Proline-based hydroxamates targeting the zinc-dependent deacetylase LpxC: Synthesis, antibacterial properties, and docking studies.

Basic Information

ID: ALA4392848

Journal: Bioorg Med Chem

Title: Proline-based hydroxamates targeting the zinc-dependent deacetylase LpxC: Synthesis, antibacterial properties, and docking studies.

Authors: Kalinin DV, Agoglitta O, Van de Vyver H, Melesina J, Wagner S, Riemann B, Schäfers M, Sippl W, Löffler B, Holl R.

Abstract: The Zn²⁺-dependent deacetylase LpxC is an essential enzyme in Gram-negative bacteria, which has been validated as antibacterial drug target. Herein we report the chiral-pool synthesis of novel d- and l-proline-derived 3,4-dihydroxypyrrolidine hydroxamates and compare their antibacterial and LpxC inhibitory activities with the ones of 4-monosubstituted and 3,4-unsubstituted proline derivatives. With potent antibacterial activities against several Gram-negative pathogens, the l-proline-based tertiary amine 41g ((S)-N-hydroxy-1-(4-{[4-(morpholinomethyl)phenyl]ethynyl}benzyl)pyrrolidine-2-carboxamide) was found to be the most active antibacterial compound within the investigated series, also showing some selectivity toward EcLpxC (K_i = 1.4 μM) over several human MMPs.

CiteXplore: 30954331

DOI: 10.1016/j.bmc.2019.03.056

Patent ID: ┄

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