Semisynthetic Analogs of the Antibiotic Fidaxomicin-Design, Synthesis, and Biological Evaluation.

Autor:	Dorst A; Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland., Berg R; Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland., Gertzen CGW; Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf and John von Neumann Institute for Computing (NIC), Institute of Biological Information Processing (IBI-7: Structural Biochemistry) & Jülich Supercomputing Centre (JSC), Forschungszentrum Jülich, 40225 Düsseldorf, Germany., Schäfle D; Institute of Medical Microbiology, University of Zurich, Gloriastrasse 28/30, 8006 Zurich, Switzerland., Zerbe K; Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland., Gwerder M; Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland., Schnell SD; Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland., Sander P; Institute of Medical Microbiology, University of Zurich, Gloriastrasse 28/30, 8006 Zurich, Switzerland.; National Center for Mycobacteria, University of Zurich, Gloriastrasse 28/30, 8006 Zurich, Switzerland., Gohlke H; Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf and John von Neumann Institute for Computing (NIC), Institute of Biological Information Processing (IBI-7: Structural Biochemistry) & Jülich Supercomputing Centre (JSC), Forschungszentrum Jülich, 40225 Düsseldorf, Germany., Gademann K; Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2020 Oct 14; Vol. 11 (12), pp. 2414-2420. Date of Electronic Publication: 2020 Oct 14 (Print Publication: 2020).
DOI:	10.1021/acsmedchemlett.0c00381
Abstrakt:	The glycoslated macrocyclic antibiotic fidaxomicin ( 1 , tiacumicin B, lipiarmycin A3) displays good to excellent activity against Gram-positive bacteria and was approved for the treatment of Clostridium difficile infections (CDI). Among the main limitations for this compound, its low water solubility impacts further clinical uses. We report on the synthesis of new fidaxomicin derivatives based on structural design and utilizing an operationally simple one-step protecting group-free preparative approach from the natural product. An increase in solubility of up to 25-fold with largely retained activity was observed. Furthermore, hybrid antibiotics were prepared that show improved antibiotic activities. Competing Interests: The authors declare the following competing financial interest(s): A patent application (WO2019135010A1, EP18150671.8A) was filed Jan 8th, 2018 that includes antibiotics presented in this work. (© 2020 American Chemical Society.)
Databáze:	MEDLINE
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