Drug Discovery, Pharmaceutical Science, Mathematical Physics
33
Scopus Publications
Scopus Publications
Novel 2-Aryl-1H-Benzimidazole Derivatives and Their Aza-Analogues as Promising Anti-Poxvirus Agents Valeria Manca, Laura Locci, Roberta Ibba, Laura Sanna, Ilenia Lupinu, Sandra Piras, Gabriele Murineddu, Gabriele Serreli, Roberta Loddo, Rebecca Piras, Luca Virdis, Michela Isola, Vanessa Palmas, Giuseppina Sanna, Antonio Carta Viruses, 2026 Introduction: Despite the impressive progress carried out in the field of biomedical sciences in recent decades, the incidence of emerging and neglected lethal viral infections mainly belonging to the Coronaviridae, Filoviridae, Arenaviridae, Bunyaviridae, and Paramyxoviridae families has considerably impaired human health. The worldwide vaccination campaign at the end of the 1970s determined the eradication of smallpox. However, the growing number of cases of diseases linked to orthopoxvirus diseases, such as the recent epidemic of monkeypox zoonosis in various countries around the world, has increased the need for knowledge of these viral pathogens. To date, there is no specific treatement for Monkeypox virus (MPXV) infection. However, several antiviral drugs used to treat Smallpox and other viral infections could also be beneficial for Monkeypox disease. In this study we report the design and synthesis of new, variously substituted benzimidazole derivatives and the evaluation of their cytotoxicity and antiviral activity against representatives of the Orthopoxvirus genus, Vaccinia Virus (VV), closely related to variola virus and MPXV. Methods: A combination of cell-based assays and experimental techniques was used to investigate the cytotoxicity, antiviral activity, and mechanisms of action of the most interesting compound. Results: In our study, new, variously substituted benzimidazoles showed interesting EC50 values against vaccinia and MPXV and a cytotoxic profile in the high micromolar range. Conclusions: Our work shows that the new tested benzimidazole derivatives possess appealing activity and selectivity, accompanied by low cytotoxicity. These results set a valid foundation with which to identify potent and selective anti-Poxvirus agents.
Synthesis of Novel Tricyclic N-Acylhydrazones as Tubulin Polymerization Inhibitors Paola Corona, Michele Lai, Battistina Asproni, Giulia Sciandrone, Ilenia Lupinu, Roberta Ibba, Sandra Piras, Antonio Carta, Gabriele Murineddu International Journal of Molecular Sciences, 2025 A series of N-acylhydrazones bearing a 1,4-dihydroindeno[1,2-b]pyrrole ring, along with benzene and thiophene rings substituted with chlorine or methyl groups, was synthesized and evaluated for their antiproliferative and cytotoxic activity against the melanoma A375 cell line and to measure the inhibition of tubulin polymerization. Four compounds elicited interesting activity: derivatives, 1g and 1h showed a 25% slowdown of tubulin polymerization, whereas compounds 2c and 2d caused a slowdown of 40% and 60%, respectively. Molecular modelling results have confirmed that the most active N-acylhydrazones (1g, 1h, 2c, and 2d) may act as tubulin polymerization inhibitors.
