121 results on '"Fiorella Meneghetti"'
Search Results
2. Structural Study of a New MbtI-Inhibitor Complex: Towards an Optimized Model for Structure-Based Drug Discovery
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Matteo Mori, Stefania Villa, Laurent R. Chiarelli, Fiorella Meneghetti, and Marco Bellinzoni
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Mycobacterium tuberculosis ,salicylate synthase ,siderophore ,iron ,co-crystal structure ,anti-virulence therapy ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
MbtI from Mycobacterium tuberculosis (Mtb) is a Mg2+-dependent salicylate synthase, belonging to the chorismate-utilizing enzyme (CUE) family. As a fundamental player in iron acquisition, MbtI promotes the survival and pathogenicity of Mtb in the infected host. Hence, it has emerged in the last decade as an innovative, potential target for the anti-virulence therapy of tuberculosis. In this context, 5-phenylfuran-2-carboxylic acids have been identified as potent MbtI inhibitors. The first co-crystal structure of MbtI in complex with a member of this class was described in 2020, showing the enzyme adopting an open configuration. Due to the high mobility of the loop adjacent to the binding pocket, large portions of the amino acid chain were not defined in the electron density map, hindering computational efforts aimed at structure-driven ligand optimization. Herein, we report a new, high-resolution co-crystal structure of MbtI with a furan-based derivative, in which the closed configuration of the enzyme allowed tracing the entirety of the active site pocket in the presence of the bound inhibitor. Moreover, we describe a new crystal structure of MbtI in open conformation and in complex with the known inhibitor methyl-AMT, suggesting that in vitro potency is not related to the observed enzyme conformation. These findings will prove fundamental to enhance the potency of this series via rational structure-based drug-design approaches.
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- 2023
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3. Synthesis and Characterization of New Triazole-Bispidinone Scaffolds and Their Metal Complexes for Catalytic Applications
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Arianna Rossetti, Alessandro Sacchetti, Fiorella Meneghetti, Greta Colombo Dugoni, Matteo Mori, and Carlo Castellano
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bispidine ,click chemistry ,metal coordination ,NMR titration ,crystal structure ,triazoles ,Organic chemistry ,QD241-441 - Abstract
Bispidines are a family of ligands that plays a pivotal role in various areas of coordination chemistry, with applications in medicinal chemistry, molecular catalysis, coordination polymers synthesis, and molecular magnetism. In the present work, triazole moieties were introduced using the CuAAC click-reaction, with the aim of expanding the number of coordination sites on the bispidine core. The 1,2,3-triazole rings were thus synthesized on propargyl-derived bispidines after reaction with different alkyl azides. The new class of triazole-bispidines was characterized, and their chelation capabilities were evaluated with different metals through NMR titration, ESI-MS spectrometry, and single-crystal X-ray diffraction (SC-XRD). Finally, the suitability of these molecules as metal ligands for the catalytic Henry reaction was demonstrated with copper and zinc.
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- 2023
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4. 5-(4-Nitrophenyl)furan-2-carboxylic Acid
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Matteo Mori, Andrea Tresoldi, Stefania Villa, Giulia Cazzaniga, Marco Bellinzoni, and Fiorella Meneghetti
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furan ,SC-XRD ,synchrotron ,Mycobacterium tuberculosis ,antitubercular agent ,iron acquisition ,Inorganic chemistry ,QD146-197 - Abstract
The ever-evolving research in the field of antitubercular agents has led to the identification of several new potential drug classes. Among them, 5-phenyl-furan-2-carboxylic acids have emerged as innovative potential therapeutics, targeting iron acquisition in mycobacterial species. In our efforts to characterize the molecular interactions between these compounds and their protein target (MbtI from M. tuberculosis) by means of co-crystallization experiments, we unexpectedly obtained the structure of 5-(4-nitrophenyl)furan-2-carboxylic acid (1). Herein, we describe the preparation of the compound and its analysis by 1H NMR, 13C NMR, HRMS, and SC-XRD.
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- 2022
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5. Methyl 5-(2-Fluoro-4-nitrophenyl)furan-2-carboxylate
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Matteo Mori, Andrea Tresoldi, Giulia Cazzaniga, Fiorella Meneghetti, and Stefania Villa
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furan ,SC-XRD ,Mycobacterium tuberculosis ,antitubercular agent ,iron acquisition ,MbtI ,Inorganic chemistry ,QD146-197 - Abstract
5-Phenyl-furan-2-carboxylic acids have emerged as a new, promising class of antimycobacterial agents that have the ability to interfere with iron homeostasis. Considering the lack of structural data on these compounds, we analyzed the crystal of a fluorinated ester derivative of 5-(4-nitrophenyl)furan-2-carboxylic acid, one of the most potent candidates in the series. Here, we describe the preparation of methyl 5-(2-fluoro-4-nitrophenyl)furan-2-carboxylate (1) and its analysis by 1H-NMR, 13C-NMR, HRMS, and SC-XRD.
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- 2022
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6. Elagolix Sodium Salt and Its Synthetic Intermediates: A Spectroscopic, Crystallographic, and Conformational Study
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Samuele Ciceri, Diego Colombo, Enrico M. A. Fassi, Patrizia Ferraboschi, Giovanni Grazioso, Paride Grisenti, Marco Iannone, Carlo Castellano, and Fiorella Meneghetti
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GnRHR antagonist ,endometriosis ,uterine fibroids ,atropisomerism ,crystal structure ,conformational analysis ,Organic chemistry ,QD241-441 - Abstract
Elagolix sodium salt is the first marketed orally active non-peptide gonadotropin-releasing hormone receptor antagonist (GnRHR-ant) for the management of hormone dependent diseases, such as endometriosis and uterine fibroids. Despite its presence on the market since 2018, a thorough NMR analysis of this drug, together with its synthetic intermediates, is still lacking. Hence, with the aim of filling this literature gap, we here performed a detailed NMR investigation, which allowed the complete assignment of the 1H, 13C, and 15N NMR signals. These data allowed, with the support of the conformational analysis, the determination of the stereochemical profile of the two atropisomers, detectable in solution. Moreover, these latter were also detected by means of cellulose-based chiral HPLC, starting from a sample prepared through an implemented synthetic procedure with respect to the reported ones. Overall, these results contribute to further understanding of the topic of atropisomerism in drug discovery and could be applied in the design of safe and stable analogs, endowed with improved target selectivity.
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- 2023
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7. Biological Screening and Crystallographic Studies of Hydroxy γ-Lactone Derivatives to Investigate PPARγ Phosphorylation Inhibition
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Davide Capelli, Giulia Cazzaniga, Matteo Mori, Antonio Laghezza, Fulvio Loiodice, Martina Quaglia, Elisa Negro, Fiorella Meneghetti, Stefania Villa, and Roberta Montanari
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X-ray crystallography ,drug design ,heterocycle ,PPARγ phosphorylation ,Microbiology ,QR1-502 - Abstract
PPARγ represents a key target for the treatment of type 2 diabetes and metabolic syndrome. To avoid serious adverse effects related to the PPARγ agonism profile of traditional antidiabetic drugs, a new opportunity is represented by the development of molecules acting as inhibitors of PPARγ phosphorylation by the cyclin-dependent kinase 5 (CDK5). Their mechanism of action is mediated by the stabilization of the PPARγ β-sheet containing Ser273 (Ser245 in PPARγ isoform 1 nomenclature). In this paper, we report the identification of new γ-hydroxy-lactone-based PPARγ binders from the screening of an in-house library. These compounds exhibit a non-agonist profile towards PPARγ, and one of them prevents Ser245 PPARγ phosphorylation by acting mainly on PPARγ stabilization and exerting a weak CDK5 inhibitory effect.
