-B inhibitors.
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Desideri, Nicoletta, Proietti Monaco, Luca, Fioravanti, Rossella, Biava, Mariangela, Yáñez, Matilde, Alcaro, Stefano, and Ortuso, Francesco
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MONOAMINE oxidase inhibitors , *MOLECULAR models , *CHROMANS , *INHIBITORY Concentration 50 , *DRUG development , *ISOFLAVONOIDS , *THERAPEUTICS - Abstract
A series of ( E )-3-heteroarylidenechroman-4-ones ( 1a-r ) was designed, synthesized and investigated in vitro for their ability to inhibit the enzymatic activity of both human monoamine oxidase (hMAO) isoforms, hMAO-A and hMAO-B. All the compounds were found to be selective hMAO-B inhibitors showing IC 50 values in the nanomolar or micromolar range. ( E )-5,7-Dichloro-3-{[(2-(dimethylamino)pyrimidin-5-yl]methylene}chroman-4-one ( 1c ) was the most interesting compound identified in this study, endowed with higher hMAO-B potency (IC 50 = 10.58 nM) and selectivity (SI > 9452) with respect to the reference selective inhibitor selegiline (IC 50 = 19.60 nM, IC 50 > 3431). Molecular modelling studies were performed for rationalizing at molecular level the target selective inhibition of our compounds, revealing a remarkable contribution of hydrogen bond network and water solvent. [ABSTRACT FROM AUTHOR]
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- 2016
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41. Exploring new chemical functionalities to improve aromatase inhibition of steroids.
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Varela, Carla L., Amaral, Cristina, Correia-da-Silva, Georgina, Costa, Saul C., Carvalho, Rui A., Costa, Giosuè, Alcaro, Stefano, Teixeira, Natércia A.A., Tavares-da-Silva, Elisiário J., and Roleira, Fernanda M.F.
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AROMATASE inhibitors , *STEROIDS , *MICROSOMES , *BREAST cancer , *ANDROSTENEDIONE - Abstract
In this work, new potent steroidal aromatase inhibitors both in microsomes and in breast cancer cells have been found. The synthesis of the 3,4-(ethylenedioxy)androsta-3,5-dien-17-one ( 12 ), a new steroid containing a heterocycle dioxene fused in the A-ring, led to the discovery of a new reaction for which a mechanism is proposed. New structure–activity relationships were established. Some 5β-steroids, such as compound 4β,5β-epoxyandrostan-17-one ( 9 ), showed aromatase inhibitory activity, because they adopt a similar A-ring conformation as those of androstenedione, the natural substrate of aromatase. Moreover, new chemical features to increase planarity were disclosed, specifically the 3α,4α-cyclopropane ring, as in 3α,4α-methylen-5α-androstan-17-one ( 5 ) (IC 50 = 0.11 μM), and the Δ 9–11 double bond in the C-ring, as in androsta-4,9(11)-diene-3,17-dione ( 13 ) (IC 50 = 0.25 μM). In addition, induced-fit docking (IFD) simulations and site of metabolism (SoM) predictions helped to explain the recognition of new potent steroidal aromatase inhibitors within the enzyme. These insights can be valuable tools for the understanding of the molecular recognition process by the aromatase and for the future design of new steroidal inhibitors. [ABSTRACT FROM AUTHOR]
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- 2016
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42. Drug design, synthesis, in vitro and in silico evaluation of selective monoaminoxidase B inhibitors based on 3-acetyl-2-dichlorophenyl-5-aryl-2,3-dihydro-1,3,4-oxadiazole chemical scaffold.
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Distinto, Simona, Meleddu, Rita, Yanez, Matilde, Cirilli, Roberto, Bianco, Giulia, Sanna, Maria Luisa, Arridu, Antonella, Cossu, Pietro, Cottiglia, Filippo, Faggi, Cristina, Ortuso, Francesco, Alcaro, Stefano, and Maccioni, Elias
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DRUG design , *DRUG synthesis , *AROMATIC compound derivatives , *MONOAMINE oxidase inhibitors , *MOLECULAR interactions , *CHEMICAL structure , *STEREOCHEMISTRY , *IN vitro studies - Abstract
With the aim to identify new, potent and selective monoamine oxidase B (MAO-B) inhibitors, molecular interaction field analysis has been applied to a MAO-B complex with 3-acetyl-2,5-diaryl-2,3-dihydro-1,3,4-oxadiazole chemical structure, known as a privileged scaffold for this target. Several compounds displayed potent in vitro activity, exhibiting IC 50 values in the medium to low nanomolar range. The enantiomers of most promising derivatives were separated by enantioselective HPLC and in vitro evaluated. Experimental results, according to theoretical drug design, clearly indicated a key role of the ligand stereochemistry in the target recognition/inhibition. In particular the ( R )- enantiomers showed the best activity with respect to the ( S )- stereoisomer. Finally, docking experiments coupled to molecular dynamics (MD) simulations, were applied for understanding the putative MAO -B binding modes of the new compounds providing detailed information for further structural optimization. [ABSTRACT FROM AUTHOR]
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- 2016
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43. Design and synthesis of chromone-based monoamine oxidase B inhibitors with improved drug-like properties.
