title: Metal-chelating 2-hydroxyphenyl amide pharmacophore for inhibition of influenza virus endonuclease.
abstract: The influenza virus PA endonuclease is an attractive target for development of novel anti-influenza virus therapeutics. Reported PA inhibitors chelate the divalent metal ion(s) in the enzyme's catalytic site, which is located in the N-terminal part of PA (PA-Nter). In this work, a series of 2-hydroxybenzamide-based compounds have been synthesized and biologically evaluated in order to identify the essential pharmacophoric motif, which could be involved in functional sequestration of the metal ions (probably Mg(2+)) in the catalytic site of PA. By using HL(1), H2L(2), and HL(3) as model ligands with Mg(2+) ions, we isolated and fully characterized a series of complexes and tested them for inhibitory activity toward PA-Nter endonuclease. H2L(2) and the corresponding Mg(2+) complex showed an interesting inhibition of the endonuclease activity. The crystal structures of the uncomplexed HL(1) and H2L(2) and of the isolated magnesium complex [Mg(L(3))2(MeOH)2]·2MeOH were solved by X-ray diffraction analysis. Furthermore, the speciation models for HL(1), H2L(2), and HL(3) with Mg(2+) were obtained, and the formation constants of the complexes were measured. Preliminary docking calculations were conducted to investigate the interactions of the title compounds with essential amino acids in the PA-Nter active site. These findings supported the "two-metal" coordination of divalent ions by a donor triad atoms chemotype as a powerful strategy to develop more potent PA endonuclease inhibitors.
authors.affiliation: Dipartimento di Chimica,‡Dipartimento di Farmacia, Università di Parma , Parco Area delle Scienze 17/A, 43124 Parma, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Carcelli
authors.forename: Dominga
authors.initials: D
authors.lastname: Rogolino
authors.forename: Alessia
authors.initials: A
authors.lastname: Bacchi
authors.forename: Gabriele
authors.initials: G
authors.lastname: Rispoli
authors.forename: Emilia
authors.initials: E
authors.lastname: Fisicaro
authors.forename: Carlotta
authors.initials: C
authors.lastname: Compari
authors.forename: Mario
authors.initials: M
authors.lastname: Sechi
authors.forename: Annelies
authors.initials: A
authors.lastname: Stevaert
authors.forename: Lieve
authors.initials: L
authors.lastname: Naesens
mesh_terms: D001549:Benzamides / Q000737:chemistry*; D020134:Catalytic Domain; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D008274:Magnesium / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry* / Q000378:metabolism; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014961:X-Ray Diffraction
chemical_list: C524082:2-hydroxybenzamide; D001549:Benzamides; D002614:Chelating Agents; D056831:Coordination Complexes; C061290:PA protein, influenza viruses; D011994:Recombinant Proteins; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase; D008274:Magnesium