title: Anti-prion activities and drug-like potential of functionalized quinacrine analogs with basic phenyl residues at the 9-amino position.
abstract: In this paper, we report the synthesis and cell-based anti-prion activity of quinacrine analogs derived by replacing the basic alkyl side chain of quinacrine with 4-(4-methylpiperazin-I-yl)phenyl, (1-benzylpiperidin-4-yl) and their structural variants. Several promising analogs were found that have a more favorable anti-prion profile than quinacrine in terms of potency and activity across different prion-infected murine cell models. They also exhibited greater binding affinities for a human prion protein fragment (hPrP(121-231)) than quinacrine, and had permeabilities on the PAMPA-BBB assay that fall within the range of CNS permeant candidates. When evaluated on bidirectional assays on a Pgp overexpressing cell line, one analog was less susceptible to Pgp efflux activity compared to quinacrine. Taken together, the results point to an important role for the substituted 9-amino side chain attached to the acridine, tetrahydroacridine and quinoline scaffolds. The nature of this side chain influenced cell-based potency, PAMPA permeability and binding affinity to hPrP(121-231).
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
authors.forename: Thuy
authors.initials: T
authors.lastname: Nguyen
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sakasegawa
authors.forename: Katsumi
authors.initials: K
authors.lastname: Doh-Ura
authors.forename: Mei-Lin
authors.initials: ML
authors.lastname: Go
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects; D045744:Cell Line, Tumor; D004285:Dogs; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010539:Permeability; D010879:Piperazines / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry*; D017096:Prion Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011328:Prions / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011796:Quinacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010446:Peptide Fragments; D010879:Piperazines; D010880:Piperidines; D011328:Prions; D011994:Recombinant Proteins; C100569:prion protein (121-231); D011796:Quinacrine