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Cancer and viral infections continue to threaten humankind causing death worldwide. Hence, the discovery of new anticancer and antiviral agents still represents a major scientific goal. Heterocycles designed to mimic the chemical structure of natural pyrimidines and purines have been designed over the years, exerting their activity acting as false substrates on several different targets. We reported a series of bis-benzotriazole-dicarboxamide derivatives which inhibit viral helicase of poliovirus, and hence we planned structure modifications to obtain different series of new dicarboxamides. Here, the synthesis and characterization of 56 new compounds: 31 bis-benzotriazole dicarboxamides and 25 mono-substituted acidic derivatives are reported. The synthesized compounds were tested for their antiviral and antitumor activity. Mostly, compounds 4a, 4c and 4d showed antiviral activity against tested Picornaviruses, Coxsackievirus B5 and Poliovirus-1. Likewise, four derivatives (3b, 3d, 4d, 9b) showed notable antiproliferative activity inhibiting cell growth in two distinct antitumor screenings. Compound 3b was selected as the antitumor lead compound for the wide range of activity and the potency proved. The lead compound was proved to induce apoptosis in SK-MES1 tumor cells, in a dose-dependent manner.
Roberta Ibba; Sandra Piras; Paola Corona; Federico Riu; Roberta Loddo; Ilenia Delogu; Gabriella Collu; Giuseppina Sanna; Paola Caria; Tinuccia Dettori; Antonio Carta. Synthesis, Antitumor and Antiviral In Vitro Activities of New Benzotriazole-Dicarboxamide Derivatives. Frontiers in Chemistry 2021, 9, 1 .
AMA StyleRoberta Ibba, Sandra Piras, Paola Corona, Federico Riu, Roberta Loddo, Ilenia Delogu, Gabriella Collu, Giuseppina Sanna, Paola Caria, Tinuccia Dettori, Antonio Carta. Synthesis, Antitumor and Antiviral In Vitro Activities of New Benzotriazole-Dicarboxamide Derivatives. Frontiers in Chemistry. 2021; 9 ():1.
Chicago/Turabian StyleRoberta Ibba; Sandra Piras; Paola Corona; Federico Riu; Roberta Loddo; Ilenia Delogu; Gabriella Collu; Giuseppina Sanna; Paola Caria; Tinuccia Dettori; Antonio Carta. 2021. "Synthesis, Antitumor and Antiviral In Vitro Activities of New Benzotriazole-Dicarboxamide Derivatives." Frontiers in Chemistry 9, no. : 1.
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.
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.
The rapid emergence of drug-resistant strains and novel viruses have motivated the search for new anti-infectious agents. In this study, the chemical compositions and cytotoxicity, as well as the antibacterial, antifungal, antitrichomonas, and antiviral activities of essential oils from the leaves, rhizomes, and whole plant of Hornstedtia bella were investigated. The GC/MS analysis showed that β-pinene, E-β-caryophyllene, and α-humulene were found at high concentrations in the essential oils. The essential oils exhibited (i) inhibition against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis with minimum inhibitory concentrations (MIC) and minimum lethal concentration (MLC) values from 1 to 4% (v/v); (ii) MIC and MLC values from 2 to 16% (v/v) in Candida tropicalis and Candida parapsilosis; (iii) MIC and MLC values from 4 to 16% in Enterococcus faecalis; and (iv) MIC and MLC values from 8 to greater than or equal to 16% (v/v) in the remaining strains, including Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Candida albicans, and Candida glabrata. In antitrichomonas activity, the leaves and whole-plant oils of Hornstedtia bella possessed IC50, IC90, and MLC values of 0.008%, 0.016%, and 0.03% (v/v), respectively, whilst those of rhizomes oil had in turn, 0.004%, 0.008%, and 0.016% (v/v).Besides, the leaf oil showed a weak cytotoxicity against Vero 76 and MRC-5; meanwhile, rhizomes and whole-plant oils did not exert any toxic effects on cell monolayers. Finally, these oils were not active against EV-A71.
