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Microtubules (MTs) are the principal target for drugs acting against mitosis. These compounds, called microtubule targeting agents (MTAs), cause a mitotic arrest during G2/M phase, subsequently inducing cell apoptosis. MTAs could be classified in two groups: microtubule stabilising agents (MSAs) and microtubule destabilising agents (MDAs). In this paper we present a new series of (E)(Z)-2-(5,6-difluoro-(1H)2H-benzo[d][1,2,3]triazol-1(2)-yl)-3-(R)acrylonitrile (9a-j, 10e, 11a,b) and (E)-2-(1H-benzo[d][1,2,3]triazol-1-yl)-3-(R)acrylonitrile derivatives (13d,j), which were recognised to act as MTAs agents. They were rationally designed, synthesised, characterised and subjected to different biological assessments. Computational docking was carried out in order to investigate the potential binding to the colchicine-binding site on tubulin. From this first prediction, the di-fluoro substitution seemed to be beneficial for the binding affinity with tubulin. The new fluorine derivatives, here presented, showed an improved antiproliferative activity when compared to the previously reported compounds. The biological evaluation included a preliminary antiproliferative screening on NCI60 cancer cells panel (1-10 μM). Compound 9a was selected as lead compound of the new series of derivatives. The in vitro XTT assay, flow cytometry analysis and immunostaining performed on HeLa cells treated with 9a showed a considerable antiproliferative effect, (IC50 = 3.2 μM), an increased number of cells in G2/M-phase, followed by an enhancement in cell division defects. Moreover, β-tubulin staining confirmed 9a as a MDA triggering tubulin disassembly, whereas colchicine-9a competition assay suggested that compound 9a compete with colchicine for the binding site on tubulin. Then, the co-administration of compound 9a and an extrusion pump inhibitor (EPI) was investigated: the association resulted beneficial for the antiproliferative activity and compound 9a showed to be client of extrusion pumps. Finally, structural superimposition of different colchicine binding site inhibitors (CBIs) in clinical trial and our MDA, provided an additional confirmation of the targeting to the predicted binding site. Physicochemical, pharmacokinetic and druglikeness predictions were also conducted and all the newly synthesised derivatives showed to be drug-like molecules.
Federico Riu; Luca Sanna; Roberta Ibba; Sandra Piras; Valentina Bordoni; M. Andrea Scorciapino; Michele Lai; Simona Sestito; Luigi Bagella; Antonio Carta. A comprehensive assessment of a new series of 5′,6′-difluorobenzotriazole-acrylonitrile derivatives as microtubule targeting agents (MTAs). European Journal of Medicinal Chemistry 2021, 222, 113590 .
AMA StyleFederico Riu, Luca Sanna, Roberta Ibba, Sandra Piras, Valentina Bordoni, M. Andrea Scorciapino, Michele Lai, Simona Sestito, Luigi Bagella, Antonio Carta. A comprehensive assessment of a new series of 5′,6′-difluorobenzotriazole-acrylonitrile derivatives as microtubule targeting agents (MTAs). European Journal of Medicinal Chemistry. 2021; 222 ():113590.
Chicago/Turabian StyleFederico Riu; Luca Sanna; Roberta Ibba; Sandra Piras; Valentina Bordoni; M. Andrea Scorciapino; Michele Lai; Simona Sestito; Luigi Bagella; Antonio Carta. 2021. "A comprehensive assessment of a new series of 5′,6′-difluorobenzotriazole-acrylonitrile derivatives as microtubule targeting agents (MTAs)." European Journal of Medicinal Chemistry 222, no. : 113590.
Enterovirus A71 (EV-A71) infection has emerged as a significant public health concern atthe global level. Epidemic events of EV-A71 have been reported worldwide, and this succession of outbreaks has heightened concern that EV-A71 may become a public health threat. In recent years, widespread A71 enterovirus also occurred in European countries. EV-A71 infection causes hand-foot-mouth disease (HFMD), herpangina, and fever. However, it can sometimes induce a variety of neurological complications, including encephalitis, aseptic meningitis, pulmonary edema, and acute flaccid paralysis. We identified new benzimidazole derivatives and described their in vitro cytotoxicity and broad-spectrum anti-enterovirus activity. Among them, derivative 2b resulted in interesting activity against EV-A71, and therefore it was selected for further investigations. Compound 2b proved to be able to protect cell monolayers from EV-A71-induced cytopathogenicity, with an EC50 of 3 µM. Moreover, Vero-76 cells resulted in being significantly protected from necrosis and apoptosis when treated with 2b at 20 and 80 µM. Compound 2b reduced viral adsorption to Vero-76 cells, and when evaluated in a time-of-addition assay, the derivative had the highest effect when added during the infection period. Moreover, derivative 2b reduced viral penetration into host cells. Besides, 2b did not affect intestinal monolayers permeability, showing no toxic effects. A detailed insight into the efficacy of compound 2b against EV-A71 showed a dose-dependent reduction in the viral titer, also at low concentrations. Mechanism of action investigations suggested that our derivative can inhibit viral endocytosis by reducing viral attachment to and penetration into host cells. Pharmacokinetic and toxicity predictions validated compound 2b as a good candidate for further in vivo assays.
