کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1393046 | 1501175 | 2011 | 13 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Anti-prion activities and drug-like potential of functionalized quinacrine analogs with basic phenyl residues at the 9-amino position Anti-prion activities and drug-like potential of functionalized quinacrine analogs with basic phenyl residues at the 9-amino position](/preview/png/1393046.png)
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.
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► Functionalized quinacrine analogs with basic phenyl residues were investigated.
► Compounds were more potent and have broad ranging cell-based anti-prion activity.
► A promising analog cleared PrPSc in 3 cell models with nanomolar EC50.
► It binds to hPrP121–231, is CNS + (PAMPA-BBB), and is a weaker Pgp substrate.
► Modifications have resulted in more potent and drug-like analogs.
Journal: European Journal of Medicinal Chemistry - Volume 46, Issue 7, July 2011, Pages 2917–2929