Journal
BIOORGANIC CHEMISTRY
Volume 36, Issue 4-6, Pages 229-240Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2008.01.001
Keywords
SARS coronavirus; 3C-like proteinase; Ketones; Fluorinated ketones; Reversible inhibitors
Funding
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Canada Research Chairs Program
- Alberta Heritage Foundation for Medical Research (AHFMR)
- Killam Foundation
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The severe acute respiratory syndrome (SARS) virus depends on a chymotrypsin-like cysteine proteinase (3CL(pro)) to process the translated polyproteins to functional viral proteins. This enzyme is a target for the design of potential anti-SARS drugs. A series of ketones and corresponding mono- and di-fluoro ketones having two or three aromatic rings were synthesized as possible reversible inhibitors of SARS 3CL(pro). The design was based on previously established potent inhibition of the enzyme by oxa analogues (esters), which also act as substrates. Structure-activity relationships and modeling studies indicate that three aromatic rings, including a 5-bromopyridin-3-yl moiety, are key features for good inhibition of SARS 3CL(pro). Compound 11d, 2-(5-bromopyridin-3-yl)-1-(5-(4-chlorophenyl)furan-2-yl)ethanone and its alpha-monofluorinated analogue 12d, gave the best reversible inhibition with IC50 values of 13 mu M and 28 mu M. respectively. In contrast to inhibitors having two aromatic rings, alpha-fluorination of compounds with three rings unexpectedly decreased the inhibitory activity. (C) 2008 Elsevier Inc. All rights reserved.
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