Roberta Ibba; Antonio Carta; Silvia Madeddu; Paola Caria; Gabriele Serreli; Sandra Piras; Simona Sestito; Roberta Loddo; Giuseppina Sanna. Inhibition of Enterovirus A71 by a Novel 2-Phenyl-Benzimidazole Derivative. Viruses 2021, 13, 58 .
AMA StyleRoberta Ibba, Antonio Carta, Silvia Madeddu, Paola Caria, Gabriele Serreli, Sandra Piras, Simona Sestito, Roberta Loddo, Giuseppina Sanna. Inhibition of Enterovirus A71 by a Novel 2-Phenyl-Benzimidazole Derivative. Viruses. 2021; 13 (1):58.
Chicago/Turabian StyleRoberta Ibba; Antonio Carta; Silvia Madeddu; Paola Caria; Gabriele Serreli; Sandra Piras; Simona Sestito; Roberta Loddo; Giuseppina Sanna. 2021. "Inhibition of Enterovirus A71 by a Novel 2-Phenyl-Benzimidazole Derivative." Viruses 13, no. 1: 58.
Summary UDP-glucose:glycoprotein glucosyltransferase (UGGT) flags misfolded glycoproteins for ER retention. We report crystal structures of full-length Chaetomium thermophilum UGGT (CtUGGT), two CtUGGT double-cysteine mutants, and its TRXL2 domain truncation (CtUGGT-ΔTRXL2). CtUGGT molecular dynamics (MD) simulations capture extended conformations and reveal clamping, bending, and twisting inter-domain movements. We name "Parodi limit" the maximum distance on the same glycoprotein between a site of misfolding and an N-linked glycan that can be reglucosylated by monomeric UGGT in vitro, in response to recognition of misfold at that site. Based on the MD simulations, we estimate the Parodi limit as around 70–80 Å. Frequency distributions of distances between glycoprotein residues and their closest N-linked glycosylation sites in glycoprotein crystal structures suggests relevance of the Parodi limit to UGGT activity in vivo. Our data support a "one-size-fits-all adjustable spanner" UGGT substrate recognition model, with an essential role for the UGGT TRXL2 domain.
Carlos P. Modenutti; Juan I. Blanco Capurro; Roberta Ibba; Dominic S. Alonzi; Mauro N. Song; Snežana Vasiljević; Abhinav Kumar; Anu V. Chandran; Gabor Tax; Lucia Marti; Johan C. Hill; Andrea Lia; Mario Hensen; Thomas Waksman; Jonathan Rushton; Simone Rubichi; Angelo Santino; Marcelo A. Martí; Nicole Zitzmann; Pietro Roversi. Clamping, bending, and twisting inter-domain motions in the misfold-recognizing portion of UDP-glucose: Glycoprotein glucosyltransferase. Structure 2020, 29, 357 -370.e9.
AMA StyleCarlos P. Modenutti, Juan I. Blanco Capurro, Roberta Ibba, Dominic S. Alonzi, Mauro N. Song, Snežana Vasiljević, Abhinav Kumar, Anu V. Chandran, Gabor Tax, Lucia Marti, Johan C. Hill, Andrea Lia, Mario Hensen, Thomas Waksman, Jonathan Rushton, Simone Rubichi, Angelo Santino, Marcelo A. Martí, Nicole Zitzmann, Pietro Roversi. Clamping, bending, and twisting inter-domain motions in the misfold-recognizing portion of UDP-glucose: Glycoprotein glucosyltransferase. Structure. 2020; 29 (4):357-370.e9.
