Credit: © 2009 ACS

Although malaria can be treated with semisynthetic derivatives of artemisinin in combination with other drugs, this disease remains one of the world's biggest killers. There is a continuing need for the development of new artemisinin analogues that have improved biopharmaceutical properties and can be cheaply manufactured.

An international research team led by Jonathan Vennerstrom from the University of Nebraska developed1 the antimalarial compound arterolane, which is now in phase III clinical trials. The activity of the artemisinins is mediated by a peroxide substituent, and although arterolane is closely related, an ozonide assumes this role, giving the molecule an unusual structure for a clinical candidate. Most ozonides are unstable but in this case an adjacent bulky adamantane ring system stabilizes the ozonide sufficiently for arterolane to be an effective drug. Now, Vennerstrom and colleagues have synthesized2 a range of arterolane analogues with improved activity, and found that in vitro potency is not a reliable indicator of in vivo activity.

They elucidated structure–activity relationships for this class of compound and found that both the ozonide and adamantane substituents are essential for antimalarial activity. The ozonide moiety mediates haemoglobin alkylation and digestion within the malarial parasite. Improved understanding of the structure–activity relationships should aid the design of improved clinical candidates, and may lead to much-needed new antimalarial treatments.