title: Phenylhydrazones as Correctors of a Mutant Cystic Fibrosis Transmembrane Conductance Regulator.
abstract: The phenylhydrazone RDR-1 is endowed with moderate activity as F508del-CFTR corrector; nevertheless, its simple structure enables stimulating developments in this class of correctors. Therefore, we synthesized a number of phenylhydrazones 3 by reacting phenylhydrazine derivatives 1 with furfural derivatives 2. By the same reaction, also the pyridine derivatives 4, the thiophene derivatives 5, and the hydrazides 6 and 7 were prepared. All compounds were tested as F508del-CFTR correctors in the cystic fibrosis (CF) bronchial epithelial cell line CFBE41o-, using corr-4a and VX-809 as controls. Some of the tested compounds emerged as interesting F508del-CFTR correctors at 20 μM (3c) and 2 μM (5d). 3c and 5d administered together with VX-809 produced a satisfactory additivity of action. When the structure of 5d was overlapped with RDR-1 and five other established correctors, a shared central design was clearly visible. This fact may be of interest in the search for new F508del-CFTR correctors.
authors.affiliation: Department of Pharmacy, University of Genova, Genova, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Nieddu
authors.affiliation: Department of Pharmacy, University of Genova, Genova, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Pollarolo
authors.affiliation: Department of Pharmacy, University of Genova, Genova, Italy.
authors.forename: Marco T
authors.initials: MT
authors.lastname: Mazzei
authors.affiliation: Department of Pharmacy, University of Genova, Genova, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Anzaldi
authors.affiliation: Department of Pharmacy, University of Genova, Genova, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.affiliation: Laboratory of Molecular Genetics, Giannina Gaslini Institute, Genova, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Pedemonte
authors.affiliation: Laboratory of Molecular Genetics, Giannina Gaslini Institute, Genova, Italy.
authors.forename: Luis J V
authors.initials: LJ
authors.lastname: Galietta
authors.affiliation: Department of Pharmacy, University of Genova, Genova, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Mazzei
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D002460:Cell Line; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009154:Mutation; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C000613235:1-(4-bromophenyl)-2-((5-(4-nitrophenyl)furan-2-yl)methylene)hydrazine; C000613236:1-(4-methoxyphenyl)-2-((5-phenylthiophen-2-yl)methylene)hydrazine; D000631:Aminopyridines; D052117:Benzodioxoles; D005663:Furans; D006835:Hydrazones; D013876:Thiophenes; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C569105:lumacaftor
keywords: CFTR; Correctors; Cystic fibrosis; Ion channels; Phenylhydrazones