TY - JOUR
T1 - Anti-prion activities and drug-like potential of functionalized quinacrine analogs with basic phenyl residues at the 9-amino position
AU - Nguyen, Thuy
AU - Sakasegawa, Yuji
AU - Doh-Ura, Katsumi
AU - Go, Mei Lin
N1 - Funding Information:
The authors gratefully acknowledged support by National University of Singapore (NUS) Academic research Fund R148000064112 (to GML) and the Program for the Promotion of Fundamental Studies in Health Science of the NIBIO in Japan, and by the Health and Labor Sciences Research Grant (Research on Measures for Intractable Diseases) from the Ministry of Health, Labor, and Welfare of Japan (to KD and YS). TN was supported by the NUS Ministry of Education Research Scholarship for her graduate studies.
PY - 2011/7
Y1 - 2011/7
N2 - 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.
AB - 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.
KW - Binding to human prion protein fragment
KW - Cell-based anti-prion activity
KW - Drug-like properties
KW - PAMPA-BBB permeability
KW - Pgp substrate
KW - Quinacrine analogs
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U2 - 10.1016/j.ejmech.2011.04.016
DO - 10.1016/j.ejmech.2011.04.016
M3 - Article
C2 - 21531054
AN - SCOPUS:79957498246
VL - 46
SP - 2917
EP - 2929
JO - CHIM.THER.
JF - CHIM.THER.
SN - 0223-5234
IS - 7
ER -