Synthesis and biological evaluation of flexible and conformationally constrained LpxC inhibitors

Löppenberg M, Müller H, Pulina C, Oddo A, Teese MG, Jose J, Holl R

Abstract

Inhibitors of the UDP-3- O -[( R )-3-hydroxymyristoyl]- N -acetylglucosamine deacetylase (LpxC) represent promising candidates for the devel opment of antibiotics possessing a so far unexploited mechanism of action. In a chir al pool synthesis, starting from the D -mannose derived mannonolactone 4 , conformationally constrained C -glycosidic as well as open chained hydroxamic acids with a define d stereochemistry were prepared. Diversity was introduced by performing C- C coupling reactions like the Sonogashira and Suzuki cross-coupling reactions. Th e biological evaluation of the synthesized compounds revealed that in case of the C -glycosides a long, linear and Page 2 of 60 Organic & Biomolecular Chemistry Organic & Biomolecular Chemistry Accepted Manuscript Published on 19 July 2013. Downloaded by WESTFALISCHE WILHELMS UNIVERSITAT MUNSTER on 23/07/2013 07:34:20. View Article Online DOI: 10.1039/C3OB41082J rigid hydrophobic side chain is required for antibi otic activity against E. coli . The open chain derivatives show higher biological activity t han the conformationally constrained C -glycosides. The morpholinomethyl substituted open chain derivative 43 , being the most potent compound presented in this paper, inhib its LpxC with a K i value of 0.35 μ M and represents a promising lead structure.