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- 2023
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8. Iron Acquisition and Metabolism as a Promising Target for Antimicrobials (Bottlenecks and Opportunities): Where Do We Stand?
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Giovanni Stelitano, Mario Cocorullo, Matteo Mori, Stefania Villa, Fiorella Meneghetti, and Laurent Roberto Chiarelli
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antimicrobial resistance ,virulence factors ,metallostasis ,immunity ,siderophores ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) infections is one of the most crucial challenges currently faced by the scientific community. Developments in the fundamental understanding of their underlying mechanisms may open new perspectives in drug discovery. In this review, we conducted a systematic literature search in PubMed, Web of Science, and Scopus, to collect information on innovative strategies to hinder iron acquisition in bacteria. In detail, we discussed the most interesting targets from iron uptake and metabolism pathways, and examined the main chemical entities that exhibit anti-infective activities by interfering with their function. The mechanism of action of each drug candidate was also reviewed, together with its pharmacodynamic, pharmacokinetic, and toxicological properties. The comprehensive knowledge of such an impactful area of research will hopefully reflect in the discovery of newer antibiotics able to effectively tackle the antimicrobial resistance issue.
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- 2023
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9. Targeting Siderophore-Mediated Iron Uptake in M. abscessus: A New Strategy to Limit the Virulence of Non-Tuberculous Mycobacteria
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Matteo Mori, Giovanni Stelitano, Giulia Cazzaniga, Arianna Gelain, Andrea Tresoldi, Mario Cocorullo, Martina Roversi, Laurent R. Chiarelli, Martina Tomaiuolo, Pietro Delre, Giuseppe F. Mangiatordi, Anna Griego, Loris Rizzello, Alberto Cassetta, Sonia Covaceuszach, Stefania Villa, and Fiorella Meneghetti
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antimicrobial resistance ,cystic fibrosis ,drug design ,grating-coupled interferometry (GCI) ,homology model ,siderophores ,Pharmacy and materia medica ,RS1-441 - Abstract
Targeting pathogenic mechanisms, rather than essential processes, represents a very attractive approach for the development of new antimycobacterial drugs. In this context, iron acquisition routes have recently emerged as potentially druggable pathways. However, the importance of siderophore biosynthesis in the virulence and pathogenicity of M. abscessus (Mab) is still poorly understood. In this study, we investigated the Salicylate Synthase (SaS) of Mab as an innovative molecular target for the development of inhibitors of siderophore production. Notably, Mab-SaS does not have any counterpart in human cells, making it an interesting candidate for drug discovery. Starting from the analysis of the binding of a series of furan-based derivatives, previously identified by our group as inhibitors of MbtI from M. tuberculosis (Mtb), we successfully selected the lead compound 1, exhibiting a strong activity against Mab-SaS (IC50 ≈ 5 µM). Computational studies characterized the key interactions between 1 and the enzyme, highlighting the important roles of Y387, G421, and K207, the latter being one of the residues involved in the first step of the catalytic reaction. These results support the hypothesis that 5-phenylfuran-2-carboxylic acids are also a promising class of Mab-SaS inhibitors, paving the way for the optimization and rational design of more potent derivatives.
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- 2023
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10. Crystal Structure, Hirshfeld Surface Analysis, In-Silico and Antimycotic Investigations of Methyl 6-methyl-4-(4-nitrophenyl)-2-oxo-1,2-dihydropyrimidine-5-carboxylate
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Alakbar Huseynzada, Matteo Mori, Fiorella Meneghetti, Aygun Israyilova, Elif Guney, Koray Sayin, Laurent R. Chiarelli, Mustafa Demiralp, Ulviyya Hasanova, and Vagif Abbasov
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1,2-dihydropyrimidines ,regioselective oxidation ,intramolecular hydrogen bonds ,Hirshfeld surface analysis ,molecular docking ,antimycotic activity ,Crystallography ,QD901-999 - Abstract
Herein, we report the preparation of methyl 6-methyl-4-(4-nitrophenyl)-2-oxo-1,2-dihydropyrimidine-5-carboxylate 2, obtained by the regioselective oxidative dehydrogenation of the dihydropyrimidine derivative 1 in the presence of cerium ammonium nitrate. The structure of compound 2 was investigated by single-crystal X-ray diffraction (SC-XRD), which allowed the determination of its tautomeric form. Moreover, the presence of non-covalent interactions and their impact on the crystal structure were analyzed. To better characterize the intermolecular contacts, the Hirshfeld surface and enrichment ratio analyses were performed. Furthermore, the antimycotic activity of compounds 1 and 2 was investigated against Candida albicans, Aspergillus flavus, and Aspergillus niger, and their efficacy was compared to that of fluconazole. Computational investigations on the putative target of the compounds provided insights to explain the better activity of 2 with respect to its synthetic precursor.
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- 2022
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11. Synthesis and Assessment of the In Vitro and Ex Vivo Activity of Salicylate Synthase (Mbti) Inhibitors as New Candidates for the Treatment of Mycobacterial Infections
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Matteo Mori, Giovanni Stelitano, Anna Griego, Laurent R. Chiarelli, Giulia Cazzaniga, Arianna Gelain, Elena Pini, Marina Camera, Paola Canzano, Andrea Fumagalli, Edoardo Scarpa, Chiara Cordiglieri, Loris Rizzello, Stefania Villa, and Fiorella Meneghetti
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tuberculosis ,mycobactins ,furan ,siderophores ,drug development ,drug resistance ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of M. tuberculosis (Mtb) have developed resistance against most of the established anti-TB drugs, new therapeutic options are urgently needed. An attractive target for the development of new anti-TB agents is the salicylate synthase MbtI, the first enzyme of the mycobacterial siderophore biochemical machinery, absent in human cells. In this work, a set of analogues of 5-(3-cyanophenyl)furan-2-carboxylic acid (I), the most potent MbtI inhibitor identified to date, was synthesized, characterized, and tested to further elucidate the structural requirements for achieving an efficient MbtI inhibition and potent antitubercular activity. The structure–activity relationships (SAR) discussed herein evidenced the importance of the side chain linked to the phenyl moiety to improve the in vitro antimycobacterial activity. In detail, 1f emerged as the most effective analogue against the pathogen, acting without cytotoxicity issues. To deepen the understanding of its mechanism of action, we established a fluorescence-based screening test to quantify the pathogen infectivity within host cells, using MPI-2 murine cells, a robust surrogate for alveolar macrophages. The set-up of the new assay demonstrates significant potential to accelerate the discovery of new anti-TB drugs.
