title: Discovery of a New Class of Sortase A Transpeptidase Inhibitors to Tackle Gram-Positive Pathogens: 2-(2-Phenylhydrazinylidene)alkanoic Acids and Related Derivatives.
abstract: A FRET-based random screening assay was used to generate hit compounds as sortase A inhibitors that allowed us to identify ethyl 3-oxo-2-(2-phenylhydrazinylidene)butanoate as an example of a new class of sortase A inhibitors. Other analogues were generated by changing the ethoxycarbonyl function for a carboxy, cyano or amide group, or introducing substituents in the phenyl ring of the ester and acid derivatives. The most active derivative found was 3-oxo-2-(2-(3,4dichlorophenyl)hydrazinylidene)butanoic acid (2b), showing an IC50 value of 50 µM. For a preliminary assessment of their antivirulence properties the new derivatives were tested for their antibiofilm activity. The most active compound resulted 2a, which showed inhibition of about 60% against S. aureus ATCC 29213, S. aureus ATCC 25923, S. aureus ATCC 6538 and S. epidermidis RP62A at a screening concentration of 100 µM.
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Sezione di Chimica e Tecnologie Farmaceutiche, Università degli Studi di Palermo, Via Archirafi 32, I-90123 Palermo, Italy. benedetta.maggio@unipa.it.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Maggio
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Sezione di Chimica e Tecnologie Farmaceutiche, Università degli Studi di Palermo, Via Archirafi 32, I-90123 Palermo, Italy. demetrio.raffa@unipa.it.
authors.forename: Demetrio
authors.initials: D
authors.lastname: Raffa
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Sezione di Chimica e Tecnologie Farmaceutiche, Università degli Studi di Palermo, Via Archirafi 32, I-90123 Palermo, Italy. mariavaleria.raimondi@unipa.it.
authors.forename: Maria Valeria
authors.initials: MV
authors.lastname: Raimondi
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Sezione di Chimica e Tecnologie Farmaceutiche, Università degli Studi di Palermo, Via Archirafi 32, I-90123 Palermo, Italy. stellamaria.cascioferro@unipa.it.|IEMEST, Istituto Euromediterraneo di Scienza e Tecnologia, Via Emerico Amari 123, I-90139 Palermo, Italy. stellamaria.cascioferro@unipa.it.
authors.forename: Stella
authors.initials: S
authors.lastname: Cascioferro
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Sezione di Chimica e Tecnologie Farmaceutiche, Università degli Studi di Palermo, Via Archirafi 32, I-90123 Palermo, Italy. fabiana.plescia@unipa.it.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Plescia
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Sezione di Chimica e Tecnologie Farmaceutiche, Università degli Studi di Palermo, Via Archirafi 32, I-90123 Palermo, Italy. domenico.schillaci@unipa.it.
authors.forename: Domenico
authors.initials: D
authors.lastname: Schillaci
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Sezione di Chimica e Tecnologie Farmaceutiche, Università degli Studi di Palermo, Via Archirafi 32, I-90123 Palermo, Italy. mariagrazia.cusimano@unipa.it.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cusimano
authors.affiliation: Latvian Biomedical Research and Study Centre, Ratsupites 1 k1, 1067 Riga, Latvia. ainleo@biomed.lu.lv.
authors.forename: Ainars
authors.initials: A
authors.lastname: Leonchiks
authors.affiliation: Latvian Biomedical Research and Study Centre, Ratsupites 1 k1, 1067 Riga, Latvia. dmitry@lu.lv.
authors.forename: Dmitrijs
authors.initials: D
authors.lastname: Zhulenkovs
authors.affiliation: Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Viale A. Doria 6 Ed. 2, Città Universitaria, I-95125 Catania, Italy. livia.basile@etnalead.com.
authors.forename: Livia
authors.initials: L
authors.lastname: Basile
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Sezione di Chimica e Tecnologie Farmaceutiche, Università degli Studi di Palermo, Via Archirafi 32, I-90123 Palermo, Italy. giuseppe.daidone@unipa.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Daidone
mesh_terms: D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018441:Biofilms / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D010659:Phenylhydrazines / Q000737:chemistry* / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013212:Staphylococcus epidermidis / Q000187:drug effects
chemical_list: D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D010659:Phenylhydrazines; D019881:Aminoacyltransferases; C120542:sortase A; D003546:Cysteine Endopeptidases
keywords: 2-(2-phenylhydrazinylidene)alkanoic acid derivatives; FRET; biofilms; sortase A