SULFONE STRUCTURE-ACTIVITY ANALYSIS

用结构-活性分析方法鉴定了新的砜 具有较强抗弓形虫活性的化合物 能够引起艾滋病患者严重感染的原生动物。因为它 已经观察到，这些患者中的大多数人只能耐受 寻找市面上可买到的磺酸、氨苯砜、替代剂。 在这类化合物中。几种磺酸类似物，包括 氨苯砜，被鉴定为IC50s和1muM的有效抑制剂。然而， 平均而言，没有一种类似物比氨苯砜本身更活跃。 因此，藤田的形式主义被用来确定捐款 每种模拟取代基的药物效力，并评估新的 这些取代基的组合可能导致改进的类似物。共21个 所研究的部分，2‘-NH_2，2’-SO_2NH_2，4‘-NH(CH_2)_20H和3’-Cl 研究发现，氨苯砜的替代药物最有可能增强 对弓形虫的活性。对白粉病的进一步抑制研究 纯化的酶靶点排除了显著的增强能力 氨基乙醇衍生物。然而，3‘-c1衍生物的检测 对完好的生物体的攻击显示其活性比 用氨苯砜获得的药物。这些研究表明，磺酸类化合物可能是 治疗弓形虫感染的重要治疗药物。

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.