Discovery of BAZ2A Bromodomain Ligands

All 330 authors (show less):
Pavlína Řezáčová, Beata Żołnowska, Alice Zamagni, Paula Carolina de Souza, Jean Leandro dos Santos, Bernhard Wűnsch, R. S.-M. Wong, W.-Y. Wong, Nadia Zaffaroni, Eike-Christian WamhoffORCID, Q.-W. Wang, Oliver Werz, Shane M. Wilkinson, Simon J. A. van Kuijk, Marike W. van GisbergenORCID, Ala Yaromina, Jean-Yves WinumORCID, Giulio Vistoli, Giampietro Viola, Luca Valgimigli, Flavia VaranoORCID, Katia Varani, Fabrizio Vincenzi, Sonja Visentin, Ernst Urban, Marco Tutone, Csaba Tömböly, Giuseppe Valacchi, Ajiroghene Thomas, Manlio Tolomeo, Tiziano TuccinardiORCID, Anna Tesei, Luisa Tesoriere, Barbara Tenci, Reza Tayebee, Alessio Terenzi, Krzysztof SzafrańskiORCID, Jarosław Sławiński, Claudia Sticozzi, Dimitrios SpiliotopoulosORCID, Loredana Serpe, Ahmed M. Alafeefy, Ondrej Soukup, Sergio Schinelli, Santiago Schiaffino Ortega, Marie-Christine Scherrmann, Domenico Schillaci, Dirk Schepmann, Virginia Spanò, Bin Shen, Daniele Simoni, Silvia Selleri, Lidia Sautebin, Giulia Saponaro, Claudia Sissi, Celeste De Monte, Angelo Spinello, Giampiero Spalluto, Cenzo Congiu, Annamaria Martorana, Mikhail Krasavin, Mojgan Aghazadeh TabriziORCID, Fadi M. Awadallah, Angela Di Capua, Laura De LucaORCID, Stephanie Federico, Nanda Kumar Parvathaneni, Rehan Ahmad, Barbara Parrino, Mostafa M. Ghorab, Cristina Ciancimino, Simone Brogi, Ivana Pibiri, Alessia Salvador, Renata Perlikowska, Carmen Abate, Carla Gentile, Guilherme Felipe dos Santos FernandesORCID, Daniela De Lucia, Silvano Ellena, Antonella Ciancetta, Justyna Piekielna, Maria Rosa Buemi, Valentina Onnis, Marta Rui, Anna Carbone, Daniela Rossi, Fabio Del Bello, Hassan Ramshini, Margherita Brindisi, Raymon Niemans, Tamer A. El-Waei, P.-L. Lam, Samuel D. Banister, Annamaria Marra, Chiara Riganti, Daniela Secci, Pier Giovanni Baraldi, Simone CarradoriORCID, Alessandro Bonifazi, Vincenzo Cilibrasi, Maha Abdulla, Daniela Poli, Angela De Simone, Oscar Méndez Lucio, Stefania Ferro, Benedetta Maggio, Manuela Bartolini, Ugo Perricone, Mayra PaolilloORCID, Laura Lentini, Andrea Cappelli, Nadia Barbero, Luca Gentilucci, Mahmoud F. Abo-Ashour, Leonardo Biancolino Marino, Alessandro Deplano, Hany S. IbrahimORCID, Nicola Porta, Wagdy M. Eldehna, Filippo Prencipe, Biagia Musio, Ilaria Frasson, Corinne Beinat, Matteo Falsini, Maria Kimatrai Salvador, Daniele Giallombardo, Zdzisław Brzozowski, Riccardo Rondanin, Stella Cascioferro, Gianfabio Giorgioni, Emanuela Ruggiero, Demetrio RaffaORCID, Mona M. Hanna, Andrea Baschieri, Daniela Vullo, Alessandra Montalbano, Antonio Palumbo Piccionello, G. Y.-M. Cheng, Heba Abdelrasheed Allam, Francesca M. Damiano, Maria Laura Pati, Benedetta Mannini, Andreas Bender, Kim Y. P. Apperley, Federica Foglietta, Rossella De Marco, Konstantin Chegaev, Mohamed Fares, Daniela Curti, Severo Salvadori, Antonietta Rossi, Mikhail Korsakov, Luisa Carlota Lopez-Cara, Sara Redenti, Romeo Romagnoli, Marco Betti, Walaa R. Mahmoud, Riccardo Petrelli, K.-H. Lam, Huan Huan Chen, Maria Valeria Raimondi, Filippo Doria, Paola Oliva, Elvira Bruno, Monika Listing, Alessandro Bonardi, Abdul-Malek S. Al-Tamimi, Aneta Pogorzelska, Safinaz E. Abbas, Mansour S. Alsaid, Roberta Bartolotta, Giulia Gallucci, Simona Pace, Alessio Nocentini, Roberta Rizzo, Raffaella Melfi, Z.-X. Bian, Stefano Guglielmo, Maria Camilla Cerlesi, Dario Ghigo, Federica Prandini, Mikhail Dorogov, Michela Cortesi, Melissa Guardigni, Veronica Marconi, Cecilia Bartoli, Kaveh Khodayari, Wilma Quaglia, Sophie DennhardtORCID, Melissa D'Ascenzio, Giorgia Pastorin, Ibrahim H. Eissa, Maria Grazia Cusimano, Serena Montanari, Paola Barraja, Silvia Pastorekova, Stefania Baraldi, Alessandro Attanzio, Anna Maria Pugliese, C.