A Pyrido-Quinoxaline Derivative That Downregulates Reticulon 3 Protein Exhibits Potent Antiviral Activity Against Zika Virus Erika Plicanti, Andrea Deiana, Silvia Nottoli, Giulia Lottini, Roberta Ibba, Sandra Piras, Carlo Di Marzo, Silvia Vegni, Michele Lai, Mauro Pistello, Antonio Carta, Giulia Freer Journal of Medical Virology, 2025 In the wake of the COVID‐19 pandemic, awareness of emerging pathogens has significantly increased, prompting greater investment in research and preparedness. In this context, arboviral diseases are recognized as unmet medical challenges due to their rapid spread. Notably, the geographical range of several flaviviral diseases is expanding: Zika virus (ZIKV), a member of the Flaviviridae family, has recently been linked to outbreaks associated with a rise in microcephaly cases in tropical regions. To contribute to the development of novel antiviral therapies, evaluation of a set of compounds with an antiviral activity against ZIKV was carried out. These compounds were originally identified as inhibitors of bovine viral diarrhea virus, another member of the Flaviviridae family. Two related compounds turned out to be active against ZIKV. One emerged as a particularly strong antiviral candidate, demonstrating high efficacy in inhibiting ZIKV replication, and became the focus of this study. Its activity was tested against a number of viruses of human health relevance and the compound was found to be effective against a number of viruses that use the endoplasmic reticulum as a replication hub. Indeed, we found that the Reticulon 3 protein is potently downregulated in the presence of the compound, whereas other endoplasmic reticulum‐resident proteins are not affected. Because Reticulon 3 has a role in the replication of positive‐sense single‐stranded RNA viruses, an indirect antiviral effect of the compound studied was hypothesized. This compound may be considered as a promising lead for further studies aimed at the development of broad‐spectrum antiviral drugs.
Novel Oxadiazole-Quinoxalines as Hybrid Scaffolds with Antitumor Activity Paola Corona, Stefania Gessi, Roberta Ibba, Stefania Merighi, Prisco Mirandola, Gérard Aimè Pinna, Manuela Nigro, Giulia Pozzi, Battistina Asproni, Alessia Travagli, Sandra Piras, Antonio Carta, Paola Caria, Gabriele Murineddu International Journal of Molecular Sciences, 2025 A small library of 25 novel 1,3,4-oxadiazole-quinoxalines was synthesized and evaluated in vitro for its cytotoxic activity at 10 μM concentration against nine NCI-different cancer cell lines. Among tested compounds, derivatives 24, 25, and 26 showed good inhibition percentages over different cell lines and, therefore, progressed to the full five-dose assay. Compound 24, possessing a 1,3,4-oxadiazole-core, bearing a 7-trifluoromethyl-quinoxaline nucleus on C-2 and a C-5 phenyl ring, had activity against leukemia, CNS, ovarian, renal, prostate, and breast cancer, with highest the values against breast MCF7 (GI50: 1.85 μM) and MDA-MB-468 (GI50: 1.95 μM) cell lines, showing the better MG_MID value (−5.02). These novel derivatives were able to delay the S phase of the cell cycle and induce apoptosis.
Synthesis and biological investigation of peptidomimetic SARS-CoV-2 main protease inhibitors bearing quinoline-based heterocycles at P3 Sara Rossi, Graziano Deidda, Lia Fiaschi, Roberta Ibba, Mariachiara Pieroni, Maria Dichiara, Gabriele Carullo, Stefania Butini, Anna Ramunno, Simone Brogi, Marco Lolicato, Cristina Arrigoni, Noemi Cabella, Laura Bavagnoli, Giovanni Maga, Ilenia Varasi, Camilla Biba, Ilaria Vicenti, Sandra Gemma, Emmanuele Crespan, Maurizio Zazzi, Giuseppe Campiani Archiv Der Pharmazie, 2025 In the last few years, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has been the cause of a worldwide pandemic, highlighting the need for novel antiviral agents. The main protease (Mpro) of SARS‐CoV‐2 was immediately identified as a crucial enzyme for viral replication and has been validated as a drug target. Here, we present the design and synthesis of peptidomimetic Mpro covalent inhibitors characterized by quinoline‐based P3 moieties. Structure–activity relationships (SARs) were also investigated at P1 and P2, as well as for different warheads. The binding modes of the designed inhibitors were assessed using X‐ray crystallographic and molecular docking studies. The identified Mpro inhibitors were tested for their antiviral activities in cell‐based assays, and the results were encouraging. The SAR studies presented here can contribute to the future design of improved inhibitors by addressing some of the current or prospective issues regarding Mpro inhibitors currently used in therapy.
