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 describ ed. Saturation of the double bond between C-17 and C-20 of fusidic acid pro duces four stereoisomers differing in the configuration at C-17 and C-20. T he structure-activity relationship of the stereoisomers was studied using c omputer-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 cruci al, and there is only a limited space for bioactive side chain conformation s. This investigation demonstrates the essential role of the side chain con formations in relation to antibacterial activity and contradicts earlier as sumptions that the Delta 17(20) bond is an essential feature in the molecul e.