Research paper Chiral pool synthesis and biological evaluation of C-furanosidic and acyclic LpxC inhibitors Hannes Müller a , Valeria Gabrielli a , Oriana Agoglitta a, c , Ralph Holl a, b, * a Institut für Pharmazeutische und Medizinische Chemie der Westf€ alischen Wilhelms-Universit€ at Münster, Corrensstr. 48, D-48149 Münster, Germany b Cells-in-Motion Cluster of Excellence (EXC 1003 e CiM), University of Münster, Germany c NRW Graduate School of Chemistry, University of Münster, Germany article info Article history: Received 9 November 2015 Received in revised form 13 January 2016 Accepted 14 January 2016 Available online 20 January 2016 Keywords: LpxC inhibitors Structure-activity relationships Chiral pool synthesis C-glycosides Benzyloxyacetohydroxamic acids abstract 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 K i -values of 0.35 mM and 0.23 mM, the (S,S)-configured open-chain derivatives 8b and 8c were found to be the most potent LpxC inhibitors of these series of compounds. © 2016 Elsevier Masson SAS. All rights reserved. 1. Introduction Nowadays many bacteria have developed resistance to various classes of antibiotics [1]. Especially among Gram-negative bacteria, some pandrug-resistant strains, being resistant towards all avail- able antibiotics, have already been found [2]. For the successful treatment of infections caused by these bacteria, novel antibiotics, possessing a so far unexploited mode of action, are urgently required. The inhibition of lipid A biosynthesis is a promising strategy to combat Gram-negative bacteria. Lipid A is the lipophilic part of li- popolysaccharides (LPS), anchoring the molecules in the outer monolayer of the outer membrane of Gram-negative bacteria, and, when being released, elicits an activation of the mammalian innate immune system, which can evoke septic shock [3]. In Escherichia coli, lipid A-Kdo 2 is synthesized via nine consecutive steps of which the second one, the deacetylation of UDP-3-O-[(R)-3- hydroxymyristoyl]-N-acetylglucosamine (1) representing the first irreversible reaction of this biosynthetic pathway, is catalyzed by the Zn 2þ -dependent deacetylase LpxC (Fig. 1) [4]. As inhibition of lipid A biosynthesis is lethal to Gram-negative bacteria and due to the fact that LpxC is highly conserved among these bacteria but shows no homology with mammalian proteins, this deacetylase seems to be a suitable target for the development of antibiotics, being able to cure infections caused by Gram-negative bacteria [4,5]. In the literature, several structurally diverse LpxC inhibitors have been described, like for example the substrate analog TU-514 (3) [6], the sulfonamide BB-78485 (4) [7], the aryloxazoline L- 161,240 (5) [5] and the N-aroyl-L-threonine derivative CHIR-090 (6) [8] (Fig. 2). Most of the described LpxC inhibitors possess a Zn 2þ - chelating hydroxamate moiety and a lipophilic side chain, mimicking the fatty acyl moiety of the natural substrate of LpxC. Based on the structure of CHIR-090 (6), a series of benzylox- yacetohydroxamic acids was developed, like C-glycosides 7aec, open-chain diols 8a and 8b as well as ethylene glycol derivatives 9a and 9b lacking the hydroxymethyl group in a-position of the hydroxamate moiety (Fig. 3) [9e11]. * Corresponding author. Institut für Pharmazeutische und Medizinische Chemie der Westf€ alischen Wilhelms-Universit€ at Münster, Corrensstr. 48, D-48149 Münster, Germany. E-mail address: hollr@uni-muenster.de (R. Holl). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2016.01.032 0223-5234/© 2016 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 110 (2016) 340e375