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- 2022
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12. New insight into structure-activity of furan-based salicylate synthase (MbtI) inhibitors as potential antitubercular agents
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Laurent R. Chiarelli, Matteo Mori, Giangiacomo Beretta, Arianna Gelain, Elena Pini, Josè Camilla Sammartino, Giovanni Stelitano, Daniela Barlocco, Luca Costantino, Margherita Lapillo, Giulio Poli, Isabella Caligiuri, Flavio Rizzolio, Marco Bellinzoni, Tiziano Tuccinardi, Stefania Villa, and Fiorella Meneghetti
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tuberculosis ,siderophores ,mycobactins ,drug design ,antimycobacterial agent ,molecular modelling ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Starting from the analysis of the hypothetical binding mode of our previous furan-based hit (I), we successfully achieved our objective to replace the nitro moiety, leading to the disclosure of a new lead exhibiting a strong activity against MbtI. Our best candidate 1 h displayed a Ki of 8.8 µM and its antimycobacterial activity (MIC99 = 250 µM) is conceivably related to mycobactin biosynthesis inhibition. These results support the hypothesis that 5-phenylfuran-2-carboxylic derivatives are a promising class of MbtI inhibitors.
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- 2019
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13. Insights on the Modulation of SIRT5 Activity: A Challenging Balance
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Matteo Mori, Giulia Cazzaniga, Fiorella Meneghetti, Stefania Villa, and Arianna Gelain
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Sirtuin 5 ,HDACs ,activators ,inhibitors ,natural compounds ,small molecules ,Organic chemistry ,QD241-441 - Abstract
SIRT5 is a member of the Sirtuin family, a class of deacetylating enzymes consisting of seven isoforms, involved in the regulation of several processes, including gene expression, metabolism, stress response, and aging. Considering that the anomalous activity of SIRT5 is linked to many pathological conditions, we present herein an overview of the most interesting modulators, with the aim of contributing to further development in this field.
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- 2022
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14. 6-Hydroxy-2-methylbenzofuran-4-carboxylic Acid
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Matteo Mori, Fiorella Meneghetti, Laurent R. Chiarelli, Alessia Diego, Donatella Nava, Arianna Gelain, Giulia Cazzaniga, Stefania Villa, and Elena Pini
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6-hydroxy-2-methylbenzofuran-4-carboxylic acid methyl ester ,6-hydroxy-2-methylbenzofuran-4-carboxylic acid ,COSY ,NOESY ,HSQC ,HMBC ,Inorganic chemistry ,QD146-197 - Abstract
6-Hydroxy-2-methylbenzofuran-4-carboxylic acid was synthesized in two steps, starting from 3,5-dihydroxybenzoate. The product was obtained through a direct thermal one-pot cyclization with propargyl bromide, followed by a base-catalyzed hydrolysis. Its molecular structure was elucidated by means of mono- and bidimensional NMR techniques, ESI-MS, FT-IR and single-crystal X-ray diffraction.
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- 2020
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15. An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis
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Matteo Mori, Stefania Villa, Samuele Ciceri, Diego Colombo, Patrizia Ferraboschi, and Fiorella Meneghetti
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tuberculosis ,structure-based drug design ,fragment-based drug design ,Mycobacterium tuberculosis ,structure–activity relationships (SARs) ,Organic chemistry ,QD241-441 - Abstract
The elucidation of the structure of enzymes and their complexes with ligands continues to provide invaluable insights for the development of drugs against many diseases, including bacterial infections. After nearly three decades since the World Health Organization’s (WHO) declaration of tuberculosis (TB) as a global health emergency, Mycobacterium tuberculosis (Mtb) continues to claim millions of lives, remaining among the leading causes of death worldwide. In the last years, several efforts have been devoted to shortening and improving treatment outcomes, and to overcoming the increasing resistance phenomenon. The structural elucidation of enzyme-ligand complexes is fundamental to identify hot-spots, define possible interaction sites, and elaborate strategies to develop optimized molecules with high affinity. This review offers a critical and comprehensive overview of the most recent structural information on traditional and emerging mycobacterial enzymatic targets. A selection of more than twenty enzymes is here discussed, with a special emphasis on the analysis of their binding sites, the definition of the structure–activity relationships (SARs) of their inhibitors, and the study of their main intermolecular interactions. This work corroborates the potential of structural studies, substantiating their relevance in future anti-mycobacterial drug discovery and development efforts.
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- 2021
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16. Methanethiosulfonate derivatives as ligands of the STAT3-SH2 domain
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Elena Gabriele, Chiara Ricci, Fiorella Meneghetti, Nicola Ferri, Akira Asai, and Anna Sparatore
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Anticancer drug ,cytotoxicity ,SH2 antagonist ,STAT3 ,S3I-201 analogs ,Therapeutics. Pharmacology ,RM1-950 - Abstract
With the aim to discover new STAT3 direct inhibitors, potentially useful as anticancer agents, a set of methanethiosulfonate drug hybrids were synthesized. The in vitro tests showed that all the thiosulfonic compounds were able to strongly and selectively bind STAT3-SH2 domain, whereas the parent drugs were completely devoid of this ability. In addition, some of them showed a moderate antiproliferative activity on HCT-116 cancer cell line. These results suggest that methanethiosulfonate moiety can be considered a useful scaffold in the preparation of new direct STAT3 inhibitors. Interestingly, an unusual kind of organo-sulfur derivative, endowed with valuable antiproliferative activity, was occasionally isolated.
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- 2017
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17. Special Issue 'Novel Antibacterial Agents'
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Fiorella Meneghetti and Daniela Barlocco
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n/a ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
This Special Issue of Pharmaceuticals is devoted to significant advances achieved in the field of antibacterial agents [...]
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- 2021
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18. Synthesis, Characterization, and Biological Evaluation of New Derivatives Targeting MbtI as Antitubercular Agents
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Matteo Mori, Giovanni Stelitano, Laurent R. Chiarelli, Giulia Cazzaniga, Arianna Gelain, Daniela Barlocco, Elena Pini, Fiorella Meneghetti, and Stefania Villa
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tuberculosis ,mycobactins ,furan ,siderophores ,drug design ,bioisosterism ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of Mycobacterium tuberculosis (Mtb) have developed resistance against most of the established anti-TB drugs, new therapeutic options are urgently needed. An attractive target for the development of new antitubercular agents is the salicylate synthase MbtI, an essential enzyme for the mycobacterial siderophore biochemical machinery, absent in human cells. A set of analogues of I and II, two of the most potent MbtI inhibitors identified to date, was synthesized, characterized, and tested to elucidate the structural requirements for achieving an efficient MbtI inhibition and a potent antitubercular activity with this class of compounds. The structure-activity relationships (SAR) here discussed evidenced the importance of the furan as part of the pharmacophore and led to the preparation of six new compounds (IV–IX), which gave us the opportunity to examine a hitherto unexplored position of the phenyl ring. Among them emerged 5-(3-cyano-5-(trifluoromethyl)phenyl)furan-2-carboxylic acid (IV), endowed with comparable inhibitory properties to the previous leads, but a better antitubercular activity, which is a key issue in MbtI inhibitor research. Therefore, compound IV offers promising prospects for future studies on the development of novel agents against mycobacterial infections.
