Anti-prion activities and drug-like potential of functionalized quinacrine analogs with basic phenyl residues at the 9-amino position

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.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► 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.