Matthew Gavino Donadu; Nhan Trong Le; Duc Viet Ho; Tuan Quoc Doan; Anh Tuan Le; Ain Raal; Marianna Usai; Mauro Marchetti; Giuseppina Sanna; Silvia Madeddu; Paola Rappelli; Nicia Diaz; Paola Molicotti; Antonio Carta; Sandra Piras; Donatella Usai; Hoai Thi Nguyen; Piero Cappuccinelli; Stefania Zanetti. Phytochemical Compositions and Biological Activities of Essential Oils from the Leaves, Rhizomes and Whole Plant of Hornstedtia bella Škorničk. Antibiotics 2020, 9, 334 .
AMA StyleMatthew Gavino Donadu, Nhan Trong Le, Duc Viet Ho, Tuan Quoc Doan, Anh Tuan Le, Ain Raal, Marianna Usai, Mauro Marchetti, Giuseppina Sanna, Silvia Madeddu, Paola Rappelli, Nicia Diaz, Paola Molicotti, Antonio Carta, Sandra Piras, Donatella Usai, Hoai Thi Nguyen, Piero Cappuccinelli, Stefania Zanetti. Phytochemical Compositions and Biological Activities of Essential Oils from the Leaves, Rhizomes and Whole Plant of Hornstedtia bella Škorničk. Antibiotics. 2020; 9 (6):334.
Chicago/Turabian StyleMatthew Gavino Donadu; Nhan Trong Le; Duc Viet Ho; Tuan Quoc Doan; Anh Tuan Le; Ain Raal; Marianna Usai; Mauro Marchetti; Giuseppina Sanna; Silvia Madeddu; Paola Rappelli; Nicia Diaz; Paola Molicotti; Antonio Carta; Sandra Piras; Donatella Usai; Hoai Thi Nguyen; Piero Cappuccinelli; Stefania Zanetti. 2020. "Phytochemical Compositions and Biological Activities of Essential Oils from the Leaves, Rhizomes and Whole Plant of Hornstedtia bella Škorničk." Antibiotics 9, no. 6: 334.
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.
In this work, the synthesis of the cannabinoid receptor 1 neutral antagonists 8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-4,5-dihydrobenzo-1H-6-oxa-cyclohepta[1,2-c]pyrazole-3-carboxamide 1a and its deaza N-cyclohexyl analogue 1b has led to a deepening of the structure-activity studies of this class of compounds. A series of novel 4,5-dihydrobenzo-oxa-cycloheptapyrazoles analogues of 1a,b, derivatives 1c-j, was synthesized, and their affinity towards cannabinoid receptors was determined. Representative terms were evaluated using in vitro tests and isolated organ assays. Among the derivatives, 1d and 1e resulted in the most potent CB1 receptor ligands (K i CB1 = 35 nM and 21.70 nM, respectively). Interestingly, both in vitro tests and isolated organ assays evidenced CB1 antagonist activity for the majority of the new compounds, excluding compound 1e, which showed a CB1 partial agonist behaviour. CB1 antagonist activity of 1b was further confirmed by a mouse gastrointestinal transit assay. Significant activity of the new CB1 antagonists towards food intake was showed by preliminary acute assays, evidencing the potentiality of these new derivatives in the treatment of obesity.
Gabriele Murineddu; Battistina Asproni; Paola Corona; Sandra Piras; Paolo Lazzari; Stefania Ruiu; Laura Legnani; Lucio Toma; Gérard A. Pinna. Development of Oxygen-Bridged Pyrazole-Based Structures as Cannabinoid Receptor 1 Ligands. Molecules 2019, 24, 1656 .
AMA StyleGabriele Murineddu, Battistina Asproni, Paola Corona, Sandra Piras, Paolo Lazzari, Stefania Ruiu, Laura Legnani, Lucio Toma, Gérard A. Pinna. Development of Oxygen-Bridged Pyrazole-Based Structures as Cannabinoid Receptor 1 Ligands. Molecules. 2019; 24 (9):1656.
