SULFONE STRUCTURE-ACTIVITY ANALYSIS

用构效分析方法鉴定新的砜类化合物

Structure-activity analysis has been employed to identify new sulfone compounds that exhibit strong activity against Toxoplasma gondii, a protozoan capable of inducing serious infection in AIDS patients. Since it has been observed that most of these patients can tolerate the only commercially available sulfone, dapsone, alternative agents were sought within this class of compounds. Several sulfone analogs, including dapsone, were identified as potent inhibitors with IC50s<1muM. However, none of the analogs was more active in the mean than dapsone itself. Accordingly a Fujita-Ban formalism was used to determine the contributions of each analog substituent to drug potency and to assess whether new combinations of these substituents could lead to improved analogs. Of 21 moieties investigated, 2'-NH2, 2'-SO2NH2, 4'-NH(CH2)20H, and 3'C1 substitutions on dapsone were found to be most likely to potentiate activity against T. gondii. Further inhibition studies against the purified enzyme target ruled out a significant potentiating capability of the aminoethanol derivative. However, testing of the 3'-C1 derivative against intact organisms revealed a five-fold increase in activity over that obtained with dapsone. These studies suggest that the sulfones may be important therapeutic agents for the treatment of T.gondii infections.