Discovery, synthesis, and structure-based optimization of a series of N -(tert -Butyl)-2-(N -arylamido)-2-(pyridin-3-yl) acetamides (ML188) as potent noncovalent small molecule inhibitors of the severe acute respiratory syndrome coronavirus (SARS-CoV) 3CL protease

Jon Jacobs, Valerie Grum-Tokars, Ya Zhou, Mark Turlington, S. Adrian Saldanha, Peter Chase, Aimee Eggler, Eric S. Dawson, Yahira M. Baez-Santos, Sakshi Tomar, Anna M. Mielech, Susan C. Baker, Craig W. Lindsley, Peter Hodder, Andrew Mesecar*, Shaun R. Stauffer

*Corresponding author for this work

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

A high-throughput screen of the NIH molecular libraries sample collection and subsequent optimization of a lead dipeptide-like series of severe acute respiratory syndrome (SARS) main protease (3CLpro) inhibitors led to the identification of probe compound ML188 (16-(R), (R)-N-(4-(tert-butyl)phenyl)-N- (2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide, Pubchem CID: 46897844). Unlike the majority of reported coronavirus 3CLpro inhibitors that act via covalent modification of the enzyme, 16-(R) is a noncovalent SARS-CoV 3CLpro inhibitor with moderate MW and good enzyme and antiviral inhibitory activity. A multicomponent Ugi reaction was utilized to rapidly explore structure-activity relationships within S1′, S 1, and S2 enzyme binding pockets. The X-ray structure of SARS-CoV 3CLpro bound with 16-(R) was instrumental in guiding subsequent rounds of chemistry optimization. 16-(R) provides an excellent starting point for the further design and refinement of 3CLpro inhibitors that act by a noncovalent mechanism of action.

Original languageEnglish (US)
Pages (from-to)534-546
Number of pages13
JournalJournal of Medicinal Chemistry
Volume56
Issue number2
DOIs
StatePublished - Jan 24 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Jacobs, J., Grum-Tokars, V., Zhou, Y., Turlington, M., Saldanha, S. A., Chase, P., Eggler, A., Dawson, E. S., Baez-Santos, Y. M., Tomar, S., Mielech, A. M., Baker, S. C., Lindsley, C. W., Hodder, P., Mesecar, A., & Stauffer, S. R. (2013). Discovery, synthesis, and structure-based optimization of a series of N -(tert -Butyl)-2-(N -arylamido)-2-(pyridin-3-yl) acetamides (ML188) as potent noncovalent small molecule inhibitors of the severe acute respiratory syndrome coronavirus (SARS-CoV) 3CL protease. Journal of Medicinal Chemistry, 56(2), 534-546. https://doi.org/10.1021/jm301580n