Chicago/Turabian StyleGabriele Murineddu; Battistina Asproni; Paola Corona; Sandra Piras; Paolo Lazzari; Stefania Ruiu; Laura Legnani; Lucio Toma; Gérard A. Pinna. 2019. "Development of Oxygen-Bridged Pyrazole-Based Structures as Cannabinoid Receptor 1 Ligands." Molecules 24, no. 9: 1656.
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.
A series of 2-(1H-indol-3-yl)ethylthiourea derivatives were prepared by condensation of 2-(1H-indol-3-yl)ethanamine with appropriate aryl/alkylisothiocyanates in anhydrous media. The structures of the newly synthesized compounds were confirmed by spectroscopic analysis and the molecular structures of 8 and 28 were confirmed by X-ray crystallography. All obtained compounds were tested for antimicrobial activity against Gram-positive cocci, Gram-negative rods and for antifungal activity. Microbiological evaluation was carried out over 20 standard strains and 30 hospital strains. Compound 6 showed significant inhibition against Gram-positive cocci and had inhibitory effect on the S. aureus topoisomerase IV decatenation activity and S. aureus DNA gyrase supercoiling activity. Compounds were tested for cytotoxicity and antiviral activity against a large panel of DNA and RNA viruses, including HIV-1 and other several important human pathogens. Interestingly, derivative 8 showed potent activity against HIV-1 wild type and variants bearing clinically relevant mutations. Newly synthesized tryptamine derivatives showed also a wide spectrum activity, proving to be active against positive- and negative-sense RNA viruses.
Giuseppina Sanna; Silvia Madeddu; Gabriele Giliberti; Sandra Piras; Marta Struga; Małgorzata Wrzosek; Grażyna Kubiak-Tomaszewska; Anna E. Koziol; Oleksandra Savchenko; Tadeusz Lis; Joanna Stefanska; Piotr Tomaszewski; Michał Skrzycki; Daniel Szulczyk. Synthesis and Biological Evaluation of Novel Indole-Derived Thioureas. Molecules 2018, 23, 2554 .
AMA StyleGiuseppina Sanna, Silvia Madeddu, Gabriele Giliberti, Sandra Piras, Marta Struga, Małgorzata Wrzosek, Grażyna Kubiak-Tomaszewska, Anna E. Koziol, Oleksandra Savchenko, Tadeusz Lis, Joanna Stefanska, Piotr Tomaszewski, Michał Skrzycki, Daniel Szulczyk. Synthesis and Biological Evaluation of Novel Indole-Derived Thioureas. Molecules. 2018; 23 (10):2554.
Chicago/Turabian StyleGiuseppina Sanna; Silvia Madeddu; Gabriele Giliberti; Sandra Piras; Marta Struga; Małgorzata Wrzosek; Grażyna Kubiak-Tomaszewska; Anna E. Koziol; Oleksandra Savchenko; Tadeusz Lis; Joanna Stefanska; Piotr Tomaszewski; Michał Skrzycki; Daniel Szulczyk. 2018. "Synthesis and Biological Evaluation of Novel Indole-Derived Thioureas." Molecules 23, no. 10: 2554.
Giuseppina Sanna; Silvia Madeddu; Gabriele Giliberti; Sandra Piras; Marta Struga; Małgorzata Wrzosek; Grażyna Kubiak-Tomaszewska; Anna E. Koziol; Oleksandra Savchenko; Tadeusz Lis; Joanna Stefanska; Piotr Tomaszewski; Michał Skrzycki; Daniel Szulczyk. Synthesis and Biological Evaluation of Novel Indole-Derived Thioureas. Molecules 2018, 23, 1 .
AMA StyleGiuseppina Sanna, Silvia Madeddu, Gabriele Giliberti, Sandra Piras, Marta Struga, Małgorzata Wrzosek, Grażyna Kubiak-Tomaszewska, Anna E. Koziol, Oleksandra Savchenko, Tadeusz Lis, Joanna Stefanska, Piotr Tomaszewski, Michał Skrzycki, Daniel Szulczyk. Synthesis and Biological Evaluation of Novel Indole-Derived Thioureas. Molecules. 2018; 23 (10):1.