Chicago/Turabian StyleCarlos P. Modenutti; Juan I. Blanco Capurro; Roberta Ibba; Dominic S. Alonzi; Mauro N. Song; Snežana Vasiljević; Abhinav Kumar; Anu V. Chandran; Gabor Tax; Lucia Marti; Johan C. Hill; Andrea Lia; Mario Hensen; Thomas Waksman; Jonathan Rushton; Simone Rubichi; Angelo Santino; Marcelo A. Martí; Nicole Zitzmann; Pietro Roversi. 2020. "Clamping, bending, and twisting inter-domain motions in the misfold-recognizing portion of UDP-glucose: Glycoprotein glucosyltransferase." Structure 29, no. 4: 357-370.e9.
The role of mycobacterial efflux pumps in drug-resistant tuberculosis has been widely reported. Recently, a new compound, named SS13, has been synthesized, and its activity as a potential efflux inhibitor has been demonstrated. In this work, the chemical–physical properties of the SS13 were investigated; furthermore, a formulative study aimed to develop a formulation suitable for oral administration was performed. SS13 shows nonintrinsic antitubercular activity, but it increases the antitubercular activity of all the tested drugs on several strains. SS13 is insoluble in different simulated gastrointestinal media; thus, its oral absorption could be limited. Solid lipid nanoparticles (SLNs) were, therefore, developed by using two different lipids, Witepsol and/or Gelucire. Nanoparticles, having a particle size (range of 200–450 nm with regards to the formulation composition) suitable for intestinal absorption, are able to load SS13 and to improve its permeation through the intestinal mucosa compared to the pure compound. The cytotoxicity is influenced by the concentration of nanoparticles administered. These promising results support the potential application of these nanocarriers for increasing the oral permeation of SS13 in multidrug-resistant tuberculosis management.
Antonella Obinu; Elena Piera Porcu; Sandra Piras; Roberta Ibba; Antonio Carta; Paola Molicotti; Rossana Migheli; Alessandro Dalpiaz; Luca Ferraro; Giovanna Rassu; Elisabetta Gavini; Paolo Giunchedi. Solid Lipid Nanoparticles as Formulative Strategy to Increase Oral Permeation of a Molecule Active in Multidrug-Resistant Tuberculosis Management. Pharmaceutics 2020, 12, 1132 .
AMA StyleAntonella Obinu, Elena Piera Porcu, Sandra Piras, Roberta Ibba, Antonio Carta, Paola Molicotti, Rossana Migheli, Alessandro Dalpiaz, Luca Ferraro, Giovanna Rassu, Elisabetta Gavini, Paolo Giunchedi. Solid Lipid Nanoparticles as Formulative Strategy to Increase Oral Permeation of a Molecule Active in Multidrug-Resistant Tuberculosis Management. Pharmaceutics. 2020; 12 (12):1132.
Chicago/Turabian StyleAntonella Obinu; Elena Piera Porcu; Sandra Piras; Roberta Ibba; Antonio Carta; Paola Molicotti; Rossana Migheli; Alessandro Dalpiaz; Luca Ferraro; Giovanna Rassu; Elisabetta Gavini; Paolo Giunchedi. 2020. "Solid Lipid Nanoparticles as Formulative Strategy to Increase Oral Permeation of a Molecule Active in Multidrug-Resistant Tuberculosis Management." Pharmaceutics 12, no. 12: 1132.
Background: For the last thirty years, the benzotriazole scaffold has been the object of our group interest and we have already presented some results on the antiviral activity of our compounds. Objective: In this article, we conclude the exploration of N-(4-(R-2H-benzo[d][1,2,3]triazol-2-yl)phenyl)-4-R’-benzamides and 1-(4-(R-2H-benzo[d][1,2,3]triazol-2-yl)phenyl)-3-R’-ureas by synthesizing further modified derivatives, in order to have more elements for SARs evaluation. Methods: Here, we reported the synthesis and the antiviral screening results of 38 newly synthesized benzotriazole derivatives against a panel of DNA and RNA viruses. We also analyse SARs in comparing these compounds with previously published benzotriazole analogues, taking stock of the situation. Results: Among the newly presented derivatives, compounds 17 and 18 were the most active with EC50 6.9 and 5.5 µM, respectively against Coxsackievirus B5 (CV-B5) and 20.5 and 17.5 µM against Poliovirus (Sb-1). Conclusion: we can conclude that N-(4-(2H-benzo[d] [1 - 3] triazol-2-yl)phenyl-R-amide is a good chemical scaffold for the development of new antiviral molecules.
