Synthesis and biological evaluation of flexible and conformationally constrained LpxC inhibitors

TY - JOUR

T1 - Synthesis and biological evaluation of flexible and conformationally constrained LpxC inhibitors

AU - Löppenberg, Marius

AU - Müller, Hannes

AU - Pulina, Carla

AU - Oddo, Alberto

AU - Teese, Mark

AU - Jose, Joachim

AU - Holl, Ralph

PY - 2013/9/28

Y1 - 2013/9/28

N2 - Inhibitors of the UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) represent promising candidates for the development of antibiotics possessing a so far unexploited mechanism of action. In a chiral pool synthesis, starting from the D-mannose derived mannonolactone 4, conformationally constrained C-glycosidic as well as open chained hydroxamic acids with a defined stereochemistry were prepared. Diversity was introduced by performing C–C coupling reactions like the Sonogashira and Suzuki cross-coupling reactions. The biological evaluation of the synthesized compounds revealed that in the case of the C-glycosides a long, linear and rigid hydrophobic side chain is required for antibiotic activity against E. coli. The open chain derivatives show higher biological activity than the conformationally constrained C-glycosides. The morpholinomethyl substituted open chain derivative 43, being the most potent compound presented in this paper, inhibits LpxC with a Ki value of 0.35 μM and represents a promising lead structure.

AB - Inhibitors of the UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) represent promising candidates for the development of antibiotics possessing a so far unexploited mechanism of action. In a chiral pool synthesis, starting from the D-mannose derived mannonolactone 4, conformationally constrained C-glycosidic as well as open chained hydroxamic acids with a defined stereochemistry were prepared. Diversity was introduced by performing C–C coupling reactions like the Sonogashira and Suzuki cross-coupling reactions. The biological evaluation of the synthesized compounds revealed that in the case of the C-glycosides a long, linear and rigid hydrophobic side chain is required for antibiotic activity against E. coli. The open chain derivatives show higher biological activity than the conformationally constrained C-glycosides. The morpholinomethyl substituted open chain derivative 43, being the most potent compound presented in this paper, inhibits LpxC with a Ki value of 0.35 μM and represents a promising lead structure.

U2 - 10.1039/c3ob41082j

DO - 10.1039/c3ob41082j

M3 - Journal article

C2 - 23917427

SN - 1477-0520

VL - 11

SP - 6056

EP - 6070

JO - Organic & Biomolecular Chemistry

JF - Organic & Biomolecular Chemistry

IS - 36

ER -