Chicago/Turabian StyleGiuseppina Sanna; Silvia Madeddu; Gabriele Giliberti; Sandra Piras; Marta Struga; Małgorzata Wrzosek; Grażyna Kubiak-Tomaszewska; Anna E. Koziol; Oleksandra Savchenko; Tadeusz Lis; Joanna Stefanska; Piotr Tomaszewski; Michał Skrzycki; Daniel Szulczyk. 2018. "Synthesis and Biological Evaluation of Novel Indole-Derived Thioureas." Molecules 23, no. 10: 1.
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 paper we report the synthesis, in vitro anticancer activity, and the experimental/computational characterization of mechanism of action of a new series of E isomers of triazolo[4,5-b/c]pyridin-acrylonitrile derivatives (6c-g, 7d-e, 8d-e, 9c-f, 10d-e, 11d-e). All new compounds are endowed with moderate to interesting antiproliferative activity against 9 different cancer cell lines derived from solid and hematological human tumors. Fluorescence-based assays prove that these molecules interfere with tubulin polymerization. Furthermore, isothermal titration calorimetry (ITC) provides full tubulin/compound binding thermodynamics, thereby ultimately qualifying and quantifying the interactions of these molecular series with the target protein. Lastly, the analysis based on the tight coupling of in vitro and in silico modeling of the interactions between tubulin and the title compounds allows to propose a molecular rationale for their biological activity.
Irene Briguglio; Erik Laurini; Maria Antonietta Pirisi; Sandra Piras; Paola Corona; Maurizio Fermeglia; Sabrina Pricl; Antonio Carta. Triazolopyridinyl-acrylonitrile derivatives as antimicrotubule agents: Synthesis, in vitro and in silico characterization of antiproliferative activity, inhibition of tubulin polymerization and binding thermodynamics. European Journal of Medicinal Chemistry 2017, 141, 460 -472.
AMA StyleIrene Briguglio, Erik Laurini, Maria Antonietta Pirisi, Sandra Piras, Paola Corona, Maurizio Fermeglia, Sabrina Pricl, Antonio Carta. Triazolopyridinyl-acrylonitrile derivatives as antimicrotubule agents: Synthesis, in vitro and in silico characterization of antiproliferative activity, inhibition of tubulin polymerization and binding thermodynamics. European Journal of Medicinal Chemistry. 2017; 141 ():460-472.
Chicago/Turabian StyleIrene Briguglio; Erik Laurini; Maria Antonietta Pirisi; Sandra Piras; Paola Corona; Maurizio Fermeglia; Sabrina Pricl; Antonio Carta. 2017. "Triazolopyridinyl-acrylonitrile derivatives as antimicrotubule agents: Synthesis, in vitro and in silico characterization of antiproliferative activity, inhibition of tubulin polymerization and binding thermodynamics." European Journal of Medicinal Chemistry 141, no. : 460-472.
Linear aromatic N-tricyclic compounds with promising antiviral activity and minimal cytotoxicity were prepared and analyzed in the last years. Specifically, the pyrido[2,3-g]quinoxalinone nucleus was found endowed with high potency against several pathogenic RNA viruses as etiological agents of important veterinary and human pathologies. Following our research program on new antiviral agents we have designed, synthesized and assayed new series of imidazo[4,5-g]quinoline and pyrido[2,3-g]quinoxalinone derivatives. Lead compounds 1–4 were further modified to enhance their antiviral activity and reduce their cytotoxicity. Thus, different substituents were introduced on N atom at position 1 or the O atom at position 2 of the leads; contextually, several groups were inserted on the nitrogen atom at position 7 of diaminoquinoline intermediates. Title compounds were tested in cell-based assays for cytotoxicity and antiviral activity against RNA virus families containing single-stranded (either positive-sense (ssRNA+) or negative-sense (ssRNA−)), and double-stranded genomes (dsRNA), and against two representatives of DNA virus families. Some derivatives emerged as potential leads for further development as antiviral agents against some viruses of public health significance, such as RSV, Reo, BVDV and HCV. Particularly, compounds 4, 11b, 11c, 13c, 15a, 18 and 21 resulted active against BVDV at concentrations ranging from 1.3 to 5 μM. Compound 21 was also evaluated for its activity on the BVDV RdRp. Compound 4 was also tested as potential anti-HCV compound in a subgenomic replication assay. Molecular simulation results provided a molecular rationale for the anti-BVDV activity of these compounds.
