title: Peroxide bond strength of antimalarial drugs containing an endoperoxide cycle. Relation with biological activity.
abstract: Several endoperoxide compounds are very efficient antimalarial analogues of the natural drug artemisinin. Quantum chemical calculations have been used to correlate the computed free energies of the O-O bond with respect to the total number of oxygen atoms contained in the cycle, and with the size/strain of the cycle (5- or 6-membered cycles). The gas-phase homolysis of the O-O bond has been studied for five- and six-membered oxygenated cycles which are models of the "real" drugs. Our results indicate that, in 6-membered cycles, the stability order is the following: 1,2-dioxane > 1,2,4-trioxane > 1,2,4,5-tetraoxane. In cycles containing 3 oxygen atoms, the 5-membered cycle 1,2,4-trioxolane was found much less stable than its 6-membered counterpart 1,2,4-trioxane. This feature indicates the possible role of the cycle strain for the O-O bond stability, and may also explain the high antimalarial activity of some trioxolane derivatives. Similar trends in the O-O bond strength have been found for the real antimalarial drugs. However, the O-O bond stability is not in itself a decisive argument to anticipate the antimalarial activity of drugs.
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, 28040, Madrid, Spain. israel@quim.ucm.es
authors.forename: Israel
authors.initials: I
authors.lastname: Fernández
authors.forename: Anne
authors.initials: A
authors.lastname: Robert
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D010100:Oxygen / Q000737:chemistry; D021261:Parasitic Sensitivity Tests; D010545:Peroxides / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D011789:Quantum Theory; D013237:Stereoisomerism
chemical_list: D000962:Antimalarials; D010545:Peroxides; D010100:Oxygen