Probing of the cis-5-phenyl proline scaffold as a platform for the synthesis of mechanism-based inhibitors of the Staphylococcus aureus sortase SrtA isoform

• Published in: Bioorganic & medicinal chemistry Vol. 17; no. 7; pp. 2886 - 2893
• Main Authors: Kudryavtsev, Konstantin V., Bentley, Matthew L., McCafferty, Dewey G.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.04.2009; Elsevier
• Subjects: Aminoacyltransferases - antagonists & inhibitors; Aminoacyltransferases - metabolism; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - metabolism; Cysteine Endopeptidases - metabolism; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Inhibitor; Proline - analogs & derivatives; Proline - chemistry; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - metabolism; Sortase; Staphylococcus aureus; Staphylococcus aureus - enzymology; Sulfones - chemical synthesis; Sulfones - chemistry; Sulfones - pharmacology; Vinyl sulfone; Inhibitor; Staphylococcus aureus; Sortase; Vinyl sulfone
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.02.008

cis-5-Phenyl prolinates with electrophilic substituents at the fourth position of a pyrrolidine ring were synthesized by 1,3-dipolar cycloaddition of arylimino esters with divinyl sulfone and acrylonitrile. 4-Vinylsulfonyl 5-phenyl prolinates inhibit Staphylococcus aureus sortase SrtA irreversibly by modification of the enzyme Cys184 and could be used as hits for the development of antibacterials and antivirulence agents.