Correction to “Ferroptosis Induction by a New Pyrrole Derivative in Triple Negative Breast Cancer and Colorectal Cancer” Domiziana Masci, Lele Ling, Lian Yang, Michela Puxeddu, Claudia Colla, Marianna Nalli, Antonio Coluccia, Martina Santelli, Pietro Sciò, Petra Cuřínová, Mohammad Salik Zeya Ansari, Chiara Naro, Claudio Sette, Lucia Jimenez, Wolfgang Link, Chiara Bigogno, Giulio Dondio, Ernest Hamel, Te Liu, Romano Silvestri, Giuseppe La Regina Journal of Medicinal Chemistry, 2026
4-(5-Chloro-3-(3,4,5-trimethoxybenzoyl)-1H-indol-1-yl)benzenesulfonamide: A Novel Polypharmacology Agent to Target Carbonic Anhydrase IX and XII With Improved Selectivity, Wnt/β-Catenin Signaling Pathway, and P-Glycoprotein Michela Puxeddu, Rosa Bordone, Claudia Colla, Gabriele Rotili, Antonio Coluccia, et al. Chemmedchem, 2026 We synthesized novel pyrrole (5-11) and indole (12-16) derivatives based on a polypharmacology approach aimed to obtain inhibitors of human carbonic anhydrase (hCA) with improved selectivity toward the IX and XII isoforms, Wnt/β-catenin pathway, and P-glycoprotein (P-gp). Inspection of the binding sites of the hCA I, II, IX, and XII isoforms highlighted small but significant differences of cavity volumes that guided the introduction of small substituents at Position 4 of the 3-phenyl ring of the pyrrole and at Position 5 of the indole. Compound 15 exhibited potent and selective inhibition of both hCA IX and XII isoforms compared to the parent compound. It inhibited the Wnt/β-catenin pathway abrogating the association of β-catenin with TCF-4 and the multidrug-resistant P-gp-expressing cancer cells. Compound 15 showed strong inhibition of viability of SW620, SW480, and HCT116 CRC and TNBC cell lines, restored the sensitivity to doxorubicin (DOX) in HT29/DX P-gp-overexpressing cells, and showed medium metabolic stability in both human and mouse microsomes and acceptable predicted oral bioavailability. Compound 15 is a robust lead compound for the development of new antitumor agents based on the polypharmacology approach.
Structure–function relationship of the Pseudomonas aeruginosa AsmA-like proteins YhdP and YdbH involved in outer membrane biogenesis Davide Sposato, Camilla Pederzoli, Marianna Bufano, Pietro Sciò, Ludovica Rossi, Livia Leoni, Giordano Rampioni, Paolo Visca, Antonio Coluccia, Francesco Imperi Protein Science, 2025 The outer membrane (OM) of Gram‐negative bacteria is an asymmetric bilayer composed of glycerophospholipids (GPLs) in the inner leaflet and lipopolysaccharide in the outer leaflet, which is critical for viability and antibiotic resistance. While the mechanisms for lipopolysaccharide and OM protein transport across the periplasm are well characterized, it has only recently been proposed that AsmA‐like proteins are likely involved in the anterograde transport of GPLs. Here, we investigated the structural and functional features of Pseudomonas aeruginosa YhdP, an AsmA‐like protein that exhibits higher activity in maintaining OM integrity than its paralogs. Through structural predictions, molecular dynamics simulations, and genetic complementation assays, we demonstrated that two hydrophobic α‐helices at the C‐terminal region of YhdP are crucial for its function. Moreover, we found that fusing the YhdP C‐terminal domain to YdbH enhances the functionality of this shorter and lower‐activity AsmA‐like protein. Specifically, a YdbH‐YhdP fusion protein long enough to potentially span the periplasmic space was more active than the wild‐type YdbH protein in promoting growth and OM integrity. Furthermore, while YdbH activity requires the OM protein partner YnbE, the functionality of the YdbH‐YhdP fusion protein is YnbE‐independent. These findings support the hypothesis that the YhdP C‐terminus provides OM anchoring and likely assists GPL insertion, and prove that it can be used as a modular element for improving the activity of other AsmA‐like proteins. Our work sheds light on the molecular determinants of GPL transport and offers a framework for studying the mode of action of AsmA‐like proteins in OM biogenesis.