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- 2021
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19. Synthesis of new dithiolethione and methanethiosulfonate systems endowed with pharmaceutical interest
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Elena Gabriele, Federica Porta, Giorgio Facchetti, Corinna Galli, Arianna Gelain, Fiorella Meneghetti, Isabella Rimoldi, Sergio Romeo, Stefania Villa, Chiara Ricci, Nicola Ferri, Akira Asai, Daniela Barlocco, and Anna Sparatore
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Organic chemistry ,QD241-441 - Published
- 2016
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20. (S)-Pramipexole and Its Enantiomer, Dexpramipexole: A New Chemoenzymatic Synthesis and Crystallographic Investigation of Key Enantiomeric Intermediates
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Samuele Ciceri, Patrizia Ferraboschi, Paride Grisenti, Shahrzad Reza Elahi, Carlo Castellano, Matteo Mori, and Fiorella Meneghetti
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chiral synthons ,pramipexole ,dexpramipexole ,Parkinson’s disease ,hypereosinophilic syndromes ,biocatalysis ,Chemical technology ,TP1-1185 ,Chemistry ,QD1-999 - Abstract
A new chemoenzymatic method has been developed for the synthesis of (S)- and (R)-N-(6-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl) acetamide, two key synthons for the preparation of (S)-pramipexole, an anti-Parkinson drug, and its enantiomer dexpramipexole, which is currently under investigation for the treatment of eosinophil-associated disorders. These two building blocks have been obtained in good yields and high enantiomeric excess (30% and >98% ee for the R-enantiomer, and 31% and >99% ee for the S- one) through a careful optimization of the reaction conditions, starting from the corresponding racemic mixture and using two consecutive irreversible transesterifications, catalyzed by Candida antarctica lipase type A. Single crystal X-ray analysis has been carried out to unambiguously define the stereochemistry of the two enantiomers, and to explore in depth their three-dimensional features.
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- 2020
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21. Towards the Inhibition of Protein–Protein Interactions (PPIs) in STAT3: Insights into a New Class of Benzothiadiazole Derivatives
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Matteo Mori, Ettore Gilardoni, Luca Regazzoni, Alessandro Pedretti, Diego Colombo, Gary Parkinson, Akira Asai, Fiorella Meneghetti, Stefania Villa, and Arianna Gelain
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benzosulfamides ,structure-based virtual screening ,STAT3-SH2 domain ,cysteine binder ,diversity-oriented synthesis ,Organic chemistry ,QD241-441 - Abstract
Signal transducer and activator of transcription 3 (STAT3) is a validated anticancer target due to the relationship between its constitutive activation and malignant tumors. Through a virtual screening approach on the STAT3-SH2 domain, 5,6-dimethyl-1H,3H-2,1,3-benzothiadiazole-2,2-dioxide (1) was identified as a potential STAT3 inhibitor. Some benzothiadiazole derivatives were synthesized by employing a versatile methodology, and they were tested by an AlphaScreen-based assay. Among them, benzosulfamide 1 showed a significant activity with an IC50 = 15.8 ± 0.6 µM as a direct STAT3 inhibitor. Notably, we discovered that compound 1 was also able to interact with cysteine residues located around the SH2 domain. By applying mass spectrometry, liquid chromatography, NMR, and UV spectroscopy, an in-depth investigation was carried out, shedding light on its intriguing and unexpected mechanism of interaction.
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- 2020
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22. Crystallographic and NMR Investigation of Ergometrine and Methylergometrine, Two Alkaloids from Claviceps Purpurea
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Fiorella Meneghetti, Patrizia Ferraboschi, Paride Grisenti, Shahrzad Reza Elahi, Matteo Mori, and Samuele Ciceri
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ergot ,9,10-unsaturated ergoline ,alkaloids ,15n nmr ,13c nmr ,1h nmr ,x-ray analysis ,oxytocic activity ,Organic chemistry ,QD241-441 - Abstract
Ergometrine and methylergometrine are two alkaloids that are used as maleate salts for the prevention and control of postpartum hemorrhage. Although the two molecules have been known for a long time, few and discordant crystallographic and NMR spectroscopic data are available in the literature. With the aim of providing more conclusive data, we performed a careful NMR study for the complete assignment of the 1H, 13C, and 15N NMR signals of ergometrine, methylergometrine, and their maleate salts. This information allowed for a better definition of their conformational equilibria. In addition, the stereochemistry and the intermolecular interactions in the solid state of the two maleate salts were deeply investigated by means of single-crystal X-ray diffraction, showing the capability of these derivatives to act as both hydrogen-bond donors and acceptors, and evidencing a correlation between the number of intermolecular interactions and their different solubility.
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- 2020
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23. Asymmetric Ugi 3CR on isatin-derived ketimine: synthesis of chiral 3,3-disubstituted 3-aminooxindole derivatives
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Giordano Lesma, Fiorella Meneghetti, Alessandro Sacchetti, Mattia Stucchi, and Alessandra Silvani
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isatin ,multicomponent ,oxindole ,peptidomimetics ,Ugi ,Science ,Organic chemistry ,QD241-441 - Abstract
An efficient Ugi three-component reaction of a preformed chiral ketimine derived from isatin with various isonitrile and acid components has been developed. The reactions proceeded smoothly and in a stereocontrolled manner with regard to the new center of the Ugi products due to the stereoinduction of the amine chiral residue. A wide variety of novel chiral 3,3-disubstituted 3-aminooxindoles were obtained, a selection of which were subjected to post-Ugi transformations, paving the way to application as peptidomimetics.
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- 2014
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24. Unexpected synthesis of 3,5-dimethyl-1-phenyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one by non-classical Pschorr reaction, endowed with binding affinity for the central benzodiazepine receptor
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Giuseppe Daidone, Benedetta Maggio, Demetrio Raffa, and Fiorella Meneghetti
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Organic chemistry ,QD241-441 - Published
- 2014
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25. Exploiting the Nucleophilicity of the Nitrogen Atom of Imidazoles: One-Pot Three-Component Synthesis of Imidazo-Pyrazines
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Ubaldina Galli, Rejdia Hysenlika, Fiorella Meneghetti, Erika Del Grosso, Sveva Pelliccia, Ettore Novellino, Mariateresa Giustiniano, and Gian Cesare Tron
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multicomponent reactions ,interrupted Ugi reactions ,isocyanides ,Organic chemistry ,QD241-441 - Abstract
A novel one-pot multicomponent reaction to synthesize substituted imidazopyrazines is described. In brief, 1H-(imidazol-5-yl)-N-substituted methanamines react with aldehydes and isocyanides in methanol at room temperature to give imidazopyrazine derivatives in excellent yields. The imidazole nitrogen atom was able to intercept the nascent nitrilium ion, channeling the reaction toward to the sole formation of imidazopyrazines, suppressing the competitive formation of other possible side products deriving from the reaction with the high-energy nitrilium ion. The number of examples and the variability of the nature of isocyanides, aldehydes, and amine components herein employed, witness the robustness of this novel methodology.
