Potent inhibition of influenza sialidase by a benzoic acid containing a 2-pyrrolidinone substituent.

Abstract

On the basis of the lead compound 4-(N-acetylamino)-3-guanidinobenzoic acid (BANA 113), which inhibits influenza A sialidase with a Ki of 2.5 microM, several novel aromatic inhibitors of influenza sialidases were designed. In this study the N-acetyl group of BANA 113 was replaced with a 2-pyrrolidinone ring, which was designed in part to offer opportunities for introduction of spatially directed side chains that could potentially interact with the 4-, 5-, and/or 6-subsites of sialidase. While the parent structure 1-(4-carboxy-2-guanidinophenyl)pyrrolidin-2-one (8) was only a modest inhibitor of sialidase, the introduction of a hydroxymethyl or bis(hydroxymethyl) substituent at the C5' position of the 2-pyrrolidinone ring resulted in inhibitors (9 and 12, respectively) with low micromolar activity. Crystal structures of these inhibitors in complex with sialidase demonstrated that the substituents at the 5'-position of the 2-pyrrolidinone ring interact in the 4- and/or 5-subsites of the enzyme. Replacement of the guanidine in 12 with a hydrophobic 3-pentylamino group resulted in a large enhancement in binding to produce an inhibitor (14) with an IC50 of about 50 nM against influenza A sialidase, although the inhibition of influenza B sialidase was 2000-fold less. This represents the first reported example of a simple, achiral benzoic acid with potent (low nanomolar) activity as an inhibitor of influenza sialidase.

• Authors: V R Atigadda, W J Brouillette, F Duarte, S M Ali, Y S Babu, S Bantia, P Chand, N Chu, J A Montgomery, D A Walsh, E A Sudbeck, J Finley, M Luo, G M Air, G W Laver
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 42 Issue 13 Pg. 2332-43 (Jul 01 1999) ISSN: 0022-2623 [Print] United States
• PMID: 10395473 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Benzoates
• Enzyme Inhibitors
• Pyrrolidinones
• Neuraminidase

Topics

• Benzoates (chemical synthesis, chemistry)
• Crystallography, X-Ray
• Enzyme Inhibitors (chemical synthesis, chemistry)
• Influenza A virus (chemistry)
• Influenza B virus (chemistry)
• Models, Molecular
• Neuraminidase (antagonists & inhibitors, isolation & purification)
• Pyrrolidinones (chemical synthesis, chemistry)
• Spectrometry, Fluorescence
• Structure-Activity Relationship