Ferroptosis Induction by a New Pyrrole Derivative in Triple Negative Breast Cancer and Colorectal Cancer Domiziana Masci, Lele Ling, Lian Yang, Michela Puxeddu, Claudia Colla, Antonio Coluccia, Martina Santelli, Pietro Sciò, Petra Cuřínová, Mohammad Salik Zeya Ansari, Chiara Naro, Claudio Sette, Lucia Jimenez, Wolfgang Link, Chiara Bigogno, Giulio Dondio, Ernest Hamel, Te Liu, Romano Silvestri, Giuseppe La Regina Journal of Medicinal Chemistry, 2025 Ferroptosis-inducing agents are an emerging class of nonapoptotic, iron-dependent compounds for anticancer chemotherapy. We describe the synthesis of new aroyl diheterocyclyl pyrrole derivatives 2–21 . Compound 12 exhibited the most potent in vitro anticancer activity against breast cancer (BC), triple-negative breast cancer (TNBC), and colorectal cancer (CRC) cell lines, as well as significant efficacy in an HCT116 CRC xenograft model. Compound 12 showed typical hallmarks of ferroptosis in HCT116 cells from tumor tissues both in immunofluorescence and a qPCR gene assay and in the expression of ferroptosis inhibited proteins. Compound 12 significantly lowered GSH, NADP +, and NADPH levels. Furthermore, lactoperoxidase, malondialdehyde, and Fe(II) levels significantly increased in 12 -treated tissues, whereas superoxide dismutase concentrations decreased. Taken together, these results indicate that the antitumor activity of compound 12 was caused by the strong induction of ferroptosis. Given its high activity, compound 12 represents a promising therapeutic candidate for TNBC and CRC.
Retrospective Benchmarking and Novel Shape-Pharmacophore Based Implementation of the MORLD Method for the Autonomous Optimization of 3-Aroyl-1,4-diarylpyrroles (ARDAP) Pietro Sciò, Marianna Bufano, Romano Silvestri, Antonio Coluccia Journal of Chemical Information and Modeling, 2025 The use of artificial intelligence (AI) is increasingly integral to the drug-discovery process, and among AI-driven methodologies, deep generative models stand out as one of the most promising approaches for hit identification and optimization. Here, we report a retrospective benchmarking analysis of a series of tubulin inhibitors, 3-aroyl-1,4-diarylpyrroles (ARDAP), using the deep-generative algorithm Molecule Optimization by Reinforcement Learning and Docking (MORLD) in combination with five docking software (QuickVina 2, AutoDock-GPU, PLANTS, GOLD, and Glide). Our results indicate that the performance of the MORLD/docking workflow is highly dependent on the availability of initial structural information; only the incorporation of a core constraint in Glide yields satisfactory predictions. To address this limitation, we developed a docking-free variant of MORLD that exploits receptor-derived shape similarity and pharmacophore alignment. Kernel-density estimation, convergence analysis, and SMARTS-based success-rate metrics confirmed that this Shape-Pharmacophore implementation autonomously generates chemically valid, SAR-consistent analogues of the reference compounds. Collectively, this work demonstrates a practical, structure-only driven paradigm for reinforcement-learning-based compound optimization, thereby extending the reach of AI-enabled drug design beyond traditional docking workflows.
Unveiling an unexpected redox regulation of the folding, function and inhibition in the phosphotyrosine binding domain of FRS2 Valeria Pennacchietti, Livia Pagano, Mariana Di Felice, Julian Toso, Marianna Bufano, Antonio Coluccia, Romano Silvestri, Riccardo Capelli, Carlo Camilloni, Francesca Malagrinò, Angelo Toto, Stefano Gianni International Journal of Biological Macromolecules, 2025 Protein-protein interaction domains are essential for cellular homeostasis and the regulation of various molecular pathways, mediating highly specific and reversible binding events. The PhosphoTyrosine-Binding domains (PTB) play a pivotal role in regulating several cellular events, by recognizing phosphorylated and, in some cases, non-phosphorylated ligands. In this study we investigated the folding and functional properties of the PTB domain of FRS2 (Fibroblast growth factor receptor substrate 2) under oxidative and reductive experimental conditions. Results demonstrate a surprising and previously undetected role of a disulfide bond between Cys61 and Cys80 residues in such events. Through an extensive site-directed mutagenesis we demonstrated that the presence/absence of such disulfide bridge, although not changing dramatically the overall structure of the domain, significantly influence its dynamic properties by rewiring a subtle energetic network stabilizing the domain. These effects result in remodulating its binding properties with phosphorylated and unphosphorylated peptides. Molecular dynamics simulations further elucidated how the oxidative/reductive conditions modulate the dynamics of the domain. Finally, we identified lead inhibitory compounds with different efficacy observed across the oxidized and reduced states of the PTB domain. Altogether, these findings provide novel insights for understanding the mechanism of regulation of the function of the PTB domain of FRS2.
