Synthesis and conformational analysis of fusidic acid side chain derivatives in relation to antibacterial activity.
Novel fusidic acid type antibiotics having flexible side chains are described. Saturation of the double bond between C-17 and C-20 of fusidic acid produces four stereoisomers differing in the configuration at C-17 and C-20. The structure-activity relationship of the stereoisomers was studied using computer-assisted analyses of low-energy conformations and crystallographic data. Only one of the four stereoisomers showed potent antibiotic activity comparable with that of fusidic acid, whereas the other three stereoisomers retained little or no activity. The orientation of the side chain is crucial, and there is only a limited space for bioactive side chain conformations. This investigation demonstrates the essential role of the side chain conformations in relation to antibacterial activity and contradicts earlier assumptions that the Delta17(20) bond is an essential feature in the molecule.
Duvold
T
T
Leo Pharmaceutical Products, Industriparken 55, DK-2750 Ballerup, Denmark. tore.duvold@leo-pharma.com
Sørensen
M D
MD
Björkling
F
F
Henriksen
A S
AS
Rastrup-Andersen
N
N
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D015169:Colony Count, Microbial; D005672:Fusidic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation
D000900:Anti-Bacterial Agents; D005672:Fusidic Acid