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

Academic Article

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.
  • Published In

    Keywords

  • Benzoates, Crystallography, X-Ray, Enzyme Inhibitors, Influenza A virus, Influenza B virus, Models, Molecular, Neuraminidase, Pyrrolidinones, Spectrometry, Fluorescence, Structure-Activity Relationship
  • Digital Object Identifier (doi)

    Author List

  • Atigadda VR; Brouillette WJ; Duarte F; Ali SM; Babu YS; Bantia S; Chand P; Chu N; Montgomery JA; Walsh DA
  • Start Page

  • 2332
  • End Page

  • 2343
  • Volume

  • 42
  • Issue

  • 13