Design and synthesis of novel thioether analogs as promising antiviral agents: In vitro activity against enteroviruses of interest Hugo Roux, Franck Touret, Antonio Coluccia, Pietro Scio, Hawa Sophia Bouzidi, Carole di Giorgio, Florence Gattacceca, Omar Khoumeri, Romano Silvestri, Patrice Vanelle, Manon Roche European Journal of Medicinal Chemistry, 2025 The Enterovirus genus contains two major subgroups: rhinovirus (RV) species A-C and enterovirus (EV) ones A-D. While RV only infects the respiratory system, the EV can cause a wide variety of diseases, ranging from non-specific febrile illness to severe neurologic complications. To date, no curative treatments are commercially available. Our research team had recently developed EV-A71 inhibitors. To improve their activity and broaden their spectrum, we performed optimization of the structure following an iterative cycle of chemical modulations. As a result, we obtained two broad-spectrum inhibitors with micromolar activity against these 3 types of viruses ( OM1260 : EC 50 (MRC-5, EV-A71) = 1.15 μM; EC 50 (RD, EV-A71) = 4.38 μM; EC 50 (MRC-5, E30) = 0.41 μM; EC 50 (MRC-5, CVA24) = 1.15 μM; HR-568 : EC 50 (MRC-5, EV-A71) = 3.25 μM; EC 50 (RD, EV-A71) = 1.53 μM; EC 50 (MRC-5, E30) = 0.40 μM; EC 50 (MRC-5, CVA24) = 1.22 μM). Docking studies shed light on structure-activity relationships, while time-of-drug addition assays confirmed their intervention during the early step of viral replication. Eventually, some pharmacokinetic modelling has been carried out to evaluate their druggability. All these results showed that OM1260 and HR-568 are promising candidates for further development. • High-yielding reaction thanks to 2 optimized synthesis strategies. • Fused bicycles in toe-end side to broaden the hydrophobic interactions with the target. • Description of new derivatives with micromolar/sub micromolar activity. • Innovative and rigorous methods to evaluate activity against EV-A71, E30, and CVA24 in 2 cell lines. • Modelling of physicochemical and pharmacokinetic parameters of the most promised compounds.
Identification of a New FtsZ Inhibitor by Virtual Screening, Mechanistic Insights, and Structure-Activity Relationship Analyses Pietro Sciò, Viola Camilla Scoffone, Anastasia Parisi, Marianna Bufano, Martina Caneva, Gabriele Trespidi, Samuele Irudal, Giulia Barbieri, Lisa Cariani, Beatrice Silvia Orena, Valeria Daccò, Francesco Imperi, Silvia Buroni, Antonio Coluccia ACS Infectious Diseases, 2025 Antimicrobial resistance (AMR) poses a major threat to human health globally. Approximately 5 million deaths were attributed to AMR in 2019, and this figure is predicted to worsen, reaching 10 million deaths by 2050. In the search for new compounds that can tackle AMR, FtsZ inhibitors represent a valuable option. In the present study, a structure-based virtual screening is reported, which led to the identification of derivative C11 endowed with an excellent minimum inhibitory concentration value of 2 μg/mL against Staphylococcus aureus. Biochemical assays clarified that compound C11 targets FtsZ by inhibiting its polymerization process. C11 also showed notable antimicrobial activity against S. aureus cystic fibrosis isolates and methicillin-resistant S. aureus strains. Derivative C11 did not show cytotoxicity, while it had a synergistic effect with methicillin. C11 also showed increased survival in the Galleria mellonella infection model. Lastly, structure-activity relationship and binding mode analyses were reported.