-L. Ho, Paola Gratteri, Maria Pia Gallo, Girolamo Calo, Loretta Lazzarato, Lorenzo Di Cesare Mannelli, Sahar M. Abou-Seri, Francesco Berardi, Angela Altomare, Hazem A. Ghabbour, Felicita Pedata, Hatem A. Abdel-Aziz, Andreas Koeberle, Odra Pinato, Erik Laurini, Azadeh Ebrahim-Habibi, Tereza Kobrlova, Jarosław Chojnacki, Andrea Brancale, Barbara Cacciari, Daniela Maftei, Yassin M. Nissan, Matteo NadaiORCID, Carla Ghelardini, Y.-H. Feng, Nicolò Prosa, Ernest Hamel, Graziano LolliORCID, Omnia E. Ismael, Sara N. RichterORCID, Omar Al-Obaid, Ulrike Garscha, Sabrina Pricl, Kamil Brożewicz, Manlio PalumboORCID, Fabrizio CartaORCID, Marzia Pennati, Renzo Levi, Roberto Artali, Andrea PaceORCID, Diego Dal Ben, Roberta Fruttero, Salvatore Ferla, Aurelia Falcicchio, Klára Pospíšilová, Stefania Grimaudo, Eleonora Da PozzoORCID, Christoph RademacherORCID, Beyza Ecem Oz, Mariangela Ceruso, Azam Sadat Moghaddasi, R. Gambari, Gianluca Giorgi, Giovanni Beretta, Timur Mavlyutov, Girolamo CirrincioneORCID, Lucia Negri, Fabiana Plescia, Jan Balzarini, Karl Norbert Klotz, Barbara Manachini, Marianna Lauricella, Vincenza Andrisano, Francesco Mingoia, Claudia Barolo, Eslam S. Ibrahim, Man Chin Chung, Patrizia Diana, Rosanna Matucci, Antonio Giordani, Daniela CatarziORCID, Ilaria Palchetti, Marco Folini, Claudia MartiniORCID, Reem K. Arafa, Nurcan Dedeoglu, Ludwig J. Dubois, Sandra Liekens, Rosaria Maria Pipitone, Jiří Brynda, Mauro FrecceroORCID, Y.-H. Lo, Alba Chimirri, Mahmoud M. Elaasser, Stefano Manfredini, Jeffrey W. Keillor, Lian-Wang Guo, Dalal A. Abou El Ella, Giampaolo BaroneORCID, Ozen Ozensoy Guler, Adriano Martinelli, Peter Matyus, Giovanna Poce, Roberta Lattanzi, Andrea Angeli, Francesca Bettazzi, Stefano Moro, Abdulla A. Al-Kahtani, Elena Mattiuzzo, Antonella D’Anneo, Roberto Canaparo, Alicja Kluczyk, Frederick T. Chin, Anna Maria Almerico, Fernando Rogério Pavan, Maria Meli, Amedeo CaflischORCID, Manuela Basso, Giuseppe Basso, Vittorio Pace, Balázs Balogh, Mariangela Biava, Vittoria ColottaORCID, Fabrizio Chiti, Andrea MilelliORCID, Simona Collina, Giuseppe DaidoneORCID, Michael Kassiou, Steven V. Ley, Claudiu T. SupuranORCID, C.-H. Chui, Aldo Di Leonardo, Alessandro Piergentili, Anna Janecka, Rosaria Gitto, Philippe Lambin, Arnold Ruoho, Maurizio Anzini, Antonino LauriaORCID, Gianfranco Balboni

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Abstract
Tuberculosis (TB) remains a serious health problem responsible to cause millions of deaths annually. The scenario becomes alarming when it is evaluated that the number of new drugs does not increase proportionally to the emergence of resistance to the current therapy. Furoxan derivatives, known as nitric oxide (NO) donors, have been described to exhibit antitubercular activity. Herein, a novel series of hybrid furoxan derivatives (1,2,5-oxadiazole 2-N-oxide) (compounds 4a-c, 8a-c and 14a-c) were designed, synthesized and evaluated in vitro against Mycobacterium tuberculosis (MTB) H37Rv (ATCC 27294) and a clinical isolate MDR-TB strain. The furoxan derivatives have exhibited MIC90 values ranging from 1.03 to 62 mM (H37Rv) and 7.0e50.0 mM (MDR-TB). For the most active compounds (8c, 14a, 14b and 14c) the selectivity index ranged from 3.78 to 52.74 (MRC-5 cells) and 1.25e34.78 (J774A.1 cells). In addition, it was characterized for those compounds logPo/w values between 2.1 and 2.9. All compounds were able to release NO at levels ranging from 0.16 to 44.23%. Among the series, the phenylsulfonyl furoxan derivatives (compounds 14a-c) were the best NO-donor with the lowest MIC90 values. The most active compound (14c) was also stable at different pHs (5.0 and 7.4). In conclusion, furoxan derivatives were identified as new promising compounds useful to treat tuberculosis.