Issue in Honor of Prof. G. Karabatsos ARKIVOC 2002 (xiii) 62-69 ISSN 1424-6376 Page 62 © ARKAT USA, Inc Antimalarial endoperoxides: synthesis and implications of the mode of action Constantinos Koutsoupakis, Irene Gialou, Eleni Pavlidou, Sofia Kapetanaki, and Constantinos Varotsis* Department of Chemistry, University of Crete, Heraklion 71409, Crete, Greece E-mail: varotsis@edu.uoc.gr Dedicated to Professor Gerasimos J. Karabatsos on the occasion of his 70 th birthday (received 01 Mar 03; accepted 09 Jul 03; published on the web 09 Jul 03) Abstract 6,7-Dioxabicyclo[3.2.2]non-8-ene 2 and 1-isopropyl-4-methyl-2,3-dioxabicyclo[2.2.2]oct-5-ene (ascaridol) 3 were prepared as simplified, endoperoxide versions of clinically used antimalarial drugs. Fourier transform infrared (FTIR) technique in conjunction with 18 O 2 -enriched compound 2 has been applied in probing the bonds of the endoperoxide moiety and the bonds of the rings owing to the presence of the O–O, the C–O, the O–O–C as well as the C=O modes in the spectrum. The endoperoxide moiety is especially useful in this regard because the homolytic cleavage of the O–O bond can be characterized and hence can be used to assess the vibrational properties of the O- and C-centered radicals and subsequently that of the C–C bond cleavage. The cleavage of the O–O bond, and the ability to correlate vibrational properties of the reaction products with structural properties of the isolated products suggest that infrared spectroscopy is an appropriate tool to study the mode of action of antimalarial endoperoxides. Keywords: FTIR spectroscopy, 18 O 2 endoperoxide, O–O bond cleavage mechanism Introduction Malaria is one of the most widespread parasitic diseases caused by invasion protozoan parasites of the class of Plasmodium into the human body. 1 It is estimated that there are 240 million people who are chronically affected, and there are 120 million new cases reported every year. 2,3 There is a general consensus that antimalarial peroxides, both of natural and synthetic origin, kill the Plasmodium parasite through a mode of action that is entirely different from that of the traditional quinoline-based drugs such as quinine and chloroquine. 4 While the mechanism of action of the antimalarial endoperoxides is not completely understood, there is growing evidence that the initial key step is the reductive cleavage of the O–O bond of the endoperoxide moiety,