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

作者：Thuy Nguyen; Sakasegawa Yuji; Doh ura Katsumi; Go Mei Lin^*

来源：European Journal of Medicinal Chemistry, 2011, 46(7): 2917-2929.

DOI：10.1016/j.ejmech.2011.04.016

• Cell-based anti-prion activity
• Quinacrine analogs
• Drug-like properties
• Binding to human prion protein fragment
• PAMPA-BBB permeability
• Pgp substrate

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).

• 出版日期2011-7