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Synthesis and Biological Evaluation of Iodinated Fidaxomicin Antibiotics


Dorst, Andrea; Shchelik, Inga S; Schäfle, Daniel; Sander, Peter; Gademann, Karl (2020). Synthesis and Biological Evaluation of Iodinated Fidaxomicin Antibiotics. Helvetica Chimica Acta, 103(9):e2000130.

Abstract

Fidaxomicin (1, tiacumicin B, lipiarmycin A3) is a marketed antibiotic that is used in the treatment of Clostridium difficile infections. Based on the analysis of a cryo‐EM structure of fidaxomicin binding to its target enzyme (RNA‐polymerase), a cation‐π 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 the search for new fidaxomicin analogs. Herein, we report the first semisynthetic access to new fidaxomicin analogs with varying halogen substituents through 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.

Abstract

Fidaxomicin (1, tiacumicin B, lipiarmycin A3) is a marketed antibiotic that is used in the treatment of Clostridium difficile infections. Based on the analysis of a cryo‐EM structure of fidaxomicin binding to its target enzyme (RNA‐polymerase), a cation‐π 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 the search for new fidaxomicin analogs. Herein, we report the first semisynthetic access to new fidaxomicin analogs with varying halogen substituents through 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
04 Faculty of Medicine > Institute of Medical Microbiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Physical Sciences > Catalysis
Life Sciences > Biochemistry
Life Sciences > Drug Discovery
Physical Sciences > Physical and Theoretical Chemistry
Physical Sciences > Organic Chemistry
Physical Sciences > Inorganic Chemistry
Language:English
Date:21 July 2020
Deposited On:19 Jan 2021 12:32
Last Modified:24 Jan 2021 08:47
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0018-019X
OA Status:Closed
Publisher DOI:https://doi.org/10.1002/hlca.202000130

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Content: Accepted Version
Filetype: PDF - Registered users only until 21 July 2021
Size: 656kB
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Embargo till: 2021-07-21