Paola Corona; Sandra Piras; Roberta Ibba; Federico Riu; Gabriele Murineddu; Giuseppina Sanna; Silvia Madeddu; Ilenia Delogu; Roberta Loddo; Antonio Carta. Antiviral Activity of Benzotriazole Based Derivatives. The Open Medicinal Chemistry Journal 2020, 14, 83 -98.
AMA StylePaola Corona, Sandra Piras, Roberta Ibba, Federico Riu, Gabriele Murineddu, Giuseppina Sanna, Silvia Madeddu, Ilenia Delogu, Roberta Loddo, Antonio Carta. Antiviral Activity of Benzotriazole Based Derivatives. The Open Medicinal Chemistry Journal. 2020; 14 (1):83-98.
Chicago/Turabian StylePaola Corona; Sandra Piras; Roberta Ibba; Federico Riu; Gabriele Murineddu; Giuseppina Sanna; Silvia Madeddu; Ilenia Delogu; Roberta Loddo; Antonio Carta. 2020. "Antiviral Activity of Benzotriazole Based Derivatives." The Open Medicinal Chemistry Journal 14, no. 1: 83-98.
Background: Pestivirus genus includes animal pathogens which are involved in economic impact for the livestock industry. Among others, Bovine Viral Diarrhoea Virus (BVDV) establish a persistent infection in cattle causing a long list of symptoms and a high mortality rate. In the last decades, we synthesised and reported a certain number of anti-BVDV compounds. Methods: In them, imidazoquinoline derivatives turned out as the most active. Their mechanism of actions has been deeply investigated, BVDV RNA-dependent RNA polymerase (RpRd) resulted as target and the way of binding was predicted in silico through three main H-bond interaction with the target. The prediction could be confirmed by target or ligand mutation. The first approach has already been performed and published confirming the in silico prediction. Results: Here, we present how the ligand chemical modification affects the anti-BVDV activity. The designed compounds were synthesised and tested against BVDV as in silico assay negative control. Conclusion: The antiviral results confirmed the predicted mechanism of action, as the newly synthesised compounds resulted not active in the in vitro BVDV infection inhibition.
Roberta Ibba; Sandra Piras; Ilenia Delogu; Roberta Loddo; Antonio Carta. Anti-BVDV Activity Evaluation of Naphthoimidazole Derivatives Compared with Parental Imidazoquinoline Compounds. The Open Medicinal Chemistry Journal 2020, 14, 65 -70.
AMA StyleRoberta Ibba, Sandra Piras, Ilenia Delogu, Roberta Loddo, Antonio Carta. Anti-BVDV Activity Evaluation of Naphthoimidazole Derivatives Compared with Parental Imidazoquinoline Compounds. The Open Medicinal Chemistry Journal. 2020; 14 (1):65-70.
Chicago/Turabian StyleRoberta Ibba; Sandra Piras; Ilenia Delogu; Roberta Loddo; Antonio Carta. 2020. "Anti-BVDV Activity Evaluation of Naphthoimidazole Derivatives Compared with Parental Imidazoquinoline Compounds." The Open Medicinal Chemistry Journal 14, no. 1: 65-70.
Background: Coxsackievirus infections are associated with cases of aseptic meningitis, encephalitis, myocarditis, and some chronic disease. Methods: A series of benzo[d][1,2,3]triazol-1(2)-yl derivatives (here named benzotriazol-1(2)-yl) (4a-i, 5a-h, 6a-e, g, i, j and 7a-f, h-j) were designed, synthesized and in vitro evaluated for cytotoxicity and antiviral activity against two important human enteroviruses (HEVs) members of the Picornaviridae family [Coxsackievirus B 5 (CVB-5) and Poliovirus 1 (Sb-1)]. Results: Compounds 4c (CC50 >100 μM; EC50 = 9 μM), 5g (CC50 >100 μM; EC50 = 8 μM), and 6a (CC50 >100 μM; EC50 = 10 μM) were found active against CVB-5. With the aim of evaluating the selectivity of action of this class of compounds, a wide spectrum of RNA (positive- and negativesense), double-stranded (dsRNA) or DNA viruses were also assayed. For none of them, significant antiviral activity was determined. Conclusion: These results point towards a selective activity against CVB-5, an important human pathogen that causes both acute and chronic diseases in infants, young children, and immunocompromised patients.
