|Publication Type||Journal Article|
|Year of Publication||2009|
|Authors||Martyn, DC, Beletsky, G, Cortese, JF, Tyndall, E, Liu, H, Fitzgerald, MM, O'Shea, TJ, Liang, B, Clardy, J|
|Journal||Bioorg Med Chem Lett|
|Date Published||2009 Oct 01|
|Keywords||Animals, Antimalarials, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System, Dioxolanes, Humans, Microsomes, Liver, Plasmodium falciparum, Protein Isoforms, Rats, Small Molecule Libraries|
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 EC(50)s30nM against Plasmodium falciparum 3D7 and Dd2 strains, and another 15 compounds had EC(50)s50nM 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, LogD 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.
|Alternate Journal||Bioorg. Med. Chem. Lett.|