caa a22 4500 605507201 CHVBK 20210128100631.0 cr unu---uuuuu 210128e20151001xx s 000 0 eng 10.1007/s00775-015-1292-0 doi (NATIONALLICENCE)springer-10.1007/s00775-015-1292-0 Investigation of the salicylaldehyde thiosemicarbazone scaffold for inhibition of influenza virus PA endonuclease [Elektronische Daten] [Dominga Rogolino, Alessia Bacchi, Laura De Luca, Gabriele Rispoli, Mario Sechi, Annelies Stevaert, Lieve Naesens, Mauro Carcelli] The influenza virus PA endonuclease is an attractive target for the development of novel anti-influenza virus therapeutics, which are urgently needed because of the emergence of drug-resistant viral strains. Reported PA inhibitors are assumed to chelate the divalent metal ion(s) (Mg2+ or Mn2+) in the enzyme's catalytic site, which is located in the N-terminal part of PA (PA-Nter). In the present work, a series of salicylaldehyde thiosemicarbazone derivatives have been synthesized and evaluated for their ability to inhibit the PA-Nter catalytic activity. Compounds 1-6 have been evaluated against influenza virus, both in enzymatic assays with influenza virus PA-Nter and in virus yield assays in MDCK cells. In order to establish a structure-activity relationship, the hydrazone analogue of the most active thiosemicarbazone has also been evaluated. Since chelation may represent a mode of action of such class of molecules, we studied the interaction of two of them, one with and one without biological activity versus the PA enzyme, towards Mg2+, the ion that is probably involved in the endonuclease activity of the heterotrimeric influenza polymerase complex. The crystal structure of the magnesium complex of the o-vanillin thiosemicarbazone ligand 1 is also described. Moreover, docking studies of PA endonuclease with compounds 1 and 2 were performed, to further analyse the possible mechanism of action of this class of inhibitors. SBIC, 2015 Influenza virus nationallicence Thiosemicarbazone nationallicence Endonuclease nationallicence Metal chelation nationallicence Antiviral nationallicence Rogolino Dominga Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, 43124, Parma, Italy aut Bacchi Alessia Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, 43124, Parma, Italy aut De Luca Laura Dipartimento di Scienze del Farmaco e Prodotti per la Salute, Università di Messina, Polo Universitario SS. Annunziata, 98158, Messina, Italy aut Rispoli Gabriele Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, 43124, Parma, Italy aut Sechi Mario Dipartimento di Chimica e Farmacia, Università di Sassari, Via Vienna 2, 07100, Sassari, Italy aut Stevaert Annelies Rega Institute for Medical Research, KU Leuven, 3000, Louvain, Belgium aut Naesens Lieve Rega Institute for Medical Research, KU Leuven, 3000, Louvain, Belgium aut Carcelli Mauro Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, 43124, Parma, Italy aut JBIC Journal of Biological Inorganic Chemistry Springer Berlin Heidelberg 20/7(2015-10-01), 1109-1121 0949-8257 20:7<1109 2015 20 775 https://doi.org/10.1007/s00775-015-1292-0 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00775-015-1292-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Rogolino Dominga Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, 43124, Parma, Italy aut NATIONALLICENCE 700 1- Bacchi Alessia Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, 43124, Parma, Italy aut NATIONALLICENCE 700 1- De Luca Laura Dipartimento di Scienze del Farmaco e Prodotti per la Salute, Università di Messina, Polo Universitario SS. Annunziata, 98158, Messina, Italy aut NATIONALLICENCE 700 1- Rispoli Gabriele Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, 43124, Parma, Italy aut NATIONALLICENCE 700 1- Sechi Mario Dipartimento di Chimica e Farmacia, Università di Sassari, Via Vienna 2, 07100, Sassari, Italy aut NATIONALLICENCE 700 1- Stevaert Annelies Rega Institute for Medical Research, KU Leuven, 3000, Louvain, Belgium aut NATIONALLICENCE 700 1- Naesens Lieve Rega Institute for Medical Research, KU Leuven, 3000, Louvain, Belgium aut NATIONALLICENCE 700 1- Carcelli Mauro Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, 43124, Parma, Italy aut NATIONALLICENCE 773 0- JBIC Journal of Biological Inorganic Chemistry Springer Berlin Heidelberg 20/7(2015-10-01), 1109-1121 0949-8257 20:7<1109 2015 20 775