Sandra Piras; Paola Corona; Roberta Ibba; Federico Riu; Gabriele Murineddu; Giuseppina Sanna; Silvia Madeddu; Ilenia Delogu; Roberta Loddo; Antonio Carta. Preliminary Anti-Coxsackie Activity of Novel 1-[4-(5,6-dimethyl(H)- 1H(2H)-benzotriazol-1(2)-yl)phenyl]-3-alkyl(aryl)ureas. Medicinal Chemistry 2020, 16, 677 -688.
AMA StyleSandra Piras, Paola Corona, Roberta Ibba, Federico Riu, Gabriele Murineddu, Giuseppina Sanna, Silvia Madeddu, Ilenia Delogu, Roberta Loddo, Antonio Carta. Preliminary Anti-Coxsackie Activity of Novel 1-[4-(5,6-dimethyl(H)- 1H(2H)-benzotriazol-1(2)-yl)phenyl]-3-alkyl(aryl)ureas. Medicinal Chemistry. 2020; 16 (5):677-688.
Chicago/Turabian StyleSandra Piras; Paola Corona; Roberta Ibba; Federico Riu; Gabriele Murineddu; Giuseppina Sanna; Silvia Madeddu; Ilenia Delogu; Roberta Loddo; Antonio Carta. 2020. "Preliminary Anti-Coxsackie Activity of Novel 1-[4-(5,6-dimethyl(H)- 1H(2H)-benzotriazol-1(2)-yl)phenyl]-3-alkyl(aryl)ureas." Medicinal Chemistry 16, no. 5: 677-688.
Orthohantaviruses, previously known as hantaviruses (family Hantaviridae, order Bunyavirales), are emerging zoonoses hosted by different rodent and insectivore species. Orthohantaviruses are transmitted by aerosolized excreta (urine, saliva and feces) of their reservoir hosts. When transmitted to humans, they cause hemorrhagic fever with renal syndrome (HFRS) in Asia and Europe and hantavirus (cardio) pulmonary syndrome (HPS) in the Americas. Clinical studies have shown that early treatments of HFRS patients with ribavirin (RBV) improve prognosis. Nevertheless, there is the need for urgent development of specific antiviral drugs. In the search for new RNA virus inhibitors, we recently identified a series of variously substituted 5,6-dichloro-1(2)-phenyl-1(2)H-benzo[d][1,2,3]triazole derivatives active against the human respiratory syncytial virus (HRSV). Interestingly, several 2-phenyl-benzotriazoles resulted in fairly potent inhibitors of the Hantaan virus in a chemiluminescence focus reduction assay (C-FRA) showing an EC50 = 4–5 µM, ten-fold more active than ribavirin. Currently, there are no FDA approved drugs for the treatment of orthohantavirus infections. Antiviral activities and cytotoxicity profiles suggest that 5,6-dichloro-1(2)-phenyl-1(2)H-benzo[d][1,2,3]triazoles could be promising candidates for further investigation as a potential treatment of hantaviral diseases.
Giuseppina Sanna; Sandra Piras; Silvia Madeddu; Bernardetta Busonera; Boris Klempa; Paola Corona; Roberta Ibba; Gabriele Murineddu; Antonio Carta; Roberta Loddo. 5,6-Dichloro-2-Phenyl-Benzotriazoles: New Potent Inhibitors of Orthohantavirus. Viruses 2020, 12, 122 .
AMA StyleGiuseppina Sanna, Sandra Piras, Silvia Madeddu, Bernardetta Busonera, Boris Klempa, Paola Corona, Roberta Ibba, Gabriele Murineddu, Antonio Carta, Roberta Loddo. 5,6-Dichloro-2-Phenyl-Benzotriazoles: New Potent Inhibitors of Orthohantavirus. Viruses. 2020; 12 (1):122.
Chicago/Turabian StyleGiuseppina Sanna; Sandra Piras; Silvia Madeddu; Bernardetta Busonera; Boris Klempa; Paola Corona; Roberta Ibba; Gabriele Murineddu; Antonio Carta; Roberta Loddo. 2020. "5,6-Dichloro-2-Phenyl-Benzotriazoles: New Potent Inhibitors of Orthohantavirus." Viruses 12, no. 1: 122.
