Synthesis and SAR study of acridine, 2-methylquinoline and 2-phenylquinazoline analogues as anti-prion agents

Cope, H.; Mutter, R.; Heal, W.; Pascoe, C.; Brown, P.; Pratt, S.; Chen, B.

doi:10.1016/j.ejmech.2006.05.002

Synthesis and SAR study of acridine, 2-methylquinoline and 2-phenylquinazoline analogues as anti-prion agents

Cope, H.; Mutter, R.; Heal, W.; Pascoe, C.; Brown, P.; Pratt, S.; Chen, B.

Authors

H. Cope

R. Mutter

W. Heal

C. Pascoe

P. Brown

S. Pratt

B. Chen

Abstract

Transmissible spongiform encephalopathies (TSEs) are thought to arise from aggregation of a protease resistant protein denoted PrPSc, which is a misfolded isoform of the normal cellular prion protein PrPC. Using virtual high-throughput screening we have selected structures analogous to acridine, 2-methyquinoline and 2-phenylquinazoline as potential therapeutic candidates for the treatment of TSEs. From the synthesis and screening of constructed libraries we have shown that an electron-rich aromatic ring attached through an amine linker to the position para to the ring nitrogen is beneficial to both binding to PrPC and the suppression of PrPSc accumulation for acridine and 2-methylquinoline analogues. 2-Phenylquinazoline analogues appear to utilise a different mode of action by binding at a different location and/or pose. We report IC50s in the nanomolar range.

Citation

Cope, H., Mutter, R., Heal, W., Pascoe, C., Brown, P., Pratt, S., & Chen, B. (2006). Synthesis and SAR study of acridine, 2-methylquinoline and 2-phenylquinazoline analogues as anti-prion agents. European Journal of Medicinal Chemistry, 41(10), 1124-1143. https://doi.org/10.1016/j.ejmech.2006.05.002

Journal Article Type	Article
Publication Date	Oct 1, 2006
Deposit Date	Feb 11, 2009
Journal	European Journal of Medicinal Chemistry
Print ISSN	0223-5234
Publisher	Elsevier
Peer Reviewed	Peer Reviewed
Volume	41
Issue	10
Pages	1124-1143
DOI	https://doi.org/10.1016/j.ejmech.2006.05.002
Publisher URL	http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6VKY-4K71619-2-57&_cdi=6135&_user=121711&_orig=search&_coverDate=06%2F19%2F2006&_qd=1&_sk=999999999&view=c&wchp=dGLbVzb-zSkWA&md5=ca4f0c3cb0c00d1d2e42183a1da12969&ie=/sdarticle.pdf