Discovery of pyridoquinoxaline-based new P-gp inhibitors as coadjutant against Multi Drug Resistance in cancer Roberta Ibba, Simona Sestito, Francesca Alessandra Ambrosio, Emanuela Marchese, Giosuè Costa, Francesco Paolo Fiorentino, Fabio Fusi, Irene Marchesi, Beatrice Polini, Grazia Chiellini, Stefano Alcaro, Sandra Piras, Antonio Carta European Journal of Medicinal Chemistry, 2024 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 CaV1.2 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.
Anticancer potential of decursin, decursinol angelate, and decursinol from Angelica gigas Nakai: A comprehensive review and future therapeutic prospects Simona Sestito, Roberta Ibba, Federico Riu, Sara Carpi, Antonio Carta, Clementina Manera, Solomon Habtemariam, Balakyz Yeskaliyeva, Zainab M. Almarhoon, Javad Sharifi‐Rad, Simona Rapposelli Food Science and Nutrition, 2024 Many naturally derived compounds are currently used in oncotherapy. Besides official medicine, complementary and alternative medicine practices, including old herbal remedies, are widely used and accepted as additional tools in cancer treatment. Angelica gigas Nakai (AGN), a medicinal herb in Asia, has roots historically used in medicine. This review focuses on key bioactive compounds from AGN roots – decursin, decursinol angelate (DA), and decursinol (DOH). Exploring their source, biosynthesis, and therapeutic mechanisms, the review highlights their role in cancer treatment. Biotechnological strategies for enhanced production and semisynthetic derivatives with anticancer properties are discussed. The study emphasizes the promising pharmacological potential of decursin, DA, and DOH in various therapeutic applications, particularly cancer treatment. The review also underscores innovative approaches to increase production and explores semisynthetic derivatives as a promising avenue for future natural product‐based drug discovery. This concise overview provides valuable insights into the potential of AGN‐derived compounds in the field of natural product‐based therapeutics.
A quinolin-8-ol sub-millimolar inhibitor of UGGT, the ER glycoprotein folding quality control checkpoint Kevin P. Guay, Roberta Ibba, J.L. Kiappes, Snežana Vasiljević, Francesco Bonì, Maria De Benedictis, Ilaria Zeni, James D. Le Cornu, Mario Hensen, Anu V. Chandran, Anastassia L. Kantsadi, Alessandro T. Caputo, Juan I. Blanco Capurro, Yusupha Bayo, Johan C. Hill, Kieran Hudson, Andrea Lia, Juliane Brun, Stephen G. Withers, Marcelo Martí, Emiliano Biasini, Angelo Santino, Matteo De Rosa, Mario Milani, Carlos P. Modenutti, Daniel N. Hebert, Nicole Zitzmann, Pietro Roversi Iscience, 2023 Misfolded glycoprotein recognition and endoplasmic reticulum (ER) retention are mediated by the ER glycoprotein folding quality control (ERQC) checkpoint enzyme, UDP-glucose glycoprotein glucosyltransferase (UGGT). UGGT modulation is a promising strategy for broad-spectrum antivirals, rescue-of-secretion therapy in rare disease caused by responsive mutations in glycoprotein genes, and many cancers, but to date no selective UGGT inhibitors are known. The small molecule 5-[(morpholin-4-yl)methyl]quinolin-8-ol (5M-8OH-Q) binds a Ct UGGT GT24 "WY" conserved surface motif conserved across UGGTs but not present in other GT24 family glycosyltransferases. 5M-8OH-Q has a 47 μM binding affinity for Ct UGGT GT24 in vitro as measured by ligand-enhanced fluorescence. In cellula , 5M-8OH-Q inhibits both human UGGT isoforms at concentrations higher than 750 μM. 5M-8OH-Q binding to Ct UGGT GT24 appears to be mutually exclusive to M5-9 glycan binding in an in vitro competition experiment. A medicinal program based on 5M-8OH-Q will yield the next generation of UGGT inhibitors.