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- 2019
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26. Synthesis and biological evaluation of new indazole derivatives
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Salvatore Plescia, Demetrio Raffa, Fabiana Plescia, Giovanni Casula, Benedetta Maggio, Giuseppe Daidone, Maria Valeria Raimondi, Maria Grazia Cusimano, Gabriella Bombieri, and Fiorella Meneghetti
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Organic chemistry ,QD241-441 - Published
- 2010
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27. New Chromane-Based Derivatives as Inhibitors of Mycobacterium tuberculosis Salicylate Synthase (MbtI): Preliminary Biological Evaluation and Molecular Modeling Studies
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Elena Pini, Giulio Poli, Tiziano Tuccinardi, Laurent Roberto Chiarelli, Matteo Mori, Arianna Gelain, Luca Costantino, Stefania Villa, Fiorella Meneghetti, and Daniela Barlocco
- Subjects
antimycobacterial agent ,siderophore ,mycobactin ,iron ,consensus docking ,chorismate ,MD simulation ,Organic chemistry ,QD241-441 - Abstract
Tuberculosis is the leading cause of death from a single infectious agent worldwide; therefore, the need for new antitubercular drugs is desperate. The recently validated target salicylate synthase MbtI is the first enzyme involved in the biosynthesis of mycobactins, compounds able to chelate iron, an essential cofactor for the survival of Mycobacterium tuberculosis in the host. Here, we report on the synthesis and biological evaluation of chromane-based compounds as new potential inhibitors of MbtI. Our approach successfully allowed the identification of a novel lead compound (1), endowed with a promising activity against this enzyme (IC50 = 55 μM). Molecular modeling studies were performed in order to evaluate the binding mode of 1 and rationalize the preliminary structure-activity relationships, thus providing crucial information to carry out further optimization studies.
- Published
- 2018
- Full Text
- View/download PDF
28. Comparative studies of the Pschorr reaction in the pyrazole series. Access to the new dibenzo[e,g]pyrazolo[1,5-a][1,3]diazocine system of pharmaceutical interest
- Author
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Benedetta Maggio, Demetrio Raffa, Maria V. Raimondi, Stella Cascioferro, Salvatore Plescia, Maria A. Sabatino, Gabriella Bombieri, Fiorella Meneghetti, and Giuseppe Daidone
- Subjects
Organic chemistry ,QD241-441 - Published
- 2008
- Full Text
- View/download PDF
29. Special Issue: Frontiers in Antimicrobial Drug Discovery and Design
- Author
-
Daniela Barlocco and Fiorella Meneghetti
- Subjects
n/a ,Organic chemistry ,QD241-441 - Abstract
Since the discovery of Penicillin, antibiotics have saved millions of lives every year.[...]
- Published
- 2017
- Full Text
- View/download PDF
30. Crystal structure of 3-(3-oxo-2,3,4,4a,5,6-hexahydrobenzo[h]cinnolin-2-yl)propionic acid
- Author
-
Fiorella Meneghetti, Daniela Masciocchi, Arianna Gelain, and Stefania Villa
- Subjects
crystal structure ,pyridazinone moiety ,stat3 inhibitor ,Crystallography ,QD901-999 - Abstract
The asymmetric unit of the title compound, C15H16N2O3, contains two independent molecules, which present a different conformation of the carboxylic acid side chain [C—C—C—OH torsion angles = 65.3 (7) and −170.1 (5)°]. In both molecules, the dihydropyridazinone ring adopts a geometry intermediate between a twisted-boat and a half-chair conformation, while the central six-membered ring is almost in a half-boat conformation. In the crystal, molecules are linked by O—H...Ok (k = ketone) hydrogen bonds, generating [01-1] chains. Aromatic π–π stacking contacts between the benzene and the dihydropyridazinone rings [centroid–centroid distance [3.879 (9) Å] are also observed.
- Published
- 2014
- Full Text
- View/download PDF
31. (E)-2-{[1-(3,11-Dimethyl-4-methylene-10-oxo-1-phenyl-4,5,10,11-tetrahydro-1H-benzo[b]pyrazolo[3,4-f][1,5]diazocin-5-yl)ethylidene]amino}-N-methyl-N-(3-methyl-1-phenyl-1H-pyrazol-5-yl)benzamide
- Author
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Fiorella Meneghetti and Benedetta Maggio
- Subjects
Crystallography ,QD901-999 - Abstract
The central eight-membered ring of the title compound, C40H36N8O2, deviates from the ideal boat conformation because the bond between the exo-ethylene group and the adjacent N atom is twisted by 60.0 (4)° due to steric hindrance. Its adjacent benzene and pyrazole rings are oriented almost perpendicular to each other, making a dihedral angle of 85.8 (3)°. In the crystal, the molecules are linked by C(ar)—H...O hydrogen bonds, generating a three-dimensional network.
- Published
- 2013
- Full Text
- View/download PDF
32. N-(4-Acetyl-3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-methyl-2-(2-methyl-4-oxo-3,4-dihydroquinazolin-3-yl)benzamide
- Author
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Fiorella Meneghetti and Benedetta Maggio
- Subjects
Crystallography ,QD901-999 - Abstract
In the title compound, C29H25N5O3, the dihedral angle between the benzene ring and the pendant quinazoline ring system (r.m.s. deviation = 0.036Å) is 87.60 (17)°. The equivalent angle between the pyrazole ring and the phenyl group is 70.0 (2)°. The dihedral angle between the benzene and pyrazole rings is 30.7 (2)° and overall, the molecular conformation approximates to a Z shape. A short intramolecular C—H...O contact occurs. In the crystal, the molecules are linked by Cπ—H...O-type hydrogen bonds and aromatic π–π stacking interactions [centroid–centroid distance = 3.860 (3) Å], generating a three-dimensional network.
- Published
- 2013
- Full Text
- View/download PDF
33. 6-Chloro-1-(3,5-dimethylphenylsulfonyl)-1H-benzimidazol-2(3H)-one
- Author
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Fiorella Meneghetti, Gabriella Bombieri, Laura De Luca, and Patrizia Logoteta
- Subjects
Crystallography ,QD901-999 - Abstract
The title compound, C15H13ClN2O3S, is one of a series of N1-benzyl-1,3-dihydro-2H-benzimidazol-2-one derivatives, a new class of non-nucleoside HIV-1 reverse transcriptase inhibitors. The dihedral angle between the two pharmacophoric groups, the dimethylbenzene ring and the benzimidazolone ring system, is 88 (1)°, giving a butterfly-like conformation to the molecule. The molecular packing is characterized by a bifurcated N—H...(O,O) hydrogen bond and short Cl...O contacts of 3.122 (2) Å. In addition, π–π stacking of the benzimidazolone rings is also present, with interplanar separations of 3.95 (1) Å.
- Published
- 2009
- Full Text
- View/download PDF
34. 3-(4-Chlorophenyldiazenyl)-1-methyl-1,4,5,6-tetrahydropyridine
- Author
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Fiorella Meneghetti, Michele Tonelli, and Gabriella Bombieri
- Subjects
Crystallography ,QD901-999 - Abstract
The title compound, C12H14ClN3, represents the planar azoenamine tautomer. The benzene ring forms a dihedral angle of 2.5 (1)° with the azoenamine group. Electron delocalization is indicated by the values of the bond lengths in the chain. The tetrahydropyridine ring adopts a half-chair conformation and the dihedral angle between the least-squares plane defined by the five coplanar C atoms and the azoenamine unit is 2.0 (1)°, while the envelope-flap C atom lies out of this plane by 0.579 (2) Å. The molecular packing is governed by van der Waals interactions through the stacking of adjacent molecules, resulting in a two-dimensional sheet structure.
