AROMATIC DICATIONS AS ANTI-OPPORTUNISTIC INFECTION AGENTS

这个项目的主要目标是设计和合成新的 阳离子分子治疗艾滋病相关机会性疾病 感染。拟议的项目将建立在我们的 头两年的资金。在此期间，我们获得了相当大的收益 对其作用机制、毒性和药代动力学的深入研究 阳离子化合物。我们实验室开发的一种化合物，用于 卡氏肺炎的治疗目前处于临床前试验阶段， 计划在1994年底之前进行第一阶段临床试验。此外, 我们证明了这些化合物对C. 微小念珠菌、新生葡萄球菌、白色念珠菌和结核分枝杆菌。把这些放在一起 机会性病原体占发病率的大部分， 艾滋病患者的死亡率。单一治疗药物的开发 其中两种或两种以上的感染在 艾滋病患者的临床管理。 新化合物的设计将重点放在两个方面：L)设计 基于表观关系的具有改进活性的新型结构 抗菌活性与富含AT的DNA小沟槽的结合 以及对微生物(超过哺乳动物)拓扑异构酶的选择性抑制。Ii) 结构修改将极大地增加这些设备的容量 从胃肠道吸收的强阳离子分子。这个 本项目中建议的结构将补充 项目二(博伊金)。这两种合成纤维的综合生产率 实验室允许进行广泛的结构修改，从而 到一个全面的结构/活动数据库。这将提供一个 大好时机梳理反腐败行动机制(S) 精选的生物体。 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 生化和酶研究(Dykstra)，生物物理学 研究与计算机模拟(威尔逊)，分子生物学 调查(完美)和抗菌研究(布拉本；霍尔； 完美)。提高药物效力的设计战略将包括 以下因素：L)曲率半径2)阳离子放置 基团3)面向DNA表面的氢键供体和受体4) 背离DNA表面的大基团以增强对DNA的抑制 定向的酶和延伸的分子覆盖6-8个碱基对 相比之下，有3-4个碱基对。提高口语能力的主要途径 该分子的生物利用度将包括合成前药和 Zwitterion。前药方法将重点放在分子的设计上 这降低了阳离子化合物的pKa，从而允许增加 从胃肠道摄取。这些前分子就会成为 代谢回具有生物活性的强电荷药。这个 两性离子方法将导致阳离子基团的中和 伴随而来的是从肠道吸收的增加。 成功完成拟议的工作应导致新的口头- 用于治疗艾滋病的一些重要的活跃剂 机会主义的病原体。

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.