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Reis, Joana, Fernandes, Carlos, Salem, Hoda, Maia, Marta, Tomé, Cláudia, Benfeito, Sofia, Teixeira, José, Oliveira, Paulo J., Uriarte, Eugenio, Ortuso, Francesco, Alcaro, Stefano, Bagetta, Donatella, Cagide, Fernando, and Borges, Fernanda
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MONOAMINE oxidase inhibitors , *PARKINSON'S disease , *DRUG target , *CHROMONES , *IRON compounds , *MONOAMINE oxidase , *APOMORPHINE - Abstract
The absence of disease modifying drugs in Parkinson's disease therapy urges for new chemical entities acting on relevant PD-associated biological targets. As a result, developing selective and reversible inhibitors targeting MAO-B is still a desirable line of therapeutic research. Within this framework, a small library of chromone derivatives was synthesized and screened towards human monoamine oxidases. Structural modifications on the chromone 3-phenylcarboxamide resulted in potent MAO-B inhibitors with an improved drug-like profile, and for the first time we obtained potent and selective chromone 2-phenylcarboxamides acting in the low nanomolar range. Compounds 5-hydroxy-4-oxo- N -phenyl-4H-chromene-3-carboxamide (38) (IC 50 = 13.0 nM) and N -(4-chlorophenyl)-5-hydroxy-4-oxo-4H-chromene-3-carboxamide (41) (IC 50 = 8.3 nM) stood out as reversible, potent, selective and non-cytotoxic MAO-B inhibitors bearing a favourable drug-like profile. Both compounds displayed cytoprotective effects towards iron(III) oxidative stressor. [Display omitted] • New chromone 3-phenylcarboxamide-based IMAO-B upsurge from lead optimization. • Pioneering effective chromone 2-phenylcarboxamide based-IMAO-B were described. • Chromones 38 and 41 stand out as the most potent/selective IMAO-B. • Chromones 38 and 41 display favourable drug-like/cytotoxic/cytoprotective profiles. [ABSTRACT FROM AUTHOR]
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- 2022
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44. Evaluation of chromane derivatives: Promising privileged scaffolds for lead discovery within Alzheimer's disease.
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Moutayakine, Amina, Marques, Carolina, López, Óscar, Bagetta, Donatella, Leitzbach, Luisa, Hagenow, Stefanie, Carreiro, Elisabete P., Stark, Holger, Alcaro, Stefano, Fernández-Bolaños, José G., and Burke, Anthony J.
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ALZHEIMER'S disease , *MONOAMINE oxidase , *PARKINSON'S disease , *PHARMACEUTICAL chemistry , *MOLECULAR docking - Abstract
[Display omitted] 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 (eq BuChE) (in the range 2.9 – 7.3 μM) 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 eq BuChE presenting inhibitions in the range 7.6 – 67 μM. 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 µM on MAO-B). Overall, our compounds were found to be best suited as inhibitors for BuChE. [ABSTRACT FROM AUTHOR]
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- 2022
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45. New 4-[(3-cyclohexyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulfonamides, synthesis and inhibitory activity toward carbonic anhydrase I, II, IX, XII.
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Meleddu, Rita, Maccioni, Elias, Distinto, Simona, Bianco, Giulia, Melis, Claudia, Alcaro, Stefano, Cottiglia, Filippo, Ceruso, Mariangela, and Supuran, Claudiu T.
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CYCLOHEXYLAMINE , *CARBONIC anhydrase inhibitors , *THIAZOLES , *DRUG synthesis , *CHEMICAL derivatives ,SULFONAMIDE drugs - Abstract
A series of 4-[(3-cyclohexyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulfonamides was synthesised and the activity of the new compounds as inhibitors of hCA I, II, IX, and XII was evaluated. These new derivatives exhibited some peculiarities with respect to previously reported sulfonamide based inhibitors of CA. We observed that the nature of the substituents in the position 3 and 4 of the dihydro-thiazole ring was relevant in determining both activity and selectivity profiles. [ABSTRACT FROM AUTHOR]
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- 2015
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46. Macrocyclic naphthalene diimides as G-quadruplex binders.
