Divergent Synthesis of Novel Cylindrocyclophanes that Inhibit Methicillin-Resistant Staphylococcus aureus (MRSA).
cross metathesis
cylindrocyclophane
macrocycles
ring-closing metathesis
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
20 07 2020
20 07 2020
Historique:
received:
23
03
2020
pubmed:
20
5
2020
medline:
16
6
2021
entrez:
20
5
2020
Statut:
ppublish
Résumé
The cylindrocyclophanes are a family of macrocyclic natural products reported to exhibit antibacterial activity. Little is known about the structural basis of this activity due to the challenges associated with their synthesis or isolation. We hypothesised that structural modification of the cylindrocyclophane scaffold could streamline their synthesis without significant loss of activity. Herein, we report a divergent synthesis of the cylindrocyclophane core enabling access to symmetrical macrocycles by means of a catalytic, domino cross-metathesis-ring-closing metathesis cascade, followed by late-stage diversification. Phenotypic screening identified several novel inhibitors of methicillin-resistant Staphylococcus aureus. The most potent inhibitor has a unique tetrabrominated [7,7]paracyclophane core with no known counterpart in nature. Together these illustrate the potential of divergent synthesis using catalysis and unbiased screening methods in modern antibacterial discovery.
Identifiants
pubmed: 32424962
doi: 10.1002/cmdc.202000179
pmc: PMC7522682
doi:
Substances chimiques
Anti-Bacterial Agents
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1289-1293Subventions
Organisme : Medical Research Council
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/M019411
Pays : United Kingdom
Informations de copyright
© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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