Synthesis of <i>S</i> - or <i>N</i> -glycomimetics of <scp>d</scp> -galactono-1,4-lactone: inhibitors of a β-galactofuranosidase

In the search for β-galactofuranosidase inhibitors, the synthesis of 4-thio-D-galactonic acid 1,4-thiolactone and 4-deoxy-D-galactono-1,4-lactam was undertaken. These compounds are analogs of D-galactono-1,4-lactone, a known inhibitor of the enzyme. Additionally, a synthetic route to access benzyl, alkyl and hydroxyalkyl <i>N</i>-substituted galactonolactams is outlined. All syntheses began with derivatives of D-glucono-1,5- or 1,4-lactones as starting compounds. They underwent substitution at C-4 <i>via</i> sulfur or nitrogen nucleophiles, yielding products with <i>galacto</i> configuration. All synthesized compounds were found to inhibit the <i>Penicillium fellutanum</i> β-galactofuranosidase. 4-Thio-D-galactonic acid 1,4-thiolactone was a weak inhibitor, while 4-deoxy-D-galactono-1,4-lactam was the strongest (<i>K</i>_i = 88 ± 4 µM) within this series. Kinetic studies further revealed that this is a competitive inhibitor. Furthermore, a preliminary docking analysis with the β-galactofuranosidase from <i>Streptomyces</i> sp. JHA19 ORF 1110 demonstrated that the lactam is also a potential inhibitor of this enzyme. Inhibition of β-galactofuranosidases may serve as a novel chemotherapeutic approach for treating human pathogens that contain galactofuranosyl structures, such as those responsible for leprosy and tuberculosis.