LIPOPHILIC ANTIFOLATES AND AIDS OPPORTUNISTIC INFECTIONS

描述：(改编自申请人的摘要。)的总目标是 建议的工作是发现新的抗PC和TG的药物 感染，两种危及生命的机会性疾病与 艾滋病和艾滋病相关综合体(ARC)。更具体地说，这个项目将 重点设计和合成新型二环和三环化合物 结构上与亲脂性相关的二氨基嘧啶环系 二氢叶酸还原酶(DHFR)抑制剂曲美曲辛(TMX)和匹立曲辛 (PTX)。TMX和PTX最近被发现具有良好的活性 在给予叶酸(FA)以保护宿主组织时抗PC和TG 从抗叶酸毒性，并可能提供一些优势比老年人 抗叶酸药物，如甲氧苄啶和磺胺类药物。复合到 在这个项目中被合成的将包括六种一般类型的缩合 二氨基嘧啶环系统，每一组的初始重点是 在芳基部分中至少有两个甲氧基的类似物上，因为这 TMX和PTX中已存在模式。然而，综合方案将 要足够普遍，以允许制备与其他环的同系物 取代基，例如包括卤素。目标化合物将是 评估其抑制DHFR哺乳动物细胞和来自PC和 Tg以确定是否显示了对任一寄生虫的选择性 酵素。这些化合物还将进行抑制PC的能力测试 大鼠肺成纤维细胞单层培养中TG的增殖 叶酸的存在。如果任何化合物表现出足够的活性和 在这些体外检测中，它的选择性将重新合成在一个更大的 标尺为随后的体内药理学和 老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.