AROMATIC DICATIONS AS ANTI-OPPORTUNISTIC INFECTION AGENTS

本项目的主要目标是设计和合成新颖的 用于治疗艾滋病相关机会性疾病的双阳离子分子 感染.建议的项目将建立在我们的 前两年的融资。在此期间，我们获得了可观的 深入了解的作用机制，毒性和药代动力学 双阳离子化合物。我们实验室开发的一种化合物， 卡氏肺孢子虫肺炎的治疗目前处于临床前试验中， 计划在1994年底前进行第一阶段临床试验。此外，本发明还提供了一种方法， 我们已经证明这些化合物显示出抗C. parvum、小花C. neoformans，新形隐翅虫C. albicans和M.结核综合这些 机会致病菌占发病率的大部分， 艾滋病患者的死亡率。单一药物治疗的发展 两种或两种以上的感染将是非常重要的， 艾滋病患者的临床管理。 新化合物的设计将集中在两个方面： 基于表观关系具有改进活性的新结构 抗微生物活性、与富含AT的DNA小沟结合 和选择性抑制微生物（超过哺乳动物）拓扑异构酶。（二） 结构上的修改，将大大增加这些能力 强双阳离子分子从胃肠道吸收。的 本项目中提出的结构将补充 项目二（博伊金）。两种合成方法的综合生产率 实验室允许广泛的结构修改， 一个全面的结构/活动数据库。这将提供一个 这是一个很好的机会，可以找出对 选择有机体。 更有效和毒性更低的化合物的设计将在很大程度上依赖于 生物化学和酶学研究（Dykstra），生物物理 研究和计算机建模（威尔逊），分子生物学 调查（完美）和抗菌研究（Blagburn; Hall; 完美）。提高药物效力的设计策略将包括 以下因素：1）曲率半径2）阳离子 3）面向DNA表面的氢键供体和受体4） 远离DNA表面的大体积基团，以增强对DNA的抑制 定向酶和5）延伸分子以覆盖6-8个碱基对， 与3-4个碱基对相比。提高口腔健康的主要途径 分子的生物利用度将包括前药的合成， 两性离子前药方法将集中在分子的设计上 这降低了双阳离子化合物的pKa，从而允许增加 从胃肠道摄取。这些前体分子 代谢回生物活性的强电荷指示剂。的 两性方法将导致阳离子基团的中和 并伴随着肠吸收的增加。 成功完成拟议的工作应导致新的口头- 活性剂用于治疗一些重要的艾滋病相关 机会致病菌

The major goal of this project is the design and synthesis of novel dicationic molecules for the treatment of AIDS associated opportunistic infections. The proposed project will build on the momentum created by our first two years of funding. During this period we have gained considerable insight into the mechanism of action, toxicity and pharmacokinetics of dicationic compounds. One compound developed in our laboratory for treatment of P. carinii Pneumonia is currently in preclinical trials and scheduled for Phase 1 clinical trials before the end of 1994. In addition, we have demonstrated that these compounds exhibit activity against C. parvum, C. neoformans, C. albicans, and M. tuberculosis. Together these opportunistic pathogens account for the majority of morbidity and mortality in AIDS patients. The development of a single drug for treatment of two or more of these infections would be extremely important in the clinical management of AIDS patients. The design of new compounds will focus on two areas: l) The design of novel structures with improved activity based on the apparent relationship between antimicrobial activity, binding to AT rich minor grooves of DNA and selective inhibition of microbial (over mammalian) Topoisomerases. II) Structural modifications that will greatly increase the capacity for these strongly dicationic molecules to be absorbed from the GI tract. The structures proposed in this Project will complement compounds proposed in Project II (Boykin). The combined productivity of the two synthetic laboratories allows for a wide range of structural modifications leading to a comprehensive structure/activity data base. This will provide an excellent opportunity to sort out mechanism(s) of action against the selected organisms. The design of more potent and less toxic compounds will relay heavily on biochemical and enzymological investigations (Dykstra), biophysical studies and computer modeling (Wilson), molecular biological investigations (Perfect) and antimicrobial studies (Blagburn; Hall; Perfect). The design strategy for improving drug potency will include the following factors: l)radius of curvature 2) placement of the cationic groups 3) hydrogen bonding donors and acceptors facing the DNA surface 4) bulky groups facing away from the DNA surface to enhance inhibition of DNA directed enzymes and 5) extended molecules to cover 6-8 base pairs as compared to 3-4 base pairs. The major approaches to increasing the oral bioavailability of the molecule will include the synthesis of prodrugs and zwitterions. The prodrug approach will focus on the design of molecules that reduce the pKa of the dicationic compounds, thus allowing increased uptake from the gastrointestinal tract. These promolecules would then be metabolized back to the bioactive strongly charged dications. The zwitterion approach will result in neutralization of the cationic groups and concomitant increased absorption from the gut. Successful completion of the proposed work should lead to new orally- active agents for the treatment of a number of important AIDS related opportunistic pathogens.