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Marchetti, Chiara, Minarini, Anna, Tumiatti, Vincenzo, Moraca, Federica, Parrotta, Lucia, Alcaro, Stefano, Rigo, Riccardo, Sissi, Claudia, Gunaratnam, Mekala, Ohnmacht, Stephan A., Neidle, Stephen, and Milelli, Andrea
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NAPHTHALENE , *QUADRUPLEX nucleic acids , *CHEMICAL synthesis , *IMIDES , *STRUCTURE-activity relationship in pharmacology , *DRUG design , *MOLECULAR models , *CANCER cells , *THERAPEUTICS - Abstract
The synthesis, biological and molecular modeling evaluation of a series of macrocyclic naphthalene diimides is reported. The present investigation expands on the study of structure–activity relationships of prototype compound 2 by constraining the molecule into a macrocyclic structure with the aim of improving its G-quadruplex binding activity and selectivity. The new derivatives, compounds 4 – 7 carry spermidine- and spermine-like linkers while in compound 8 the inner basic nitrogen atoms of spermine have been replaced with oxygen atoms. The design strategy has led to potent compounds stabilizing both human telomeric (F21T) and c-KIT2 quadruplex sequences, and high selectivity for quadruplex in comparison to duplex DNA. Antiproliferative effects of the new derivatives 4 – 8 have been evaluated in a panel of cancer cell lines and all the tested compounds showed activity in the low micromolar or sub-micromolar range of concentrations. In order to rationalize the molecular basis of the DNA G-quadruplex versus duplex recognition preference, docking and molecular dynamics studies have been performed. The computational results support the observation that the main driving force in the recognition is due to electrostatic factors. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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47. (3Z)-3-(2-[4-(aryl)-1,3-thiazol-2-yl]hydrazin-1-ylidene)-2,3-dihydro-1H-indol-2-one derivatives as dual inhibitors of HIV-1 reverse transcriptase.
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Meleddu, Rita, Distinto, Simona, Corona, Angela, Bianco, Giulia, Cannas, Valeria, Esposito, Francesca, Artese, Anna, Alcaro, Stefano, Matyus, Peter, Bogdan, Dora, Cottiglia, Filippo, Tramontano, Enzo, and Maccioni, Elias
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INDOLE derivatives , *REVERSE transcriptase inhibitors , *HIV , *AIDS treatment , *TARGETED drug delivery , *DNA polymerases , *DRUG synthesis , *DRUG design - Abstract
The HIV-1 Reverse Transcriptase (RT) is a validated and deeply explored biological target for the treatment of AIDS. However, only drugs targeting the RT-associated DNA polymerase (DP) function have been approved for clinical use. We designed and synthesised a new generation of HIV-1 RT inhibitors, based on the (3Z)-3-(2-[4-(aryl)-1,3-thiazol-2-yl]hydrazin-1-ylidene)-2,3-dihydro- 1H -indol-2-one scaffold. These compounds are active towards both RT-associated functions, DNA polymerase and ribonuclease H. The structure, biological activity and mode of action of the new derivatives have been investigated. In particular, the nature of the aromatic group in the position 4 of the thiazole ring plays a key role in the modulation of the activity towards the two RT-associated functions. [ABSTRACT FROM AUTHOR]
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- 2015
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- View/download PDF
48. Synthesis of 2H-Imidazo[2′,1':2,3] [1,3]thiazolo[4,5-e]isoindol-8-yl-phenylureas with promising therapeutic features for the treatment of acute myeloid leukemia (AML) with FLT3/ITD mutations.