SummaryUDP-glucose:glycoprotein glucosyltransferase (UGGT) is the only known glycoprotein folding quality control checkpoint in the eukaryotic glycoprotein secretory pathway. When the enzyme detects a misfolded glycoprotein in the Endoplasmic Reticulum (ER), it dispatches it for ER retention by re-glucosylating it on one of its N-linked glycans. Recent crystal structures of a fungal UGGT have suggested the enzyme is conformationally mobile. Here, a negative stain electron microscopy reconstruction of UGGT in complex with a monoclonal antibody confirms that the misfold-sensing N-terminal portion of UGGT and its C-terminal catalytic domain are tightly associated. Molecular Dynamics (MD) simulations capture UGGT in so far unobserved conformational states, giving new insights into the molecule’s flexibility. Principal component analysis of the MD trajectories affords a description of UGGT’s overall inter-domain motions, highlighting three types of inter-domain movements: bending, twisting and clamping. These inter-domain motions modify the accessible surface area of the enzyme’s central saddle, likely enabling the protein to recognize and re-glucosylate substrates of different sizes and shapes, and/or re-glucosylate N-linked glycans situated at variable distances from the site of misfold. We propose to name “Parodi limit” the maximum distance between a site of misfolding on a UGGT glycoprotein substrate and an N-linked glycan that monomeric UGGT can re-glucosylate on the same glycoprotein. MD simulations estimate the Parodi limit to be around 60-70 Å. Re-glucosylation assays using UGGT deletion mutants suggest that the TRXL2 domain is necessary for activity against urea-misfolded bovine thyroglobulin. Taken together, our findings support a “one-size-fits-all adjustable spanner” substrate recognition model, with a crucial role for the TRXL2 domain in the recruitment of misfolded substrates to the enzyme’s active site.
Carlos P. Modenutti; Juan I. Blanco Capurro; Roberta Ibba; Snežana Vasiljević; Mario Hensen; Dominic S. Alonzi; Anu V. Chandran; Johan C. Hill; Jonathan Rushton; Abhinav Kumar; Simone Rubichi; Andrea Lia; Gábor Tax; Lucia Marti; Angelo Santino; Marcelo A. Martí; Nicole Zitzmann; Pietro Roversi. Clamping, bending, and twisting inter-domain motions in the misfold-recognising portion of UDP-glucose:glycoprotein glucosyl-transferase. 2019, 1 .
AMA StyleCarlos P. Modenutti, Juan I. Blanco Capurro, Roberta Ibba, Snežana Vasiljević, Mario Hensen, Dominic S. Alonzi, Anu V. Chandran, Johan C. Hill, Jonathan Rushton, Abhinav Kumar, Simone Rubichi, Andrea Lia, Gábor Tax, Lucia Marti, Angelo Santino, Marcelo A. Martí, Nicole Zitzmann, Pietro Roversi. Clamping, bending, and twisting inter-domain motions in the misfold-recognising portion of UDP-glucose:glycoprotein glucosyl-transferase. . 2019; ():1.
Chicago/Turabian StyleCarlos P. Modenutti; Juan I. Blanco Capurro; Roberta Ibba; Snežana Vasiljević; Mario Hensen; Dominic S. Alonzi; Anu V. Chandran; Johan C. Hill; Jonathan Rushton; Abhinav Kumar; Simone Rubichi; Andrea Lia; Gábor Tax; Lucia Marti; Angelo Santino; Marcelo A. Martí; Nicole Zitzmann; Pietro Roversi. 2019. "Clamping, bending, and twisting inter-domain motions in the misfold-recognising portion of UDP-glucose:glycoprotein glucosyl-transferase." , no. : 1.
Human Respiratory Syncytial Virus (RSV) is the primary cause of bronchopneumonia in infants and children worldwide. Clinical studies have shown that early treatments of RSV patients with ribavirin improve prognosis, even if the use of this drug is limited due to myelosuppression and toxicity effects. Furthermore, effective vaccines to prevent RSV infection are currently unavailable. Thus, the development of highly effective and specific antiviral drugs for pre-exposure prophylaxis and/or treatment of RSV infections is a compelling need. In the quest of new RSV inhibitors, in this work we evaluated the antiviral activity of a series of variously substituted 5,6-dichloro-1-phenyl-1(2)H-benzo[d][1,2,3]triazole derivatives in cell-based assays. Several 1- and 2-phenyl-benzotriazoles resulted fairly potent (μM concentrations) inhibitors of RSV infection in plaque reduction assays, accompanied by low cytotoxicity in human highly dividing T lymphoid-derived cells and primary cell lines. Contextually, no inhibitory effects were observed against other RNA or DNA viruses assayed, suggesting specific activity against RSV. Further results revealed that the lead compound 10d was active during the early phase of the RSV infection cycle. To understand whether 10d interfered with virus attachment to target cells or virus-cell fusion events, inhibitory activity tests against the RSV mutant strain B1 cp-52—expressing only the F envelope glycoprotein—and a plasmid-based reporter assay that quantifies the bioactivity of viral entry were also performed. The overall biological results, in conjunction with in silico modeling studies, supported the conclusion that the RSV fusion process could be the target of this new series of compounds.
