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Synthesis of S- or N-glycomimetics of D-galactono-1,4-lactone: inhibitors of a beta-galactofuranosidase #MMPMID41369983
Jara WE; Marino C; Toro Melgarejo L; Varela O; Repetto E
Org Biomol Chem 2025[Dec]; ? (?): ? PMID41369983show ga
In the search for beta-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 N-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 via sulfur or nitrogen nucleophiles, yielding products with galacto configuration. All synthesized compounds were found to inhibit the Penicillium fellutanum beta-galactofuranosidase. 4-Thio-D-galactonic acid 1,4-thiolactone was a weak inhibitor, while 4-deoxy-D-galactono-1,4-lactam was the strongest (K(i) = 88 +/- 4 microM) within this series. Kinetic studies further revealed that this is a competitive inhibitor. Furthermore, a preliminary docking analysis with the beta-galactofuranosidase from Streptomyces sp. JHA19 ORF 1110 demonstrated that the lactam is also a potential inhibitor of this enzyme. Inhibition of beta-galactofuranosidases may serve as a novel chemotherapeutic approach for treating human pathogens that contain galactofuranosyl structures, such as those responsible for leprosy and tuberculosis.
Org+Biomol+Chem 2025 ; ? (?): ?
