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Title: Anti-prion activities and drug-like potential of functionalized quinacrine analogs with basic phenyl residues at the 9-amino position
Authors: Nguyen, T.
Sakasegawa, Y.
Doh-Ura, K.
Go, M.-L. 
Keywords: Binding to human prion protein fragment
Cell-based anti-prion activity
Drug-like properties
PAMPA-BBB permeability
Pgp substrate
Quinacrine analogs
Issue Date: Jul-2011
Citation: Nguyen, T., Sakasegawa, Y., Doh-Ura, K., Go, M.-L. (2011-07). Anti-prion activities and drug-like potential of functionalized quinacrine analogs with basic phenyl residues at the 9-amino position. European Journal of Medicinal Chemistry 46 (7) : 2917-2929. ScholarBank@NUS Repository.
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 (hPrP121-231) 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 hPrP121-231. © 2011 Elsevier Masson SAS. All rights reserved.
Source Title: European Journal of Medicinal Chemistry
ISSN: 02235234
DOI: 10.1016/j.ejmech.2011.04.016
Appears in Collections:Staff Publications

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