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Synthesis and Structure-Activity Relationship of Xenocoumacin 1 and Analogues as Inhibitors of Ribosomal Protein Synthesis.
- Source :
-
ChemMedChem [ChemMedChem] 2021 Mar 03; Vol. 16 (5), pp. 891-897. Date of Electronic Publication: 2020 Dec 11. - Publication Year :
- 2021
-
Abstract
- Ribosomal protein synthesis is an important target in antibacterial drug discovery. Numerous natural products have served as starting points for the development of antibiotics. We report here the total synthesis of xenocoumacin 1, a natural product that binds to 16S ribosomal RNA at a highly conserved region, as well as analogues thereof. Preliminary structure-activity relationship studies were aimed at understanding and modulating the selectivity between eukaryotic and prokaryotic ribosomes. Modifications were mainly tolerated in the aromatic region. Whole-cell activity against Gram-negative bacteria is limited by efflux and penetration, as demonstrated in genetically modified strains of E. coli. Analogues with high selectivity for eukaryotic ribosomes were identified, but it was not possible to obtain inhibitors selective for bacterial protein synthesis. Achieving high selectivity (albeit not the desired one) was thus possible despite the high homology between eukaryotic and prokaryotic ribosomes in the binding region.<br /> (© 2020 Wiley-VCH GmbH.)
- Subjects :
- Anti-Bacterial Agents chemistry
Benzopyrans chemistry
Crystallography, X-Ray
Dose-Response Relationship, Drug
Escherichia coli metabolism
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Ribosomal Proteins biosynthesis
Structure-Activity Relationship
Anti-Bacterial Agents pharmacology
Benzopyrans pharmacology
Escherichia coli drug effects
Ribosomal Proteins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1860-7187
- Volume :
- 16
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- ChemMedChem
- Publication Type :
- Academic Journal
- Accession number :
- 33236408
- Full Text :
- https://doi.org/10.1002/cmdc.202000793