Irene Briguglio; Roberta Loddo; Erik Laurini; Maurizio Fermeglia; Sandra Piras; Paola Corona; Paolo Giunchedi; Elisabetta Gavini; Giuseppina Sanna; Gabriele Giliberti; Cristina Ibba; Pamela Farci; Paolo La Colla; Sabrina Pricl; Antonio Carta. Synthesis, cytotoxicity and antiviral evaluation of new series of imidazo[4,5-g]quinoline and pyrido[2,3-g]quinoxalinone derivatives. European Journal of Medicinal Chemistry 2015, 105, 63 -79.
AMA StyleIrene Briguglio, Roberta Loddo, Erik Laurini, Maurizio Fermeglia, Sandra Piras, Paola Corona, Paolo Giunchedi, Elisabetta Gavini, Giuseppina Sanna, Gabriele Giliberti, Cristina Ibba, Pamela Farci, Paolo La Colla, Sabrina Pricl, Antonio Carta. Synthesis, cytotoxicity and antiviral evaluation of new series of imidazo[4,5-g]quinoline and pyrido[2,3-g]quinoxalinone derivatives. European Journal of Medicinal Chemistry. 2015; 105 ():63-79.
Chicago/Turabian StyleIrene Briguglio; Roberta Loddo; Erik Laurini; Maurizio Fermeglia; Sandra Piras; Paola Corona; Paolo Giunchedi; Elisabetta Gavini; Giuseppina Sanna; Gabriele Giliberti; Cristina Ibba; Pamela Farci; Paolo La Colla; Sabrina Pricl; Antonio Carta. 2015. "Synthesis, cytotoxicity and antiviral evaluation of new series of imidazo[4,5-g]quinoline and pyrido[2,3-g]quinoxalinone derivatives." European Journal of Medicinal Chemistry 105, no. : 63-79.
Based on our previous results on the ascertained potent growth inhibition effect against a panel of 60 human tumors cell lines at National Cancer Institute of Bethesda (NCI), we have synthesized a novel series of thirty-one 2-[N-methyl(R-phenyl)-aminomethyl]-3-phenyl-7-trifluoromethylquinoxalines (1–31). The lead compound 1 was previously reported to be endowed with significant inhibition against hDHFR enzyme, with a Ki of 0.2 μM. Docking studies were performed on compound 1 and here reported to predict its binding conformation to human dihydrofolate reductase (hDHFR). All compounds (1–31) were assayed versus hDHFR and human thymidylate synthase (hTS). From the screening emerged that all compounds inhibited hDHFR with Ki values included between 0.2 and 11 μM, while only a few (6, 21, 24, 27, 29) showed great activity and selectivity towards hTS. Evaluation of the anticancer activity was performed by NCI, first against the three cell line panel, and only the most active compounds (17, 21, 24, 26, 27) were evaluated on a panel of 60 human tumor cell lines. Compound 21 was the most active against all cell lines with log GI50 equal to −5.49 and log LC50 equal to −4.19 and maintained significant percent of growth inhibition on seven cancer cell lines at the concentration of 1 μM. Compound 17 was the second most active and moreover showed interesting selectivity against some cell lines (Lung cancer: A549/ATCC, Melanoma: UACC-257, Ovarian Cancer: ovcar-8 and Renal cancer: RXF 393) at all concentration examined (100–0.01 μM).
