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The X-ray crystal structures of six salts composed of amino acids and sulfonated azo dyes have been determined, four of them at low temperature (173 K). The compounds are dl-lysine/4-[(4-hydroxyphenyl)azo]benzenesulfonate (HABS) monohydrate (1), dl-lysine/7-hydroxy-8-(phenylazo)-1,3-naphthalenedisulfonate (Orange G) dihydrate (2), l-lysine/Orange G 1.5-hydrate (3), dl-histidine/Orange G trihydrate (4), l-histidine/Orange G trihydrate (5), and tosylarginine methyl ester (TAME)/4-[(2-hydroxy-6-tert-butyl-1-naphthalenyl)azo]benzenesulfonate (“Little Rock Orange,” LRO) (6). By virtue of their basic side chains, these amino acids are the ones most important in the binding interactions between proteins and sulfated macromolecules such as glycosaminoglycans in living systems. The sulfonate salts described here serve as model systems for these interactions. Close intermolecular approaches between the dye sulfonate groups and neighboring amino acids and water molecules are examined, and the graph-set formalism is used to describe packing patterns and to identify corresponding interactions in different crystal structures. The recurrence of certain interactions between sulfonate groups and amino acid functional groups in these small-molecule crystal structures, including numerous interactions mediated by water molecules, suggests specificity that may also be a feature of the interactions between proteins and sulfated biological macromolecules.

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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.

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