Synthesis and in vitro DMPK profiling of a 1,2-dioxolane-based library with activity against Plasmodium falciparum

A 43-member 1,2-dioxolane library was synthesized by coupling a 1,2-dioxolane-3-acetic acid derivative to a range of amines. Ten compounds had EC50s ⩽ 30 nM against Plasmodium falciparum 3D7 and Dd2 strains, and another 15 compounds had EC50s ⩽ 50 nM against both 3D7 and Dd2. The library was then subjected to a range of in vitro DMPK assays, which revealed that side chains with a heteroatom were required for favorable solubility, Log D and membrane permeability. CYP450 inhibition was isoform dependent, with 2C19 and 3A4 particularly susceptible, and the majority of compounds tested against rat and human microsomes were metabolized rapidly.

Graphical abstractThe synthesis, antiplasmodial activity and DMPK properties of a 43-member 1,2-dioxolane library is reported.Figure optionsDownload full-size imageDownload as PowerPoint slide