Sandra Piras; Antonio Carta; Irene Briguglio; Paola Corona; Giuseppe Paglietti; Rosaria Luciani; Maria Paola Costi; Stefania Ferrari. 2-[N-Alkyl(R-phenyl)-aminomethyl]-3-phenyl-7-trifluoromethylquinoxalines as anticancer agents inhibitors of folate enzymes. European Journal of Medicinal Chemistry 2014, 75, 169 -183.
AMA StyleSandra Piras, Antonio Carta, Irene Briguglio, Paola Corona, Giuseppe Paglietti, Rosaria Luciani, Maria Paola Costi, Stefania Ferrari. 2-[N-Alkyl(R-phenyl)-aminomethyl]-3-phenyl-7-trifluoromethylquinoxalines as anticancer agents inhibitors of folate enzymes. European Journal of Medicinal Chemistry. 2014; 75 ():169-183.
Chicago/Turabian StyleSandra Piras; Antonio Carta; Irene Briguglio; Paola Corona; Giuseppe Paglietti; Rosaria Luciani; Maria Paola Costi; Stefania Ferrari. 2014. "2-[N-Alkyl(R-phenyl)-aminomethyl]-3-phenyl-7-trifluoromethylquinoxalines as anticancer agents inhibitors of folate enzymes." European Journal of Medicinal Chemistry 75, no. : 169-183.
Irene Briguglio; Sandra Piras; Paola Corona; Maria Pirisi; Daniela Jabes; Antonio Carta. SAR and Anti-Mycobacterial Activity of Quinolones and Triazoloquinolones: An Update. Anti-Infective Agents 2012, 11, 75 -89.
AMA StyleIrene Briguglio, Sandra Piras, Paola Corona, Maria Pirisi, Daniela Jabes, Antonio Carta. SAR and Anti-Mycobacterial Activity of Quinolones and Triazoloquinolones: An Update. Anti-Infective Agents. 2012; 11 (1):75-89.
Chicago/Turabian StyleIrene Briguglio; Sandra Piras; Paola Corona; Maria Pirisi; Daniela Jabes; Antonio Carta. 2012. "SAR and Anti-Mycobacterial Activity of Quinolones and Triazoloquinolones: An Update." Anti-Infective Agents 11, no. 1: 75-89.
A number of quinolone derivatives have been reported to possess anti-mycobacterial activity. Generally. Mycobacterium tuberculosis isolates expressing resistance to both isoniazid and rifampin are susceptible to fluoroquinolones. Benzotriazole is a hetero-bicyclic aromatic ring endowed with interesting chemical and biological properties and pharmacological activities. In a preliminary study we have recently reported the activity of triazolo[4,5-h]quinolone-carboxylic acids, a new class of benzotriazole derivatives active against multi-drug resistant M. tuberculosis (MDR-Mtb). In this study we confirm that this novel class of quinolones is endowed with a selective anti-mycobacterial activity, coupled with absence of cytotoxicity. The SAR analysis of the new derivatives in comparison with the previous series shows that the methyl group is the most effective substituent in both N-3 and N-9 positions of the ring system.
Antonio Carta; Michele Palomba; Irene Briguglio; Paola Corona; Sandra Piras; Daniela Jabes; Paola Guglierame; Paola Molicotti; Stefania Zanetti. Synthesis and anti-mycobacterial activities of triazoloquinolones. European Journal of Medicinal Chemistry 2011, 46, 320 -326.
AMA StyleAntonio Carta, Michele Palomba, Irene Briguglio, Paola Corona, Sandra Piras, Daniela Jabes, Paola Guglierame, Paola Molicotti, Stefania Zanetti. Synthesis and anti-mycobacterial activities of triazoloquinolones. European Journal of Medicinal Chemistry. 2011; 46 (1):320-326.
Chicago/Turabian StyleAntonio Carta; Michele Palomba; Irene Briguglio; Paola Corona; Sandra Piras; Daniela Jabes; Paola Guglierame; Paola Molicotti; Stefania Zanetti. 2011. "Synthesis and anti-mycobacterial activities of triazoloquinolones." European Journal of Medicinal Chemistry 46, no. 1: 320-326.