- Published
- 2008
- Full Text
- View/download PDF
35. 1,4-Dimethyl-3-phenyl-3H-pyrazolo[3,4-c]isoquinolin-5(4H)-one
- Author
-
Giuseppe Daidone, Benedetta Maggio, Gabriella Bombieri, and Fiorella Meneghetti
- Subjects
Crystallography ,QD901-999 - Abstract
The title compound, C18H15N3O, is the product of the thermal decomposition of the diazonium salt derived from 2-amino-N-methyl-N-(3-methyl-1-phenyl-1H-pyrazol-5-yl)benzamide. It is characterized by a trans orientation of the methyl groups with respect to the tricyclic ring system. The molecule has a nearly planar phenylpyrazolo[3,4-c]isoquinolin-5-one system, the largest deviation from the mean plane being 0.066 (2) Å for the O atom. The dihedral angle between the phenyl substituent and the heterotricycle is 67 (1)°. The packing is stabilized by C—H...N hydrogen-bond interactions, with the formation of molecular chains along the c axis.
- Published
- 2008
- Full Text
- View/download PDF
36. An introduction to the newest member of our editorial board, Associate Professor Fiorella Meneghetti
- Author
-
FIORELLA MENEGHETTI
- Subjects
Pharmacology ,Drug Discovery ,Molecular Medicine - Published
- 2022
37. Synthesis, crystal structure, Hirshfeld surface, computational and antibacterial studies of a 9-phenanthrenecarboxaldehyde-based thiodihydropyrimidine derivative
- Author
-
Alakbar Huseynzada, Matteo Mori, Fiorella Meneghetti, Aygun Israyilova, Gamze Tuzun, Koray Sayin, Laurent R. Chiarelli, Ceylan Mutlu, Mustafa Demiralp, Ulviyya Hasanova, and Vagif Abbasov
- Subjects
Inorganic Chemistry ,ADME/T ,Crystal structure ,Hirshfeld surface analysis ,Molecular docking ,Thiodihydropyrimidine ,Organic Chemistry ,Settore CHIM/06 - Chimica Organica ,Settore CHIM/08 - Chimica Farmaceutica ,Spectroscopy ,Analytical Chemistry - Published
- 2022
38. Synthesis and Conformational Analysis of Hydantoin-Based Universal Peptidomimetics
- Author
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Alessio M. Caramiello, Maria Cristina Bellucci, Gaetano Cristina, Carlo Castellano, Fiorella Meneghetti, Matteo Mori, Francesco Secundo, Fiorenza Viani, Alessandro Sacchetti, and Alessandro Volonterio
- Subjects
Organic Chemistry - Abstract
The synthesis of a collection of enantiomerically pure, systematically substituted hydantoins as structural privileged universal mimetic scaffolds is presented. It relies on a chemoselective condensation/cyclization domino process between isocyanates of quaternary or unsubstituted α-amino esters and
- Published
- 2022
39. Synthesis and characterization of a novel lanthanum (III) complex with a di(2-picolyl)amine-based ligand endowed with fluorescent properties
- Author
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Greta Colombo Dugoni, Matteo Mori, Valentina Dichiarante, Alessandro Sacchetti, and Fiorella Meneghetti
- Subjects
Inorganic Chemistry ,Settore CHIM/03 - Chimica Generale e Inorganica ,NMR titration ,Lanthanum-complex ,Crystal structure ,Organic Chemistry ,Density functional theory (DFT) calculations ,Fluorescence ,Settore CHIM/06 - Chimica Organica ,Settore CHIM/08 - Chimica Farmaceutica ,Spectroscopy ,Analytical Chemistry - Published
- 2022
40. Shedding X-ray Light on the Role of Magnesium in the Activity of Mycobacterium tuberculosis Salicylate Synthase (MbtI) for Drug Design
- Author
-
Arianna Gelain, Fiorella Meneghetti, Josè Camilla Sammartino, Giulio Poli, Elena Pini, Stefania Villa, Laurent R. Chiarelli, Marco Bellinzoni, Giovanni Stelitano, Alessio Porta, Giangiacomo Beretta, Tiziano Tuccinardi, M. Mori, Università degli Studi di Milano [Milano] (UNIMI), Università degli Studi di Pavia, University of Pisa - Università di Pisa, Temple University [Philadelphia], Pennsylvania Commonwealth System of Higher Education (PCSHE), Microbiologie structurale - Structural Microbiology (Microb. Struc. (UMR_3528 / U-Pasteur_5)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), This work was funded by University of Milan (Linea B) and the Italian Ministry of Education, University and Research (MIUR): Dipartimenti di Eccellenza Program (2018–2022) - Dept. of Biology and Biotechnology 'L. Spallanzani', University of Pavia. Partial support was also provided by institutional grants from Institut Pasteur and CNRS., Università degli Studi di Milano = University of Milan (UNIMI), Università degli Studi di Pavia = University of Pavia (UNIPV), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
- Subjects
Models, Molecular ,Siderophore ,MESH: Mycobacterium tuberculosis ,Protein Conformation ,MESH: Drug Design ,Crystallography, X-Ray ,01 natural sciences ,MESH: Protein Conformation ,MESH: Structure-Activity Relationship ,Models ,MESH: Magnesium ,Drug Discovery ,Magnesium ,Ternary complex ,chemistry.chemical_classification ,0303 health sciences ,Crystallography ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,biology ,ATP synthase ,3. Good health ,Biochemistry ,Molecular Medicine ,MESH: Models, Molecular ,[PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph] ,Lyases ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Cofactor ,Article ,Mycobacterium tuberculosis ,03 medical and health sciences ,Structure-Activity Relationship ,[CHIM.CRIS]Chemical Sciences/Cristallography ,Structure–activity relationship ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,030304 developmental biology ,Rational design ,Molecular ,MESH: Crystallography, X-Ray ,biology.organism_classification ,MESH: Lyases ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Enzyme ,chemistry ,Drug Design ,X-Ray ,biology.protein ,[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] - Abstract
International audience; The Mg2+-dependent Mycobacterium tuberculosis salicylate synthase (MbtI) is a key enzyme involved in the biosynthesis of siderophores. Because iron is essential for the survival and pathogenicity of the microorganism, this protein constitutes an attractive target for antitubercular therapy, also considering the absence of homologous enzymes in mammals. An extension of the structure-activity relationships of our furan-based candidates allowed us to disclose the most potent competitive inhibitor known to date (10, Ki = 4 μM), which also proved effective on mycobacterial cultures. By structural studies, we characterized its unexpected Mg2+-independent binding mode. We also investigated the role of the Mg2+ cofactor in catalysis, analyzing the first crystal structure of the MbtI-Mg2+-salicylate ternary complex. Overall, these results pave the way for the development of novel antituberculars through the rational design of improved MbtI inhibitors.
