ABSTRACT
The synthesis and antifungal activity of 5'- and 5'-6'-substituted azasordarin derivatives are described. Modification of the 5'-position led to the discovery of the spirocyclopentyl analogue 7g, which is the first azasordarin to register single-digit MIC values versus Aspergillus spp. Further investigation identified the 5'-i-Pr derivative 7b, which displays superior pharmacokinetic properties compared to other azasordarins.
Subject(s)
Antifungal Agents/chemistry , Antifungal Agents/pharmacokinetics , Aza Compounds/chemical synthesis , Aza Compounds/pharmacokinetics , Administration, Oral , Animals , Antifungal Agents/pharmacology , Aspergillus/drug effects , Aza Compounds/chemistry , Aza Compounds/pharmacology , Glycosides/chemistry , Indenes , Injections, Intravenous , Mice , Microbial Sensitivity Tests , Spiro Compounds/chemistry , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Core-modified sordaricin derivatives were prepared via biotransformation followed by chemical modification and tested for antifungal activity. The antifungal activity proved to be very sensitive to modifications in the sterics and/or lipophilicity of the diterpene skeleton. Introduction of polar groups such as hydroxyl in the diterpene core results in loss of potency while small and lipophilic groups such as fluorine and the 7,8-olefin are well tolerated.