SULFONE STRUCTURE-ACTIVITY ANALYSIS

砜结构-活性分析

• 批准号: 3916238
• 负责人: P F MORRISON
• 金额: --
• 依托单位: DIVISION OF RESEARCH SERVICES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3916238
• 关键词: Toxoplasma gondii; antiprotozoal agents; chemical structure function; dapsone; drug adverse effect; drug design /synthesis /production; drug screening /evaluation; drug tolerance; pharmacokinetics; sulfones

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.

用构效分析方法鉴定新的砜类化合物