Design, Synthesis, and Antiviral Activities of New Benzotriazole-Based Derivatives Roberta Ibba, Paola Corona, Francesca Nonne, Paola Caria, Gabriele Serreli, Vanessa Palmas, Federico Riu, Simona Sestito, Maria Nieddu, Roberta Loddo, Giuseppina Sanna, Sandra Piras, Antonio Carta Pharmaceuticals, 2023 Several human diseases are caused by enteroviruses and are currently clinically untreatable, pushing the research to identify new antivirals. A notable number of benzo[d][1,2,3]triazol-1(2)-yl derivatives were designed, synthesized, and in vitro evaluated for cytotoxicity and antiviral activity against a wide spectrum of RNA positive- and negative-sense viruses. Five of them (11b, 18e, 41a, 43a, 99b) emerged for their selective antiviral activity against Coxsackievirus B5, a human enteroviruses member among the Picornaviridae family. The EC50 values ranged between 6 and 18.5 μM. Among all derivatives, compounds 18e and 43a were interestingly active against CVB5 and were selected to better define the safety profile on cell monolayers by transepithelial resistance test (TEER). Results indicated compound 18e as the hit compound to investigate the potential mechanism of action by apoptosis assay, virucidal activity test, and the time of addition assay. CVB5 is known to be cytotoxic by inducing apoptosis in infected cells; in this study, compound 18e was proved to protect cells from viral infection. Notably, cells were mostly protected when pre-treated with derivative 18e, which had, however, no virucidal activity. From the performed biological assays, compound 18e turned out to be non-cytotoxic as well as cell protective against CVB5 infection, with a mechanism of action ascribable to an interaction on the early phase of infection, by hijacking the viral attachment process.
Crystal polymorphism in fragment-based lead discovery of ligands of the catalytic domain of UGGT, the glycoprotein folding quality control checkpoint Alessandro T. Caputo, Roberta Ibba, James D. Le Cornu, Benoit Darlot, Mario Hensen, Colette B. Lipp, Gabriele Marcianò, Snežana Vasiljević, Nicole Zitzmann, Pietro Roversi Frontiers in Molecular Biosciences, 2022 None of the current data processing pipelines for X-ray crystallography fragment-based lead discovery (FBLD) consults all the information available when deciding on the lattice and symmetry (i.e., the polymorph) of each soaked crystal. Often, X-ray crystallography FBLD pipelines either choose the polymorph based on cell volume and point-group symmetry of the X-ray diffraction data or leave polymorph attribution to manual intervention on the part of the user. Thus, when the FBLD crystals belong to more than one crystal polymorph, the discovery pipeline can be plagued by space group ambiguity, especially if the polymorphs at hand are variations of the same lattice and, therefore, difficult to tell apart from their morphology and/or their apparent crystal lattices and point groups. In the course of a fragment-based lead discovery effort aimed at finding ligands of the catalytic domain of UDP–glucose glycoprotein glucosyltransferase (UGGT), we encountered a mixture of trigonal crystals and pseudotrigonal triclinic crystals—with the two lattices closely related. In order to resolve that polymorphism ambiguity, we have written and described here a series of Unix shell scripts called CoALLA (crystal polymorph and ligand likelihood-based assignment). The CoALLA scripts are written in Unix shell and use autoPROC for data processing, CCP4-Dimple/REFMAC5 and BUSTER for refinement, and RHOFIT for ligand docking. The choice of the polymorph is effected by carrying out (in each of the known polymorphs) the tasks of diffraction data indexing, integration, scaling, and structural refinement. The most likely polymorph is then chosen as the one with the best structure refinement Rfree statistic. The CoALLA scripts further implement a likelihood-based ligand assignment strategy, starting with macromolecular refinement and automated water addition, followed by removal of the water molecules that appear to be fitting ligand density, and a final round of refinement after random perturbation of the refined macromolecular model, in order to obtain unbiased difference density maps for automated ligand placement. We illustrate the use of CoALLA to discriminate between H3 and P1 crystals used for an FBLD effort to find fragments binding to the catalytic domain of Chaetomium thermophilum UGGT.
