Quantitative structure-activity and structure-toxicity relationships of 4-aminodiphenyl sulphone derivatives with antiinflammatory activity

It has been shown that dapsone and its derivatives are not only potential i nhibitors of bacterial and plasmodial folate synthesis but also possess ant iinflammatory activity. The application of dapsone is, however, limited by its toxic side effects at higher dose manifested especially by its potentia l to produce methaemoglobin. We have analyzed the structural dependence of this property on a set of 29 derivatives. A highly significant nonlinear de pendence on the lipophilicity could be derived. Two exceptions to the gener al relation were found and the mechanism for these could be derived. It was also shown that the bilinear dependence is not due to lipophilicity mediat ed diffusion into erythrocytes. It was found that the diffusion is linearly dependent on lipophilicity. Principal Component (PC)-Analysis revealed tha t the antiinflammatory activities, determined as inhibition of zymosane sti mulated cell burst and cell adhesion are orthogonal to methaemoglobin forma tion and cell death potential of the studied derivatives. The antiinflammat ory activity seems to depend on electronic and steric effects of the 2'-sub stituents. The orthogonality of substituent influences on the toxic and wan ted effects opens up the possibility to further optimize the selectivity of aminodiphenylsulphones.