Identification of a broad-Spectrum azasordarin with improved pharmacokinetic properties

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. The synthesis and antifungal activity of novel azasordarin derivatives are described.