Non-Polio Enterovirus Inhibitors: Scaffolds, Targets, and Potency─What’s New? Hugo Fernando Georges Roux, Franck Touret, Pascal Rathelot, Pietro Sciò, Antonio Coluccia, Patrice Vanelle, Manon Roche ACS Infectious Diseases, 2025 Enterovirus (EV) is a genus that includes a large diversity of viruses spread around the world. They are the main cause of numerous diseases with seasonal clusters, like hand-foot-mouth disease (HFMD). A vaccine is marketed in China for the prevention of HFMD caused by EV-A71. Despite the need, no antiviral is marketed to date. Therefore, several compounds have been currently evaluated to inhibit non-polio Enterovirus (NPEV), namely direct antiviral agents and host target inhibitor. We propose to make a review of the latest molecules evaluated as NPEV inhibitors and to summarize structure-activity relationships between these inhibitors and their target. We provide access to all recent information on Enterovirus inhibitors, regardless of the species, to facilitate the design of future broad-spectrum drugs.
Fatigue Characterization Of Alsi10mg Alloy From Variable L-PBF Processing Parameters Addressed To Hybrid Joints Of Aerostructures , Sara Varetti, , Luca Margaria, , Antonio Coluccia, , Giorgio De Pasquale, , Alessandro De Zanet, , Evanthia Pappa, , Abhishek Kumar, , Mattia Cabrioli,, Matteo Vanazzi Euro Powder Metallurgy 2025 Congress and Exhibition Euro Pm 2025, 2025 Joining technologies in aviation ares considered as a backbone. Traditional mechanical methods, like rivets and fasteners add weight, require complex assemblies, and can damage the configuration of composites such as continus fibre breakage during handling. These challenges highlight the need for alternative solutions. The EU-funded MIMOSA project proposes a novel approach for joining metal (AlSi10Mg from Additive Manufacturing, AM) and CFRP, addressing these limitations. The proposed technology focuses on the implementation of mechanical interlocking mechanism between CFRP and 3D metal anchors based on AM (patented design and manufacturing process). The AM process associated with heat treatmens requires customized fatigue characterization of the material to measure the S-N curves as function of some fundamental fabrication parameters (part orientation, surface finishing and heat treatment). This study reports the experimental results of the fatigue tests to assess the feasibility of producing the innovative multi-material joints proposed.
SAR Analysis of Novel Coxsackie virus A9 Capsid Binders Chiara Tammaro, Zlatka Plavec, Laura Myllymäki, Cristopher Mitchell, Sara Consalvi, Mariangela Biava, Alessia Ciogli, Aušra Domanska, Valtteri Leppilampi, Cienna Buckner, Simone Manetto, Pietro Sciò, Antonio Coluccia, Mira Laajala, Giulio M. Dondio, Chiara Bigogno, Varpu Marjomäki, Sarah J. Butcher, Giovanna Poce Journal of Medicinal Chemistry, 2024
New potent EV-A71 antivirals targeting capsid Hugo Roux, Franck Touret, Antonio Coluccia, Omar Khoumeri, Carole Di Giorgio, Chaimae Majdi, Pietro Sciò, Romano Silvestri, Patrice Vanelle, Manon Roche European Journal of Medicinal Chemistry, 2024
4-(3-Phenylsulfonylindol-2-yl)-1-(pyridin-2-yl)piperazinyl-methanones as Potent Inhibitors of both SARS-CoV-2 and HCoV-OC43 Viruses Michela Puxeddu, Manuela Donalisio, Joachim Jakob Bugert, Angela Corona, Paolo Cocomazzi, Mario Milani, Friederike Hucke, Irene Arduino, Francesca Esposito, Paolo Moretti, Maria Grazia Ortore, Marianna Nalli, Simone Manetto, Giulia Mazzoccanti, Chiara Bigogno, Giulio Dondio, Pietro Sciò, Antonio Coluccia, Matteo Fracella, Guido Antonelli, David Lembo, Enzo Tramontano, Romano Silvestri, Eloise Mastrangelo, Giuseppe La Regina ACS Infectious Diseases, 2024
