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Bioorg Med Chem Lett DOI:10.1016/j.bmcl.2009.08.024

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

Publication TypeJournal Article
Year of Publication2009
AuthorsMartyn, DC, Beletsky, G, Cortese, JF, Tyndall, E, Liu, H, Fitzgerald, MM, O'Shea, TJ, Liang, B, Clardy, J
JournalBioorg Med Chem Lett
Date Published2009 Oct 01
KeywordsAnimals, 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 JournalBioorg. Med. Chem. Lett.
PubMed ID19699641