Two libraries of mono- and dimeric pyrrolidine iminosugars were synthesized by CuAAC and (thio)urea-bond-forming reactions from the respective azido/aminohexylpyrrolidine iminosugar precursors. The resulting monomeric and dimeric compounds were screened for inhibition of β-N-acetylglucosaminidase from Jack beans, the plant ortholog of human lysosomal hexosaminidases. A selection of the best inhibitors of these libraries was then evaluated against human lysosomal β-N-acetylhexosaminidase B (hHexB) and human nucleocytoplasmic β-N-acetylglucosaminidase (hOGA). This evaluation identified a potent (nM) and selective monomeric inhibitor of hOGA (compound 7A) that showed a 6770-fold higher affinity for this enzyme than for hHexB. The corresponding dimeric derivative (compound 9D) further remarkably improved the selectivity in the inhibition of hOGA (2.7 × 104 times more selective for hOGA over hHexB) and the inhibition potency (by one order of magnitude). Docking studies were performed to explain the selectivity of inhibition observed in compound 7A.

Departamento de Química Orgánica Facultad de Química Universidad de Sevilla C Prof García González 1 41012 Sevilla Spain

Laboratory of Biotransformation Institute of Microbiology of the Czech Academy of Sciences Vídeňská 1083 14220 Prague 4 Czech Republic

Laboratory of Biotransformation Institute of Microbiology of the Czech Academy of Sciences Vídeňská 1083 14220 Prague 4 Czech Republic; Faculty of Food and Biochemical Technology University of Chemistry and Technology Prague Technická 1903 3 CZ 16628 Praha 6 Czech Republic

Laboratory of Structural Biology and Informatics Institute of Microbiology of the Czech Academy of Sciences Zámek 136 CZ 37333 Nové Hrady Czech Republic

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