Sandra Piras; Giuseppina Sanna; Antonio Carta; Paola Corona; Roberta Ibba; Roberta Loddo; Silvia Madeddu; Paola Caria; Suzana Aulic; Erik Laurini; Maurizio Fermeglia; Sabrina Pricl. Dichloro-Phenyl-Benzotriazoles: A New Selective Class of Human Respiratory Syncytial Virus Entry Inhibitors. Frontiers in Chemistry 2019, 7, 247 .
AMA StyleSandra Piras, Giuseppina Sanna, Antonio Carta, Paola Corona, Roberta Ibba, Roberta Loddo, Silvia Madeddu, Paola Caria, Suzana Aulic, Erik Laurini, Maurizio Fermeglia, Sabrina Pricl. Dichloro-Phenyl-Benzotriazoles: A New Selective Class of Human Respiratory Syncytial Virus Entry Inhibitors. Frontiers in Chemistry. 2019; 7 ():247.
Chicago/Turabian StyleSandra Piras; Giuseppina Sanna; Antonio Carta; Paola Corona; Roberta Ibba; Roberta Loddo; Silvia Madeddu; Paola Caria; Suzana Aulic; Erik Laurini; Maurizio Fermeglia; Sabrina Pricl. 2019. "Dichloro-Phenyl-Benzotriazoles: A New Selective Class of Human Respiratory Syncytial Virus Entry Inhibitors." Frontiers in Chemistry 7, no. : 247.
Introduction: with the continuous emergence of pathogenic resistance to conventional drugs through efflux pumps, increasing efforts are directed toward discovering efflux inhibitory molecules. Methodology: in this study three P-glycoprotein (P13CP, P22CP, P34CP) efflux-inhibitors (EIs), belonging to the series of phenoxymethylquinoxalines capable to restore/potentiate the antiproliferative activity of doxorubicin and vincristine against human tumor cell lines and different antibiotics against clinical isolates, were investigated on 10 clinical strains of Candida and 12 clinical and ATCC strains of Gram positive and Gram-negative bacteria. Results: MFC values of FLC were reduced in all Candida strains by the P22CP and P34CP inhibitors, and in 5/10 fungal strains by the P13CP inhibitor. Conclusion: novel antibiotics with new modes of action are urgently required to suppress the rise of MDR bacteria. An alternative approach would be to identify molecules that can interfere with the process of efflux.
Donatella Usai; Matthew Donadu; Alessandra Bua; Paola Molicotti; Stefania Zanetti; Sandra Piras; Paola Corona; Roberta Ibba; Antonio Carta. Enhancement of antimicrobial activity of pump inhibitors associating drugs. The Journal of Infection in Developing Countries 2019, 13, 162 -164.
AMA StyleDonatella Usai, Matthew Donadu, Alessandra Bua, Paola Molicotti, Stefania Zanetti, Sandra Piras, Paola Corona, Roberta Ibba, Antonio Carta. Enhancement of antimicrobial activity of pump inhibitors associating drugs. The Journal of Infection in Developing Countries. 2019; 13 (2):162-164.
Chicago/Turabian StyleDonatella Usai; Matthew Donadu; Alessandra Bua; Paola Molicotti; Stefania Zanetti; Sandra Piras; Paola Corona; Roberta Ibba; Antonio Carta. 2019. "Enhancement of antimicrobial activity of pump inhibitors associating drugs." The Journal of Infection in Developing Countries 13, no. 2: 162-164.
In this study, we designed and synthesized a series of new 5-chlorobenzotriazole derivatives. Compounds were tested for cytotoxicity and antiviral activity in cell-based assays against several positive single-stranded RNA viruses: BVDV, YFV, CVB-5, and Sb-1; two negative single-stranded RNA viruses: RSV and VSV; a double-stranded RNA virus (Reo-1); and two DNA viruses: VV and HSV-1. N-[4-(5-Chloro-2H-benzo[d][1,2,3]triazol-2-yl)phenyl]-3,4,5-trimethoxybenzamide turned out to be the most potent compound against bovine viral diarrhea virus (BVDV). Its activity was shown to be comparable to the activity of the reference drug NM 107 (EC50 3.0 vs. 1.7 μM). It is going to be used as a lead compound for future antiviral drug developments.