- Published
- 2020
41. An analytical investigation of hydroxylated cinnamoyl polyamines as biomarkers of commercial bee pollen botanical origin
- Author
-
Rita Nasti, Serena Orlandini, Sandra Furlanetto, Monica Casale, Armond Daci, Avni Hajdari, Fiorella Meneghetti, Stefania Villa, Matteo Mori, and Giangiacomo Beretta
- Subjects
ATR-FTIR ,bee pollen ,HPLC-PDA ,polyhydroxylated-cinnamoyl-spermidine ,sporopollenin ,Settore CHIM/08 - Chimica Farmaceutica ,Industrial and Manufacturing Engineering ,Food Science - Published
- 2022
42. An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis
- Author
-
Samuele Ciceri, Diego Colombo, Fiorella Meneghetti, Stefania Villa, M. Mori, and Patrizia Ferraboschi
- Subjects
Tuberculosis ,Treatment outcome ,Antitubercular Agents ,Pharmaceutical Science ,Organic chemistry ,Computational biology ,Review ,World health ,Analytical Chemistry ,Mycobacterium tuberculosis ,Structure-Activity Relationship ,QD241-441 ,Bacterial Proteins ,Political science ,Catalytic Domain ,Drug Discovery ,Global health ,medicine ,Humans ,Physical and Theoretical Chemistry ,Enzyme Inhibitors ,Crystallography ,biology ,Drug discovery ,Hydrogen Bonding ,medicine.disease ,biology.organism_classification ,fragment-based drug design ,structure–activity relationships (SARs) ,tuberculosis ,Chemistry (miscellaneous) ,Drug Design ,Molecular Medicine ,structure-based drug design - Abstract
The elucidation of the structure of enzymes and their complexes with ligands continues to provide invaluable insights for the development of drugs against many diseases, including bacterial infections. After nearly three decades since the World Health Organization’s (WHO) declaration of tuberculosis (TB) as a global health emergency, Mycobacterium tuberculosis (Mtb) continues to claim millions of lives, remaining among the leading causes of death worldwide. In the last years, several efforts have been devoted to shortening and improving treatment outcomes, and to overcoming the increasing resistance phenomenon. The structural elucidation of enzyme-ligand complexes is fundamental to identify hot-spots, define possible interaction sites, and elaborate strategies to develop optimized molecules with high affinity. This review offers a critical and comprehensive overview of the most recent structural information on traditional and emerging mycobacterial enzymatic targets. A selection of more than twenty enzymes is here discussed, with a special emphasis on the analysis of their binding sites, the definition of the structure–activity relationships (SARs) of their inhibitors, and the study of their main intermolecular interactions. This work corroborates the potential of structural studies, substantiating their relevance in future anti-mycobacterial drug discovery and development efforts.
- Published
- 2021
43. Stereoselective Synthesis of α,α′-Dihydroxy-β,β′-diaryl-β-amino Acids by Mannich-Like Condensation of Hydroarylamides
- Author
-
Fiorella Meneghetti, Raffaella Bucci, Michele Penso, Carlo Castellano, Francesca Foschi, Ilir Pecnikaj, and Maria Luisa Gelmi
- Subjects
chemistry.chemical_classification ,Stereochemistry ,Chemistry ,Organic Chemistry ,Condensation ,Stereoselectivity ,Physical and Theoretical Chemistry ,Amino acid - Published
- 2019
44. Insights on the Modulation of SIRT5 Activity: A Challenging Balance
- Author
-
FIORELLA MENEGHETTI, Arianna Gelain, Matteo Mori, Stefania Villa, and Giulia Cazzaniga
- Subjects
Chemistry (miscellaneous) ,Organic Chemistry ,Drug Discovery ,Protein Isoforms ,Sirtuins ,Molecular Medicine ,Pharmaceutical Science ,Physical and Theoretical Chemistry ,Analytical Chemistry - Abstract
SIRT5 is a member of the Sirtuin family, a class of deacetylating enzymes consisting of seven isoforms, involved in the regulation of several processes, including gene expression, metabolism, stress response, and aging. Considering that the anomalous activity of SIRT5 is linked to many pathological conditions, we present herein an overview of the most interesting modulators, with the aim of contributing to further development in this field.
- Published
- 2022
45. Exploring the Biological Activity of a Library of 1,2,5-Oxadiazole Derivatives Endowed With Antiproliferative Activity
- Author
-
Arianna Gelain, Fiorella Meneghetti, Aída Nelly García-Argáez, M. Mori, F. Porta, Lisa Dalla Via, Akira Asai, Salvatore Guccione, Stefania Villa, Livia Basile, Gaetano Marverti, and Mariafrancesca Hyeraci
- Subjects
Cancer Research ,Cytotoxicity ,HCT-116 ,Type I ,Oxadiazole ,Drug Screening Assays ,HeLa ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Neoplasms ,Humans ,Structure–activity relationship ,MTT assay ,Docking studies ,Cell Proliferation ,Oxadiazoles ,biology ,Topoisomerase ,Biological activity ,Antitumor ,General Medicine ,HCT116 Cells ,biology.organism_classification ,Topoisomerase I ,Molecular Docking Simulation ,DNA Topoisomerases, Type I ,Oncology ,chemistry ,Biochemistry ,Docking (molecular) ,030220 oncology & carcinogenesis ,biology.protein ,Drug Screening Assays, Antitumor ,HeLa Cells ,DNA Topoisomerases - Abstract
BACKGROUND/AIM The identification of a series of oxadiazole-based compounds, as promising antiproliferative agents, has been previously reported. The aim of this study was to explore the SAR of newly-synthesized oxadiazole derivatives and identify their molecular targets. MATERIALS AND METHODS A small library of 1,2,5-oxadiazole derivatives was synthetized and their antiproliferative activity was tested by the MTT assay. Their interaction with topoisomerase I was evaluated and a molecular docking study was performed. RESULTS Several candidates showed cytotoxicity towards two human tumor cell lines, HCT-116 (colorectal carcinoma) and HeLa (cervix adenocarcinoma). Some derivatives exhibited inhibitory effects on the catalytic activity of topoisomerase I and this effect was supported by docking studies. CONCLUSION The enzyme inhibition results, although not directly related to cytotoxicity, suggest that a properly modified 1,2,5 oxadiazole scaffold could be considered for the development of new anti-topoisomerase agents.
- Published
- 2018
46. Special Issue 'Novel Antibacterial Agents'
- Author
-
Daniela Barlocco and Fiorella Meneghetti
- Subjects
0301 basic medicine ,Computer science ,Management science ,Field (Bourdieu) ,Pharmaceutical Science ,RS1-441 ,03 medical and health sciences ,n/a ,Pharmacy and materia medica ,030104 developmental biology ,0302 clinical medicine ,Editorial ,030220 oncology & carcinogenesis ,Drug Discovery ,Medicine ,Molecular Medicine - Abstract
This Special Issue of Pharmaceuticals is devoted to significant advances achieved in the field of antibacterial agents. Here, we report recent efforts made to develop new antimicrobials with novel modes of action/resistance, and offer perspectives on the future directions of antibacterial agents. Antimicrobial resistance has become a major threat to global health and the twenty-two published articles, included here, evidence that the discovery and development of new antibiotics is extremely challenging. This Special Issue is focused on the search for new chemical entities, starting from both natural and synthetic compounds and addressing different targets. In addition, recent findings are presented and discussed, highlighting strategies of fighting bacterial resistance. [...]
