Synthesis and Kinetic
Evaluation of Cyclophostin and
Cyclipostins Phosphonate Analogs As Selective and Potent Inhibitors
of Microbial Lipases
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Abstract
A new series of customizable diastereomeric <i>cis-</i> and <i>trans</i>-monocyclic enol-phosphonate analogs to
Cyclophostin and Cyclipostins were synthesized. Their potencies and
mechanisms of inhibition toward six representative lipolytic enzymes
belonging to distinct lipase families were examined. With mammalian
gastric and pancreatic lipases no inhibition occurred with any of
the compounds tested. Conversely, <i>Fusarium solani</i> Cutinase and lipases from <i>Mycobacterium tuberculosis</i> (Rv0183 and LipY) were all fully inactivated. The best inhibitors
displayed a <i>cis</i> conformation (H and OMe) and exhibited
higher inhibitory activities than the lipase inhibitor Orlistat toward
the same enzymes. Our results have revealed that chemical group at
the γ-carbon of the phosphonate ring strongly impacts the inhibitory
efficiency, leading to a significant improvement in selectivity toward
a target lipase over another. The powerful and selective inhibition
of microbial (fungal and mycobacterial) lipases suggests that these
seven-membered monocyclic enol-phosphonates should provide useful
leads for the development of novel and highly selective antimicrobial
agents