In the process of drug discovery the lead-identification phase may be critical due to the likely poor safety profile of the candidates, causing the delay or even the abandonment of a certain project. Nowadays, combining molecular modeling and in vivo cellular evaluation can help to identify compounds with an enhanced safety profile. Previously, two quinoxalines have been identified as inhibitors of the folate-dependent proteins belonging to the thymidylate synthase cycle. Unfortunately, cytotoxic activity against a panel of cisplatin(cDDP)-sensitive ovarian carcinoma cell lines and their resistant counterparts was coupled with toxicity to non-tumorigenic Vero cells. Here we describe the application of a ligand-based virtual screening, and several [1,2,4]triazolo[4,3-a]quinoxalines were optimized to improve their ADME-tox profile. The resulting 4-(trifluoromethyl)-1-p-tolyl-[1,2,4]triazolo[4,3-a]quinoxaline (24), which interferes intracellularly with DHFR and TS reducing the protein levels like 5-FU, but without inducing TS ternary complex formation, was 2-times less toxic in vitro than cisplatin and 5-FU.
Emanuele Carosati; Gianluca Sforna; Massimiliano Pippi; Gaetano Marverti; Alessio Ligabue; Davide Guerrieri; Sandra Piras; Giambattista Guaitoli; Rosaria Luciani; Maria Paola Costi; Gabriele Cruciani. Ligand-based virtual screening and ADME-tox guided approach to identify triazolo-quinoxalines as folate cycle inhibitors. Bioorganic & Medicinal Chemistry 2010, 18, 7773 -7785.
AMA StyleEmanuele Carosati, Gianluca Sforna, Massimiliano Pippi, Gaetano Marverti, Alessio Ligabue, Davide Guerrieri, Sandra Piras, Giambattista Guaitoli, Rosaria Luciani, Maria Paola Costi, Gabriele Cruciani. Ligand-based virtual screening and ADME-tox guided approach to identify triazolo-quinoxalines as folate cycle inhibitors. Bioorganic & Medicinal Chemistry. 2010; 18 (22):7773-7785.
Chicago/Turabian StyleEmanuele Carosati; Gianluca Sforna; Massimiliano Pippi; Gaetano Marverti; Alessio Ligabue; Davide Guerrieri; Sandra Piras; Giambattista Guaitoli; Rosaria Luciani; Maria Paola Costi; Gabriele Cruciani. 2010. "Ligand-based virtual screening and ADME-tox guided approach to identify triazolo-quinoxalines as folate cycle inhibitors." Bioorganic & Medicinal Chemistry 18, no. 22: 7773-7785.
In this preliminary study we report the antiviral screening of triazolo[4,5-g]quinoline derivatives (compounds 1–6). 4,9-Dihydrotriazolo[4,5-g]quinoline-1-oxide (1) stood out as a new, small molecule endowed with a selective, promising activity in cell-based assays against HIV-1wt and clinically relevant NNRTI resistant mutants. In order to identify the molecular target, compound 1 was assayed in enzyme assay against the HIV-1wt RT. The molecular modeling strategy adopted yielded a rationale, in terms of molecular interactions and free energy of binding, for the possible reasons of the activity of this compound against NNRTI-resistant HIV-1 mutants with the RT isoforms K103N and Y181C.
Antonio Carta; Sabrina Pricl; Sandra Piras; Maurizio Fermeglia; Paolo La Colla; Roberta Loddo. Activity and molecular modeling of a new small molecule active against NNRTI-resistant HIV-1 mutants. European Journal of Medicinal Chemistry 2009, 44, 5117 -5122.
AMA StyleAntonio Carta, Sabrina Pricl, Sandra Piras, Maurizio Fermeglia, Paolo La Colla, Roberta Loddo. Activity and molecular modeling of a new small molecule active against NNRTI-resistant HIV-1 mutants. European Journal of Medicinal Chemistry. 2009; 44 (12):5117-5122.
