Acetylenic Replacement of Albicidin's Methacrylamide Residue Circumvents Detrimental E/Z Photoisomerization and Preserves Antibacterial Activity.
| Autor: | Behroz I; Institut für Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623, Berlin, Germany., Kleebauer L; Institut für Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623, Berlin, Germany., Hommernick K; Institut für Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623, Berlin, Germany., Seidel M; Institut für Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623, Berlin, Germany., Grätz S; Institut für Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623, Berlin, Germany., Mainz A; Institut für Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623, Berlin, Germany., Weston JB; Institut für Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623, Berlin, Germany., Süssmuth RD; Institut für Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623, Berlin, Germany. |
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| Jazyk: | angličtina |
| Zdroj: | Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2021 Jun 21; Vol. 27 (35), pp. 9077-9086. Date of Electronic Publication: 2021 May 21. |
| DOI: | 10.1002/chem.202100523 |
| Abstrakt: | The natural product albicidin is a highly potent inhibitor of bacterial DNA gyrase. Its outstanding activity, particularly against Gram-negative pathogens, qualifies it as a promising lead structure in the search for new antibacterial drugs. However, as we show here, the N-terminal cinnamoyl moiety of albicidin is susceptible to photochemical E/Z isomerization. Moreover, the newly formed Z isomer exhibits significantly reduced antibacterial activity, which hampers the development and biological evaluation of albicidin and potent derivatives thereof. Hence, we synthesized 13 different variants of albicidin in which the vulnerable para-coumaric acid moiety was replaced; this yielded photostable analogues. Biological activity assays revealed that diaryl alkyne analogues exhibited virtually undiminished antibacterial efficacy. This promising scaffold will therefore serve as a blueprint for the design of a potent albicidin-based drug. (© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.) |
| Databáze: | MEDLINE |
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