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Synthesis and Biological Evaluation of Iodinated Fidaxomicin Antibiotics

preprint
revised on 21.07.2020, 10:16 and posted on 21.07.2020, 11:51 by Andrea Dorst, Inga S. Shchelik, Daniel Schäfle, Peter Sander, Karl Gademann

Fidaxomicin (1, tiacumicin B, lipiarmycin A3) is a marketed antibiotic that is used in the treatment of C. difficile infections. Based on the analysis of a cryo- EM structure of fidaxomicin binding to its target enzyme (RNA-polymerase), a cation-p interaction of the aromatic moiety with an arginine residue was identified. Therefore, the variation of the substituents and concurrently changing the electronic properties of the aryl moiety represents an interesting strategy in search for new fidaxomicin analogs. Herein, we report the first semisynthetic access to new fidaxomicin analogs with varying halogen substituents via a Pd-catalyzed hydrodechlorination reaction. Subsequent iodination gave access to the first iodo-fidaxomicin derivatives, which matched or improved antibacterial properties compared to fidaxomicin against Mycobacterium tuberculosis and Staphylococcus aureus ATCC 29213.

Funding

Swiss National Science Foundation (182043)

Swiss National Science Foundation ( 31003A_153349/1)

Swiss Lung Association (2018-02)

History

Email Address of Submitting Author

karl.gademann@uzh.ch

Institution

University of Zurich

Country

Switzerland

ORCID For Submitting Author

/0000-0003-3053-0689

Declaration of Conflict of Interest

A patent application (WO2019135010A1, EP18150671.8A) was filed Jan 8 2018 that includes antibiotics presented in this work.

Version Notes

Updated mechanism, typos corrected, H/D exchange data

Exports