- Published
- 2021
47. Design and physicochemical characterization of novel hybrid SLN-liposome nanocarriers for the smart co-delivery of two antitubercular drugs
- Author
-
Eleonora Truzzi, Angela Capocefalo, Fiorella Meneghetti, Eleonora Maretti, Matteo Mori, Valentina Iannuccelli, Fabio Domenici, Carlo Castellano, and Eliana Leo
- Subjects
body regions ,Settore CHIM/02 ,AFM ,Isoniazid ,Nanoparticles ,Rifampicin ,SANS ,Pharmaceutical Science - Abstract
In the present work a novel hybrid system for the delivery of two first-line antitubercular drugs, rifampicin (RIF) and isoniazid (INH), was designed. In order to control the release of the drugs and improve the efficiency of conventional carriers, like liposomes or solid lipid nanoparticles (SLNs), the new systems were developed by embedding SLNs into lecithin-based liposomes through the reverse-phase evaporation method. The hybrid system was characterized and compared to SLNs and liposomes in terms of size, encapsulation efficiency, morphology, and drug release. Detailed structural data and further evidence of the successful formation of the hybrid nanoparticles were obtained by applying small-angle neutron scattering (SANS). The hybrid system displayed a particle size comparable to liposomes and a high encapsulation efficiency. Morphological results obtained by atomic force microscopy (AFM) highlighted the possible presence of SLNs into the phospholipid bilayer; this hypothesis was supported by the slower in vitro release of the hydrophilic drug INH compared to liposomes and SLNs. Moreover, scattering differences of the inner core of the nanoparticles, evidenced in the SANS analysis, further corroborated the successful formation of the hybrid carrier. These novel systems were able to release their content as expected from an efficient dosage form in a perspective of an inhaled administration, improving the stability and the drug release profile with respect to plain liposomes. The physicochemical characterization of our systems opens new avenues towards a better understanding of the formulation of vesicles encapsulating SLNs.
- Published
- 2022
48. Tuneable solvent adsorption and exchange by 1D bispidine-based Mn(II) coordination polymers via ligand design
- Author
-
Carlo Castellano, Martina Lippi, Javier Martí-Rujas, Fiorella Meneghetti, Massimo Cametti, and Josefina Caputo
- Subjects
Inorganic Chemistry ,Solvent ,chemistry.chemical_classification ,Nitrobenzene ,chemistry.chemical_compound ,Crystallography ,Chloroform ,Adsorption ,chemistry ,Ligand ,Polymer ,Single crystal ,Powder diffraction - Abstract
Here we report novel bispidine-based coordination polymers (CPs) 2·TCM, 3·TCM, 3·NB, 5·TCM and 5·TCM·NB, of compostition [Mn(Cl)2(L2)2·(TCM)2], [Mn(Cl)2(L3)2·(TCM)5], [Mn(Cl)2(L3)2·(NB)8], [Mn(Cl)2(L5)2·(TCM)4], [Mn(Cl)2(L5)2·(TCM)2·(NB)2], respectively (NB = nitrobenzene; TCM = chloroform). They were obtained starting from novel bispidine ligands L2 (dimethyl 7-isopropyl-3-methyl-9-oxo-2,4-di(pyridin-4-yl)-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarboxylate), L3 (dimethyl 7-(cyclohexylmethyl)-3-methyl-9-oxo-2,4-di(pyridin-4-yl)-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarboxylate) and L5 (dimethyl 7-(4-(dimethylamino)benzyl)-3-methyl-9-oxo-2,4-di(pyridin-4-yl)-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarboxylate), The novel CPs were characterized by single crystal X-ray diffraction (SC-XRD), powder X-ray diffraction (PXRD) and thermal analyses (TGA). We describe their structural and dynamic properties in terms of solvent exchange and adsorption processes, and we outline the general trends observed on the basis of a total of 16 X-ray structures (4 new) and 21 microcrystalline powder phases (10 new), which have been obtained so far for CPs by coordination of ligands L1–L5, having different substitution at the N7 position. This large set of CPs comprises monosolvated, bisolvated and desolvated species, and it shows a good demonstration of how small differences in the functionalization of the organic ligand can have a strong impact on the resulting structural and dynamic properties of this class of 1D CPs.
- Published
- 2020
49. On-water pyrrolidine-mediated domino synthesis of 2-iminoisatins
- Author
-
Robert C. Hider, Ettore Novellino, Vincenzo Abbate, Gian Cesare Tron, Mariateresa Giustiniano, Fiorella Meneghetti, Nunzianda Frascione, Sveva Pelliccia, Pelliccia, Sveva, Abbate, Vincenzo, Meneghetti, Fiorella, Frascione, Nunzianda, Hider, Robert Charle, Novellino, Ettore, Tron, Gian Cesare, and Giustiniano, Mariateresa
- Subjects
chemistry.chemical_classification ,Reaction mechanism ,010405 organic chemistry ,Iminium ,010402 general chemistry ,01 natural sciences ,Pollution ,Combinatorial chemistry ,Heterolysis ,Domino ,Pyrrolidine ,0104 chemical sciences ,Sulfonamide ,Catalysis ,chemistry.chemical_compound ,chemistry ,Environmental Chemistry ,Bond cleavage - Abstract
The on-water reaction between 2-(sulfonylamino)-benzaldehydes, isocyanides and pyrrolidine is able to afford a library of poorly synthetically accessible 2-iminoisatins. The pyrrolidine exhibits for the first time the unique role of promoting a triple domino process, i.e. the formation of an N-alkyl-2,3-diaminoindole, the sulfonamide heterolytic N–S bond cleavage, and the hydrolysis of the resulting iminium ion, with the loss of p-toluenesulfinic acid. RP HPLC-DAD and UHPLC-HRMS real-time monitoring of the reaction provided experimental data that support the reaction mechanism. The use of water as a solvent under ultrasound catalysis and the convergent nature of this approach allow, for the first time, a green and sustainable synthesis of 2-iminoisatins.
- Published
- 2018
50. Natural products against key Mycobacterium tuberculosis enzymatic targets: Emerging opportunities for drug discovery
- Author
-
Arianna Gelain, Fiorella Meneghetti, Laurent R. Chiarelli, Giulia Cazzaniga, Stefania Villa, and M. Mori
- Subjects
Pharmacology ,Biological Products ,Tuberculosis ,biology ,Chemistry ,Drug discovery ,Bioactive molecules ,Organic Chemistry ,Treatment outcome ,Antitubercular Agents ,Structural diversity ,Mycobacterium tuberculosis ,General Medicine ,Computational biology ,medicine.disease ,biology.organism_classification ,World health ,Drug Discovery ,Global health ,medicine ,Humans - Abstract
For centuries, natural products (NPs) have served as powerful therapeutics against a variety of human ailments. Nowadays, they still represent invaluable resources for the treatment of many diseases, including bacterial infections. After nearly three decades since the World Health Organization's (WHO) declaration of tuberculosis (TB) as a global health emergency, Mycobacterium tuberculosis (Mtb) continues to claim millions of lives, remaining among the leading causes of death worldwide. In the last years, several efforts have been devoted to shortening and improving treatment outcomes, and to overcoming the increasing resistance phenomenon. Nature has always provided a virtually unlimited source of bioactive molecules, which have inspired the development of new drugs. NPs are characterized by an exceptional chemical and structural diversity, the result of millennia of evolutionary responses to various stimuli. Thanks to their favorable structural features and their enzymatic origin, they are naturally prone to bind proteins and exhibit bioactivities. Furthermore, their worldwide distribution and ease of accessibility has contributed to promote investigations on their activity. Overall, these characteristics make NPs excellent models for the design of novel therapeutics. This review offers a critical and comprehensive overview of the most promising NPs, isolated from plants, fungi, marine species, and bacteria, endowed with inhibitory properties against traditional and emerging mycobacterial enzymatic targets. A selection of 86 compounds is here discussed, with a special emphasis on their biological activity, structure-activity relationships, and mechanism of action. Our study corroborates the antimycobacterial potential of NPs, substantiating their relevance in future drug discovery and development efforts.
- Published
- 2021
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