The antimalarial activity of a series of synthetic 1,2,4-trioxanes is correlated with molecular structure by using a pharmacophore search method (CATALYST). The technique is shown to have predictive accuracy and confirms that docking between an active trioxane and the receptor, heme, is the crucial step for drug action.

The main geometric elements of three 3,6-substituted 1,2,4-trioxan-5-ones have been calculated by using molecular mechanics (MM2), and semiempirical (AM1, PM3) methods. The results are compared with those obtained by X-ray analysis.

The 3,6-substituted 1,2,4-trioxan-5-ones 11-14, on heating to 170-200°, underwent unimolecular thermolysis to generate electronically excited singlet ketones with an efficiency of ca. 0.2%. The chemiluminescence quantum yields (ΦoS_CL) depended on the nature of the 6-substitutents and increased linearly with temperature. The Arrhenius activation energies were obtained by measuring the rate of decay of luminescence and determined as 22.9, 30.4, 35.6, and 34.2 kcal/mol for 11-14, respectively. Step analysis of the chemiluminescence of 14 afforded an average activation energy of 44.3 kcal/mol. This latter result is explicable in terms of two decomposition paths, higher and lower in energy, leading to excited and 'dark' products, respectively. The thermolysis of trioxanones 12-14 lacking a H-atom at the 6-position is interpreted as involving successive rupture of the peroxide bond, excision of ketone at the 3-substituted end, and loss of CO₂, to finally produce ketone originating from the 6-position (see Scheme 4).

The vibrational spectra of some 1,2,4-trioxanes present two characteristic bands at 790 and 880 cm^−1. On the basis of ¹⁸O-isotopic substitution and comparison with analogous compounds, these bands have been assigned to coupled C—O and O—O stretching modes of the C—O—O element.