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Molecules 2018, 23(11), 2868; https://doi.org/10.3390/molecules23112868

Analogues of Muraymycin Nucleoside Antibiotics with Epimeric Uridine-Derived Core Structures

1
Department of Chemistry, Institute of Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstr. 2, 37077 Göttingen, Germany
2
Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 21 September 2018 / Revised: 28 October 2018 / Accepted: 30 October 2018 / Published: 3 November 2018
(This article belongs to the Special Issue Bioactive Nucleosides and Nucleotides)
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Abstract

Nucleoside analogues have found widespread application as antiviral and antitumor agents, but not yet as antibacterials. Naturally occurring uridine-derived ‘nucleoside antibiotics’ target the bacterial membrane protein MraY, an enzyme involved in peptidoglycan biosynthesis and a promising target for the development of novel antibacterial agents. Muraymycins represent a nucleoside-peptide subgroup of such MraY-inhibiting natural products. As part of detailed structure-activity relationship (SAR) studies on muraymycins and their analogues, we now report novel insights into the effects of stereochemical variations in the nucleoside core structure. Using a simplified version of the muraymycin scaffold, it was shown that some formal inversions of stereochemistry led to about one order of magnitude loss in inhibitory potency towards the target enzyme MraY. In contrast, epimers of the core motif with retained inhibitory activity were also identified. These 5′,6′-anti-configured analogues might serve as novel chemically tractable variations of the muraymycin scaffold for the future development of uridine-derived drug candidates. View Full-Text
Keywords: antibiotics; natural products; nucleoside analogues; structure–activity relationships. antibiotics; natural products; nucleoside analogues; structure–activity relationships.
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Spork, A.P.; Koppermann, S.; Schier (née Wohnig), S.; Linder, R.; Ducho, C. Analogues of Muraymycin Nucleoside Antibiotics with Epimeric Uridine-Derived Core Structures. Molecules 2018, 23, 2868.

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