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Abstract The indolizinium natural product ficuseptine, produced by the tropical fig tree Ficus septica, has been reported to have antibacterial properties. Herein, the synthesis of ficuseptine, ten analogues with differing aryl substituents, and two aryl regioisomers is reported. Despite several previous total syntheses, synthetically prepared ficuseptine has not been subjected to biological testing to confirm its activity. In our hands, ficuseptine was moderately active in Gram-positive B. spizizenii, with an MIC of 32 μg/mL, which was maintained for most aryl substituents. The position of the aryl rings was crucial, however, since regioisomeric ficuseptine analogues, mimicking related natural products, were found to be inactive. Finally, all ficuseptine derivatives were inactive (MIC >128 μg/mL) against Gram-negative E. coli. Understanding these structure–activity relationships (SAR) is helpful for future studies to understand the molecule’s mechanism of action or further develop its antibacterial properties.
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Stabilizing Pseudouridimycin: Synthesis, RNA Polymerase Inhibitory Activity, and Antibacterial Activity of Dipeptide‐Modified Analogues
Abstract Pseudouridimycin (PUM) is a microbially produced C‐nucleoside dipeptide that selectively targets the nucleotide addition site of bacterial RNA polymerase (RNAP) and that has a lower rate of spontaneous resistance emergence relative to current drugs that target RNAP. Despite its promising biological profile, PUM undergoes relatively rapid decomposition in buffered aqueous solutions. Here, we describe the synthesis, RNAP‐inhibitory activity, and antibacterial activity of chemically stabilized analogues of PUM. These analogues feature targeted modifications that mitigate guanidine‐mediated hydroxamate bond scission. A subset of analogues in which the central hydroxamate is replaced with amide or hydrazide isosteres retain the antibacterial activity of the natural product.
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- Award ID(s):
- 2109008
- PAR ID:
- 10484941
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- ChemMedChem
- Volume:
- 19
- Issue:
- 1
- ISSN:
- 1860-7179
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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