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Cilibrasi, Vincenzo, Spanò, Virginia, Bortolozzi, Roberta, Barreca, Marilia, Raimondi, Maria Valeria, Rocca, Roberta, Maruca, Annalisa, Montalbano, Alessandra, Alcaro, Stefano, Ronca, Roberto, Viola, Giampietro, and Barraja, Paola
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ACUTE myeloid leukemia , *MOLECULAR dynamics , *PROTEIN-tyrosine kinase inhibitors , *CELL cycle , *CELL lines , *NUCLEOPHOSMIN - Abstract
Despite progressive advances in understanding the molecular biology of acute myeloid leukemia (AML), the conventional therapeutic approach has not changed substantially, and the outcome for most patients is poor. Thus, continuous efforts on the discovery of new compounds with improved features are required. Following a multistep sequence, we have identified a new tetracyclic ring system with strong antiproliferative activity towards several haematological cell lines. The new compounds possess structural properties typical of inactive-state-binding kinase inhibitors and are structurally related to quizartinib which is known as type-II tyrosine kinase inhibitor. In particular, the high activity found in two cell lines MOLM-13 and MV4-11, expressing the constitutively activated mutant FLT3/ITD, indicates inhibition of FLT3 kinase and on the basis of structure-activity relationship (SAR) the presence of an ureido moiety demonstrates to play a key role in driving the antiproliferative activity towards these cell lines. Molecular modelling studies supported the mechanism of recognition of the most active compounds within the FLT3 pocket where quizartinib binds. Moreover, Molecular Dynamics simulation (MDs) revealed the formation of a recurrent H-bond with Asp829, which more stabilizes the complex of 9c and the FLT3 inactive state. In MV4-11 cell line compound 9c reduces the phosphorylation of FLT3 (Y591) and some of its downstream targets leading to cell cycle arrest at G1 phase and induction of apoptosis. In an MV4-11 xenograft mouse model, 9c significantly reduces the tumor growth at the dose of 1–3 mg/kg without apparent toxicity. [Display omitted] • 2 H -Imidazo[2',1':2,3][1,3]thiazolo[4,5- e ]isoindol-8-yl-phenylureas were synthesized. • 9 c reduces the phosphorylation of FLT3 (Y591). • 9 c induces cell cycle arrest at G1 phase and apoptosis. • 9 c significantly reduces the tumor growth in an MV4-11 xenograft mouse model. [ABSTRACT FROM AUTHOR]
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- 2022
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49. New insights into the biological properties of Crocus sativus L.: chemical modifications, human monoamine oxidases inhibition and molecular modeling studies.
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De Monte, Celeste, Carradori, Simone, Chimenti, Paola, Secci, Daniela, Mannina, Luisa, Alcaro, Francesca, Petzer, Anél, N'Da, Clarina I., Gidaro, Maria Concetta, Costa, Giosuè, Alcaro, Stefano, and Petzer, Jacobus P.
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SAFFRON crocus , *MONOAMINE oxidase inhibitors , *MOLECULAR models , *TRANQUILIZING drugs , *ANTIDEPRESSANTS , *CLINICAL drug trials , *TREATMENT of neurodegeneration - Abstract
Abstract: Although there are clinical trials and in vivo studies in literature regarding the anxiolytic and antidepressant activities of the components of Crocus sativus L., their effects on the human monoamine oxidases (hMAO-A and hMAO-B), enzymes which are involved in mental disorders and neurodegenerative diseases, have not yet been investigated. We have thus examined the hMAO inhibitory activities of crocin and safranal (the most important active principles in saffron) and, subsequently, designed a series of safranal derivatives to evaluate which chemical modifications confer enhanced inhibition of the hMAO isoforms. Docking simulations were performed in order to identify key molecular recognitions of these inhibitors with both isoforms of hMAO. In this regard, different mechanisms of action were revealed. This study concludes that safranal and crocin represent useful leads for the discovery of novel hMAO inhibitors for the clinical management of psychiatric and neurodegenerative disorders. [Copyright &y& Elsevier]
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- 2014
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50. Identification of the stereochemical requirements in the 4-aryl-2-cycloalkylidenhydrazinylthiazole scaffold for the design of selective human monoamine oxidase B inhibitors.
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D’Ascenzio, Melissa, Carradori, Simone, Secci, Daniela, Mannina, Luisa, Sobolev, Anatoly P., De Monte, Celeste, Cirilli, Roberto, Yáñez, Matilde, Alcaro, Stefano, and Ortuso, Francesco
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MONOAMINE oxidase inhibitors , *DRUG design , *STEREOCHEMISTRY , *THIAZOLES , *DIASTEREOISOMERS , *CHIRAL centers , *THERAPEUTICS - Abstract
Abstract: Exploring the effect that substituents on the cycloaliphatic ring had on the inhibitory activity against human monoamine oxidase B of a series of 4-aryl-2-cycloalkylidenhydrazinylthiazoles led to the synthesis of a new series of 2-methylcyclopentyl and 3-methylcyclopentyl derivatives which were tested in vitro as mixtures of diastereoisomers. In fact, due to the presence of a chiral center on the cycloaliphatic ring and a trisubstituted C N bond, they exist as four diastereoisomers ((E)-(R), (E)-(S), (Z)-(R), (Z)-(S)). 4-(2,4-Difluorophenyl)-2-(2-(3-methylcyclopentylidene)hydrazinyl)thiazole was chosen as a model to investigate the influence of stereochemical requirements on the inhibitory activity against hMAO-B of these derivatives after a stereoconservative synthesis and semi-preparative HPLC diastereoseparation. (R)-(Z) isomer of this compound was endowed with a potent and selective hMAO-B inhibition higher than that of reference drugs as also corroborated by molecular modeling studies. [Copyright &y& Elsevier]
- Published
- 2014
- Full Text
- View/download PDF
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