Potent inhibition of influenza sialidase by a benzoic acid containing a 2-pyrrolidinone substituent.
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.
Department of Chemistry and Center for Macromolecular Crystallography, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
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Atigadda
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Brouillette
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Duarte
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Ali
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Babu
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Bantia
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Chand
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Chu
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Montgomery
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Walsh
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Sudbeck
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Finley
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Luo
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Air
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Laver
D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D009980:Influenza A virus / Q000737:chemistry; D009981:Influenza B virus / Q000737:chemistry; D008958:Models, Molecular; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000737:chemistry; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship
D001565:Benzoates; D004791:Enzyme Inhibitors; D011760:Pyrrolidinones; D009439:Neuraminidase