1395409-48-9Relevant academic research and scientific papers
Chiral pool synthesis and biological evaluation of C-furanosidic and acyclic LpxC inhibitors
Müller, Hannes,Gabrielli, Valeria,Agoglitta, Oriana,Holl, Ralph
, p. 340 - 375 (2018/11/21)
Inhibitors of the bacterial deacetylase LpxC have emerged as a promising new class of Gram-negative selective antibacterials. In order to find novel LpxC inhibitors, in chiral-pool syntheses starting from D-mannose, C-furanosides with altered configuration in positions 2 and/or 5 of the tetrahydrofuran ring were prepared in stereochemically pure form. Additionally, the substitution pattern in positions 3 and 4 of the tetrahydrofuran ring as well as the structure of the lipophilic side chain in position 2 were varied. Finally, all stereoisomers of the respective open chain diols were obtained via glycol cleavages of properly protected C-glycosides. The biological evaluation of the synthesized hydroxamic acids revealed that in case of the C-glycosides, 2,5-trans-configuration generally leads to superior inhibitory and antibacterial activities. The relief of the conformational strain leading to the respective open chain derivatives generally caused an increase in the inhibitory and antibacterial activities of the benzyloxyacetohydroxamic acids. With Ki-values of 0.35 μM and 0.23 μM, the (S,S)-configured open-chain derivatives 8b and 8c were found to be the most potent LpxC inhibitors of these series of compounds.
Synthesis and biological evaluation of flexible and conformationally constrained LpxC inhibitors
L?ppenberg, Marius,Müller, Hannes,Pulina, Carla,Oddo, Alberto,Teese, Mark,Jose, Joachim,Holl, Ralph
supporting information, p. 6056 - 6070 (2013/09/12)
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 K i value of 0.35 μM and represents a promising lead structure. The Royal Society of Chemistry.
Design and stereoselective synthesis of a C-aryl furanoside as a conformationally constrained CHIR-090 analogue
Oddo, Alberto,Holl, Ralph
, p. 59 - 64,6 (2020/08/31)
The UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) is a promising target for the development of novel antibiotic substances against multidrug-resistant Gram-negative bacteria. The C-aryl glycoside 3 was designed as conformationally constrained analogue of the potent LpxC-inhibitor CHIR-090. The chiral pool synthesis of 3 started with d-mannose. The C-aryl glycoside 8 was synthesized stereoselectively by nucleophilic attack of 4-iodine-substituted phenyllithium and subsequent reduction with Et 3SiH. The ester 10 was obtained in a one-pot diol cleavage, CrO 3 oxidation, and esterification. A Sonogashira reaction of the aryl iodide 11 led to the alkyne 17 which was transformed with H2NOH into the hydroxamic acid 3.
