Investigating Amine Derivatives of Ambruticin VS‐5 and VS‐4

Abstract

A structure-activity relationship around the amine group of the ambruticin VS series has been developed for antifungal activity. It was shown that the amine can be alkylated through reductive amination without loss of potency. However, if it is converted into either an amide, carbamate, or urea, a significant loss of potency is observed. Of the alkyl amines, small nonpolar groups are optimal for both potency and oral bioavailability. As a result of this study, one compound (KOS-2079) was taken into an animal efficacy model with success.

Current Landscape of Coccidioidomycosis

“…Ambruticin S, a compound first discovered in the 1970s, proved promising in activity against C. immitis [83,84]. Its antifungal activity is attributed to the effect on osmoregulation via the high-osmolarity glycerol (HOG) signaling pathway [85][86][87][88][89]. Murine modelling of analogs of the compound verified in vivo activity against CM.…”

Total Synthesis of Complex Biosynthetic Late-Stage Intermediates and Bioconversion by a Tailoring Enzyme from Jerangolid Biosynthesis

“…They are closely related to the ambruticins ( 2 ), with which they share the assumed pharmacophoric unit consisting of a dihydropyran (DHP) and a skipped diene (Figure a). Beside pyrrolnitrin, they are the only known compounds which target the high osmolarity glycerol (HOG) signaling pathway. − Total syntheses of natural jerangolids and ambruticins are described in the literature, and semisynthetic efforts gave rise to ambruticin libraries with variations in the western part of the molecule. − No access to libraries that would allow investigating the effect of alterations in the pharmacophore are yet reported.…”