Chicago/Turabian StyleAntonio Carta; Sabrina Pricl; Sandra Piras; Maurizio Fermeglia; Paolo La Colla; Roberta Loddo. 2009. "Activity and molecular modeling of a new small molecule active against NNRTI-resistant HIV-1 mutants." European Journal of Medicinal Chemistry 44, no. 12: 5117-5122.
Paola Corona; Sandra Piras; Michele Palomba; Antonio Carta. Synthesis of Linear Azolo and Pyrido Quinolines from Quinoline Derivatives. Mini-Reviews in Organic Chemistry 2008, 5, 295 -302.
AMA StylePaola Corona, Sandra Piras, Michele Palomba, Antonio Carta. Synthesis of Linear Azolo and Pyrido Quinolines from Quinoline Derivatives. Mini-Reviews in Organic Chemistry. 2008; 5 (4):295-302.
Chicago/Turabian StylePaola Corona; Sandra Piras; Michele Palomba; Antonio Carta. 2008. "Synthesis of Linear Azolo and Pyrido Quinolines from Quinoline Derivatives." Mini-Reviews in Organic Chemistry 5, no. 4: 295-302.
A series of quinoxalines variously substituted, namely 3-arylthiomethyl-1,6-dimethylquinoxalin-2-ones (6a-f), 3-arylthiomethyl-1-benzyl-7-trifluoromethylquinoxalin-2-ones (8a-g) and 2-arylthiomethyl-3-benzyloxy-6-trifluoromethylquinoxalines (10a,b,e-h), were synthesized and compared with previous arylphenoxymethylquinoxalines (1a-f, 2af and 3a-b). The purpose was to verify whether the replacement of oxygen with sulphur atom and the insertion of different substituents on the phenyl side chain were able to improve the capability to inhibit the Pgp pump and restore the antiproliferative activity of clinically useful drugs, such as doxorubicin (Doxo), vincristine (VCR) and etoposide (VP16), in drugresistant human nasopharyngeal carcinoma KB cells (KBwt, KBMDR, KB7D and KBV20C). Furthermore, 2,3-bis(aryloxymethyl)- 6-trifluoromethylquinoxalines (13a-c) were designed with the objective to evaluate the capability of the double side chain to potentiate the antiproliferative activity of the drugs tested. Biological assays showed that title compounds were, in general, endowed with good activity as Pgp inhibitors. In particular compound 3a, bearing 2-CONHPh substituent on phenoxymethyl side chain, resulted the most effective, while the double side chain (compound 13c) gives the ability to inhibit a different MRP pump (a membrane glycoprotein named mrp). Furthermore, we can conclude that replacement of oxygen with sulphur atom did not improve the biological activity.
Antonio Carta; Sandra Piras; Giuseppe Paglietti; Sabrina Pricl; Paolo Colla; Bernardetta Busonera; Roberta Loddo. 2(3)-Aryl-thio(oxy)-methylquinoxaline Derivatives: A New Class of P-Glycoprotein-Mediated Drug Efflux Inhibitors. Medicinal Chemistry 2008, 4, 194 -205.
AMA StyleAntonio Carta, Sandra Piras, Giuseppe Paglietti, Sabrina Pricl, Paolo Colla, Bernardetta Busonera, Roberta Loddo. 2(3)-Aryl-thio(oxy)-methylquinoxaline Derivatives: A New Class of P-Glycoprotein-Mediated Drug Efflux Inhibitors. Medicinal Chemistry. 2008; 4 (3):194-205.
Chicago/Turabian StyleAntonio Carta; Sandra Piras; Giuseppe Paglietti; Sabrina Pricl; Paolo Colla; Bernardetta Busonera; Roberta Loddo. 2008. "2(3)-Aryl-thio(oxy)-methylquinoxaline Derivatives: A New Class of P-Glycoprotein-Mediated Drug Efflux Inhibitors." Medicinal Chemistry 4, no. 3: 194-205.