It has been shown that dapsone and its derivatives are not only potential inhibitors of bacterial and plasmodial folate synthesis but also possess antiin¯ammatory activity. The application of dapsone is, however, limited by its toxic side effects at higher dose manifested especially by its potential to produce methaemoglobin. We have analyzed the structural dependence of this property on a set of 29 derivatives. A highly signi®cant nonlinear dependence on the lipophilicity could be derived. Two exceptions to the general relation were found and the mechanism for these could be derived. It was also shown that the bilinear dependence is not due to lipophilicity mediated diffusion into erythrocytes. It was found that the diffusion is linearly dependent on lipophilicity. Principal Component (PC)-Analysis revealed that the antiin¯ammatory activities, determined as inhibition of zymosane stimulated cell burst and cell adhesion are orthogonal to methaemoglobin formation and cell death potential of the studied derivatives. The antiin¯ammatory activity seems to depend on electronic and steric effects of the 2 H -substituents. The orthogonality of substituent in¯uences on the toxic and wanted effects opens up the possibility to further optimize the selectivity of aminodiphenylsulphones.

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