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Bioorg Med Chem Lett DOI:10.1016/j.bmcl.2008.10.083

Synthesis of spiro-1,2-dioxolanes and their activity against Plasmodium falciparum.

Publication TypeJournal Article
Year of Publication2008
AuthorsMartyn, DC, Ramirez, AP, Beattie, MJ, Cortese, JF, Patel, V, Rush, MA, Woerpel, KA, Clardy, J
JournalBioorg Med Chem Lett
Date Published2008 Dec 15
KeywordsAmines, Amino Acid Motifs, Animals, Antigens, Protozoan, Antimalarials, Antiprotozoal Agents, Chemistry, Pharmaceutical, Dioxolanes, Drug Design, Heme, Humans, Malaria, Models, Chemical, Peroxides, Plasmodium falciparum

Artemisinin-derived compounds play an integral role in current malaria chemotherapy. Given the virtual certainty of emerging resistance, we have investigated spiro-1,2-dioxolanes as an alternative scaffold. The endoperoxide functionality was generated by the SnCl(4)-mediated annulation of a bis-silylperoxide and an alkene. The first set of eight analogs gave EC(50) values of 50-150 nM against Plasmodium falciparum 3D7 and Dd2 strains, except for the carboxylic acid analog. A second series, synthesized by coupling a spiro-1,2-dioxolane carboxylic acid to four separate amines, afforded the most potent compound (EC(50) approximately 5 nM).


Alternate JournalBioorg. Med. Chem. Lett.
PubMed ID18993067