Novel N-(Heterocyclylphenyl)benzensulfonamide Sharing an Unreported Binding Site with T-Cell Factor 4 at the β-Catenin Armadillo Repeats Domain as an Anticancer Agent Marianna Nalli, Laura Di Magno, Yichao Wen, Xin Liu, Michele D’Ambrosio, Michela Puxeddu, Anastasia Parisi, Jessica Sebastiani, Andrea Sorato, Antonio Coluccia, Silvia Ripa, Fiorella Di Pastena, Davide Capelli, Roberta Montanari, Domiziana Masci, Andrea Urbani, Chiara Naro, Claudio Sette, Viviana Orlando, Sara D’Angelo, Stefano Biagioni, Chiara Bigogno, Giulio Dondio, Arianna Pastore, Mariano Stornaiuolo, Gianluca Canettieri, Te Liu, Romano Silvestri, Giuseppe La Regina ACS Pharmacology and Translational Science, 2023
Toll-Like Receptor 4-Dependent Platelet-Related Thrombosis in SARS-CoV-2 Infection Roberto Carnevale, Vittoria Cammisotto, Simona Bartimoccia, Cristina Nocella, Valentina Castellani, Marianna Bufano, Lorenzo Loffredo, Sebastiano Sciarretta, Giacomo Frati, Antonio Coluccia, Romano Silvestri, Giancarlo Ceccarelli, Alessandra Oliva, Mario Venditti, Francesco Pugliese, Claudio Maria Mastroianni, Ombretta Turriziani, Martina Leopizzi, Giulia D’Amati, Pasquale Pignatelli, Francesco Violi Circulation Research, 2023
Induction of Ferroptosis in Glioblastoma and Ovarian Cancers by a New Pyrrole Tubulin Assembly Inhibitor Michela Puxeddu, Jianchao Wu, Ruoli Bai, Michele D’Ambrosio, Marianna Nalli, Antonio Coluccia, Simone Manetto, Alessia Ciogli, Domiziana Masci, Andrea Urbani, Cinzia Fionda, Sonia Coni, Rosa Bordone, Gianluca Canettieri, Chiara Bigogno, Giulio Dondio, Ernest Hamel, Te Liu, Romano Silvestri, Giuseppe La Regina Journal of Medicinal Chemistry, 2022
Discovery of pyrrole derivatives for the treatment of glioblastoma and chronic myeloid leukemia Michela Puxeddu, Hongliang Shen, Ruoli Bai, Antonio Coluccia, Marianna Bufano, Marianna Nalli, Jessica Sebastiani, Diego Brancaccio, Eleonora Da Pozzo, Chiara Tremolanti, Claudia Martini, Viviana Orlando, Stefano Biagioni, Maria Stefania Sinicropi, Jessica Ceramella, Domenico Iacopetta, Addolorata Maria Luce Coluccia, Ernest Hamel, Te Liu, Romano Silvestri, Giuseppe La Regina European Journal of Medicinal Chemistry, 2021
Targeting the interaction between the SH3 domain of Grb2 and Gab2 Francesca Malagrinò, Antonio Coluccia, Marianna Bufano, Giuseppe La Regina, Michela Puxeddu, Angelo Toto, Lorenzo Visconti, Alessio Paone, Maria Chiara Magnifico, Francesca Troilo, Francesca Cutruzzolà, Romano Silvestri, Stefano Gianni Cells, 2020
Drug Design and Synthesis of First in Class PDZ1 Targeting NHERF1 Inhibitors as Anticancer Agents Antonio Coluccia, Giuseppe La Regina, Valentina Naccarato, Marianna Nalli, Viviana Orlando, Stefano Biagioni, Maria Laura De Angelis, Marta Baiocchi, Candice Gautier, Stefano Gianni, Fiorella Di Pastena, Laura Di Magno, Gianluca Canettieri, Addolorata Maria Luce Coluccia, Romano Silvestri ACS Medicinal Chemistry Letters, 2019
New 6- and 7-heterocyclyl-1H-indole derivatives as potent tubulin assembly and cancer cell growth inhibitors Giuseppe La Regina, Ruoli Bai, Antonio Coluccia, Valentina Naccarato, Valeria Famiglini, Marianna Nalli, Domiziana Masci, Annalisa Verrico, Paola Rovella, Carmela Mazzoccoli, Eleonora Da Pozzo, Chiara Cavallini, Claudia Martini, Stefania Vultaggio, Giulio Dondio, Mario Varasi, Ciro Mercurio, Ernest Hamel, Patrizia Lavia, Romano Silvestri European Journal of Medicinal Chemistry, 2018