Roberta Ibba; Paola Corona; Antonio Carta; Paolo Giunchedi; Roberta Loddo; Giuseppina Sanna; Ilenia Delogu; Sandra Piras. Antiviral activities of 5-chlorobenzotriazole derivatives. Monatshefte für Chemie - Chemical Monthly 2018, 149, 1247 -1256.
AMA StyleRoberta Ibba, Paola Corona, Antonio Carta, Paolo Giunchedi, Roberta Loddo, Giuseppina Sanna, Ilenia Delogu, Sandra Piras. Antiviral activities of 5-chlorobenzotriazole derivatives. Monatshefte für Chemie - Chemical Monthly. 2018; 149 (7):1247-1256.
Chicago/Turabian StyleRoberta Ibba; Paola Corona; Antonio Carta; Paolo Giunchedi; Roberta Loddo; Giuseppina Sanna; Ilenia Delogu; Sandra Piras. 2018. "Antiviral activities of 5-chlorobenzotriazole derivatives." Monatshefte für Chemie - Chemical Monthly 149, no. 7: 1247-1256.
In this work, we present and discuss a comprehensive set of both newly and previously synthesized compounds belonging to 5 distinct molecular classes of linear aromatic N-polycyclic systems that efficiently inhibits bovine viral diarrhea virus (BVDV) infection. A coupled in silico/in vitro investigation was employed to formulate a molecular rationale explaining the notable affinity of all molecules to BVDV RNA dependent RNA polymerase (RdRp) NS5B. We initially developed a three-dimensional common-feature pharmacophore model according to which two hydrogen bond acceptors and one hydrophobic aromatic feature are shared by all molecular series in binding the viral polymerase. The pharmacophoric information was used to retrieve a putative binding site on the surface of the BVDV RdRp and to guide compound docking within the protein binding site. The affinity of all compounds towards the enzyme was scored via molecular dynamics-based simulations, showing high correlation with in vitro EC50 data. The determination of the interaction spectra of the protein residues involved in inhibitor binding highlighted amino acids R295 and Y674 as the two fundamental H-bond donors, while two hydrophobic cavities HC1 (residues A221, I261, I287, and Y289) and HC2 (residues V216, Y303, V306, K307, P408, and A412) fulfill the third pharmacophoric requirement. Three RdRp (K263, R295 and Y674) residues critical for drug binding were selected and mutagenized, both in silico and in vitro, into alanine, and the affinity of a set of selected compounds towards the mutant RdRp isoforms was determined accordingly. The agreement between predicted and experimental data confirmed the proposed common molecular rationale shared by molecules characterized by different chemical scaffolds in binding to the BVDV RdRp, ultimately yielding compound 6b (EC50 = 0.3 μM; IC50 = 0.48 μM) as a new, potent inhibitor of this Pestivirus.
A. Carta; I. Briguglio; S. Piras; P. Corona; R. Ibba; E. Laurini; M. Fermeglia; S. Pricl; N. Desideri; E.M. Atzori; P. La Colla; G. Collu; I. Delogu; R. Loddo. A combined in silico / in vitro approach unveils common molecular requirements for efficient BVDV RdRp binding of linear aromatic N-polycyclic systems. European Journal of Medicinal Chemistry 2016, 117, 321 -334.
AMA StyleA. Carta, I. Briguglio, S. Piras, P. Corona, R. Ibba, E. Laurini, M. Fermeglia, S. Pricl, N. Desideri, E.M. Atzori, P. La Colla, G. Collu, I. Delogu, R. Loddo. A combined in silico / in vitro approach unveils common molecular requirements for efficient BVDV RdRp binding of linear aromatic N-polycyclic systems. European Journal of Medicinal Chemistry. 2016; 117 ():321-334.
Chicago/Turabian StyleA. Carta; I. Briguglio; S. Piras; P. Corona; R. Ibba; E. Laurini; M. Fermeglia; S. Pricl; N. Desideri; E.M. Atzori; P. La Colla; G. Collu; I. Delogu; R. Loddo. 2016. "A combined in silico / in vitro approach unveils common molecular requirements for efficient BVDV RdRp binding of linear aromatic N-polycyclic systems." European Journal of Medicinal Chemistry 117, no. : 321-334.