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The synthesis and antibacterial activity of totarol derivatives. Part 1: modifications of ring-C and pro-drugs.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 1999 Sep; Vol. 7 (9), pp. 1953-64. - Publication Year :
- 1999
-
Abstract
- A series of analogues of, and potential pro-drugs derived from, the potent antibacterial diterpene totarol (1) were synthesized in order to elucidate the minimum structural requirements for antibacterial activity and to seek compounds with good bioavailability in vivo. These analogues varied in the structural features of their aromatic rings and the prodrugs were O-glycosylated derivatives. They were tested in vitro against three gram-positive bacteria: beta-lactamase-positive and high level gentamycin-resistant Enterococcus faecalis, penicillin-resistant Streptococcus pneumoniae, and methicillin-resistant Staphylococcus aureus (MRSA); and against the gram-negative multi-drug-resistant Klebsiella pneumoniae. None of the analogues was more potent than totarol itself, which is effective against these gram-positive bacteria at MIC values of 7 microM. The results were evaluated in terms of a structure-activity relationship and this showed that a phenolic moiety was essential for potent antibacterial activity. Amongst the pro-drugs, totaryl alpha-D-mannopyranoside (22) proved the most active in vitro (MIC 18 microM). The in vivo antibacterial activities of compounds 1, 22 and totarol beta-lactoside (23) were assessed in a mouse model of infection, but they were found to be ineffective. Compounds 1 and 22 were shown to be cytotoxic towards proliferating human cell cultures, CH 2983, HeLa, and MG 63, but only at concentrations of > 30 microM.
- Subjects :
- Abietanes
Alkylation
Animals
Anti-Bacterial Agents chemical synthesis
Anti-Bacterial Agents pharmacology
Cell Line
Cell Survival drug effects
Diterpenes chemical synthesis
Diterpenes pharmacology
Esterification
Glycosylation
Humans
Isomerism
Magnetic Resonance Spectroscopy
Mice
Molecular Structure
Prodrugs chemical synthesis
Prodrugs pharmacology
Spectrum Analysis
Anti-Bacterial Agents chemistry
Diterpenes chemistry
Prodrugs chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 0968-0896
- Volume :
- 7
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 10530944
- Full Text :
- https://doi.org/10.1016/s0968-0896(99)00162-5