Synthesis and modulation properties of imidazo[4,5-b]pyridin-7-one and indazole-4,7-dione derivatives towards the Cryptosporidium parvum CpABC3 transporter.
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.
Zeinyeh
Waël
W
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.
Xia
Hexue
H
Lawton
Philippe
P
Radix
Sylvie
S
Marminon
Christelle
C
Nebois
Pascal
P
Walchshofer
Nadia
N
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
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