title: Synthesis and modulation properties of imidazo[4,5-b]pyridin-7-one and indazole-4,7-dione derivatives towards the Cryptosporidium parvum CpABC3 transporter.
abstract: The syntheses of new N-polysubstituted imidazo[4,5-b]pyridine-7-one (IP, 5 and 8a-8f) and indazole-4,7-dione (ID, 9 and 10) derivatives are described. The binding affinity of IP and ID towards the recombinant Nucleotide Binding Domain NBD1 of Cryptosporidium parvum CpABC3 was evaluated by intrinsic fluorescence quenching. IP induced a moderate quenching of the intrinsic fluorescence of H6-NBD1 whereas IDs 9 and 10 showed a binding affinity comparable to the ATP analogue TNP-ATP. In addition, 8d, 8e and 10 were shown to be competitive inhibitors of the ATPase activity, but with low affinity. These compounds could thus act like some flavonoid derivatives, which can partly overlap both the nucleotide-binding site and the adjacent hydrophobic steroid-binding region of mammalian P-glycoproteins.
authors.affiliation: Université de Lyon, Université Lyon 1, ISPB-Faculté de Pharmacie, EA 4443 (B2C) Biomolécules, Cancer et Chimiorésistances, 8, av. Rockefeller, F-69373, Lyon Cedex 08, France.
authors.forename: Waël
authors.initials: W
authors.lastname: Zeinyeh
authors.forename: Hexue
authors.initials: H
authors.lastname: Xia
authors.forename: Philippe
authors.initials: P
authors.lastname: Lawton
authors.forename: Sylvie
authors.initials: S
authors.lastname: Radix
authors.forename: Christelle
authors.initials: C
authors.lastname: Marminon
authors.forename: Pascal
authors.initials: P
authors.lastname: Nebois
authors.forename: Nadia
authors.initials: N
authors.lastname: Walchshofer
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000378:metabolism*; D016785:Cryptosporidium parvum; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D009711:Nucleotides / Q000378:metabolism; D011485:Protein Binding; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D013050:Spectrometry, Fluorescence
chemical_list: D018528:ATP-Binding Cassette Transporters; D007093:Imidazoles; D007191:Indazoles; D008024:Ligands; D009711:Nucleotides; D015800:Protozoan Proteins; D011725:Pyridines; D011728:Pyridones; C550830:imidazo(4,5-b)pyridin-7-one