LIPOPHILIC ANTIFOLATES AND AIDS OPPORTUNISTIC INFECTIONS

描述：（改编自申请人的摘要。）的总目标 所提出的工作是发现新的抗PC和TG的药剂 感染，两种威胁生命的机会性疾病， 艾滋病相关综合征（ARC） 具体而言，该项目将 重点设计和合成新型双环和三环 二氨基嘧啶环系统结构相关的亲脂性 二氢叶酸还原酶（DHFR）抑制剂曲美曲嗪（TMX）和吡曲辛 （PTX）。 最近发现TMX和PTX具有很好的活性 当给予亚叶酸（FA）以保护宿主组织时， 从抗叶酸毒性，并可能提供一些优势， 抗叶酸药物如甲氧苄啶和磺胺类药物。 化合物 在这个项目中合成的将包括六个一般类型的浓缩 二氨基嘧啶环系统，并在每个小组的初步重点将是 在芳基部分中具有至少两个甲氧基的类似物上， 模式已存在于TMX和PTX中。 然而，合成方案将 足够普遍，可与其他环制备同系物 取代基，包括例如卤素。 目标化合物将是 评价其抑制DHFR哺乳动物细胞和PC的能力， TG以确定是否显示对任一寄生虫的选择性 内切酶 这些化合物还将测试抑制PC的能力。 和TG的增殖作用 叶酸的存在。 如果任何化合物显示出足够的活性， 由于在这些体外测定中的选择性，它将在更大的 规模以提供足够的材料用于随后的体内药理学和 小鼠或其他动物的毒理学研究。

DESCRIPTION: (Adapted from the applicant's abstract.) The overall goal of the proposed work is the discovery of new agents against PC and TG infections, two life-threatening opportunistic diseases associated with AIDS and AIDS-related complex (ARC). More specifically, this project will focus on the design and synthesis of novel dicyclic and tricyclic diaminopyrimidine ring systems structurally related to the lipophilic dihydrofolate reductase (DHFR) inhibitors trimetrexate (TMX) and piritrexim (PTX). TMX and PTX have been found recently to have promising activity against PC and TG when given with folinic acid (FA) to protect host tissues from antifolate toxicity, and may offer some advantages over older antifolate drugs such as trimethoprim and the sulfonamides. Compounds to be synthesized in this project will include six general types of condensed diaminopyrimidine ring systems, and initial emphasis in each group will be on analogs with at least two methoxy groups in the aryl moiety, since this pattern already exists in TMX and PTX. However, the synthetic schemes will be general enough to allow preparation of congeners with other ring substituents, including, for example, halogens. Target compounds will be evaluated for their ability to inhibit DHFR mammalian cell and from PC and TG to determine whether selectivity is shown for either of the parasite enzymes. The compounds will also be tested for the ability to inhibit PC and TG proliferation in rat lung fibroblast monolayer culture in the presence of folinic acid. If any compound shows enough activity and selectivity in these in vitro assays, it will be re-synthesized on a larger scale to provide enough material for subsequent in vivo pharmacological and toxicological studies in mice or other animals.