New pyridine derivatives as inhibitors of acetylcholinesterase and amyloid aggregation Fabiana Pandolfi, Daniela De Vita, Martina Bortolami, Antonio Coluccia, Roberto Di Santo, Roberta Costi, Vincenza Andrisano, Francesco Alabiso, Christian Bergamini, Romana Fato, Manuela Bartolini, Luigi Scipione European Journal of Medicinal Chemistry, 2017
3-Aroyl-1,4-diarylpyrroles Inhibit Chronic Myeloid Leukemia Cell Growth through an Interaction with Tubulin Giuseppe La Regina, Ruoli Bai, Antonio Coluccia, Valeria Famiglini, Sara Passacantilli, Valentina Naccarato, Giorgio Ortar, Carmela Mazzoccoli, Vitalba Ruggieri, Francesca Agriesti, Claudia Piccoli, Tiziana Tataranni, Marianna Nalli, Andrea Brancale, Stefania Vultaggio, Ciro Mercurio, Mario Varasi, Concetta Saponaro, Sara Sergio, Michele Maffia, Addolorata Maria Luce Coluccia, Ernest Hamel, Romano Silvestri ACS Medicinal Chemistry Letters, 2017
New Indole Tubulin Assembly Inhibitors Cause Stable Arrest of Mitotic Progression, Enhanced Stimulation of Natural Killer Cell Cytotoxic Activity, and Repression of Hedgehog-Dependent Cancer Giuseppe La Regina, Ruoli Bai, Antonio Coluccia, Valeria Famiglini, Sveva Pelliccia, Sara Passacantilli, Carmela Mazzoccoli, Vitalba Ruggieri, Annalisa Verrico, Andrea Miele, Ludovica Monti, Marianna Nalli, Romina Alfonsi, Lucia Di Marcotullio, Alberto Gulino, Biancamaria Ricci, Alessandra Soriani, Angela Santoni, Michele Caraglia, Stefania Porto, Eleonora Da Pozzo, Claudia Martini, Andrea Brancale, Luciana Marinelli, Ettore Novellino, Stefania Vultaggio, Mario Varasi, Ciro Mercurio, Chiara Bigogno, Giulio Dondio, Ernest Hamel, Patrizia Lavia, Romano Silvestri Journal of Medicinal Chemistry, 2015
New pyrrole derivatives with potent tubulin polymerization inhibiting activity as anticancer agents including hedgehog-dependent cancer Giuseppe La Regina, Ruoli Bai, Antonio Coluccia, Valeria Famiglini, Sveva Pelliccia, Sara Passacantilli, Carmela Mazzoccoli, Vitalba Ruggieri, Lorenza Sisinni, Alessio Bolognesi, Whilelmina Maria Rensen, Andrea Miele, Marianna Nalli, Romina Alfonsi, Lucia Di Marcotullio, Alberto Gulino, Andrea Brancale, Ettore Novellino, Giulio Dondio, Stefania Vultaggio, Mario Varasi, Ciro Mercurio, Ernest Hamel, Patrizia Lavia, Romano Silvestri Journal of Medicinal Chemistry, 2014
Toward highly potent cancer agents by modulating the C-2 group of the arylthioindole class of tubulin polymerization inhibitors Giuseppe La Regina, Ruoli Bai, Whilelmina Maria Rensen, Erica Di Cesare, Antonio Coluccia, Francesco Piscitelli, Valeria Famiglini, Alessia Reggio, Marianna Nalli, Sveva Pelliccia, Eleonora Da Pozzo, Barbara Costa, Ilaria Granata, Amalia Porta, Bruno Maresca, Alessandra Soriani, Maria Luisa Iannitto, Angela Santoni, Junjie Li, Marlein Miranda Cona, Feng Chen, Yicheng Ni, Andrea Brancale, Giulio Dondio, Stefania Vultaggio, Mario Varasi, Ciro Mercurio, Claudia Martini, Ernest Hamel, Patrizia Lavia, Ettore Novellino, Romano Silvestri Journal of Medicinal Chemistry, 2013
Arylthioindoles, potent inhibitors of tubulin polymerization Gabriella De Martino, Giuseppe La Regina, Antonio Coluccia, Michael C. Edler, Maria Chiara Barbera, Andrea Brancale, Elizabeth Wilcox, Ernest Hamel, Marino Artico, Romano Silvestri Journal of Medicinal Chemistry, 2004