LIPOPHILIC ANTIFOLATES AND AIDS OPPORTUNISTIC INFECTIONS

亲脂性抗叶酸药和艾滋病机会性感染

• 批准号: 2651760
• 负责人: ANDRE ROSOWSKY
• 金额: $ 27.34万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-06-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2651760
• 关键词: AIDS; Cryptosporidium; Pneumocystis; Pneumocystis carinii; Pneumocystis pneumonia; Toxoplasma gondii; antiprotozoal agents; diaminopyrimidine; dihydrofolate reductase; drug design /synthesis /production; enzyme inhibitors; human immunodeficiency virus 1; opportunistic infections; toxoplasmosis

The overall goal of this continuation project is the discovery of new drugs against Pneumocystis carinii and Toxoplasma gondii, two of the opportunistic pathogens known to cause significant morbidity and mortality in patients with the acquired immune deficiency syndrome (AIDS). More specifically, the project will focus on the design and synthesis of several classes of previously uninvestigated mono- and dicyclic diaminopyrimid-ine derivatives that we hope will combine the high potency of trimetrexate (TMQ) and piritrexim (PTX) with the binding selectivity of trimethoprim (TMP) and pyrimethamine (PM) against P. carinii (Pc) and T. gondii (Tg) dihydrofolate reductase (DHFR) versus mammalian DHFR. The lack of selectivity of TMQ and PTX requires that they be used with leucovorin (LV) to prevent hematotoxicity, whereas the relatively low efficacy of TMP and PM as single agents requires them to be used with sulfonamides and other drugs that often cause intoler-able side effects. Thus new DHFR inhibitors that are both potent and selective would be highly desirable. Proposed synthetic targets include 4 general types, with emphasis on molecules with a CH2 bridge or no bridge (i.e., a zero-carbon bridge ) between the diaminopyrimidine and substituted Phe moiety. Substituents on the phenyl ring will include two MeO groups as in PTX, three MeO groups as in TMQ, or a Cl atom as in PM. The 2,4-diamino compounds to be studied include: (a) pyridol[2,3-d]pyrimidines with H or Me at C5 and a small alkyl group or substituted Phe ring at C6; (b) pyrrolo[2,3-d]pyrimidines with a substituted Phe ring joined to C5 without a bridge or via a CH2 bridge; (c) pyrimidines with a 3,4-(MeO)2-5-(C4-8-alkoxy)Phe or 2-MeO-5-(c4-8- alkoxy)Phe ring joined to C5 via a CH2 bridge; and (d) pyridol[2,3- d]pyrimidines with a 3,4-(MeO)2-5-(C4-8 alkoxy)Phe or 2-MeO-5-(c4-8- alkoxy)Phe ring joined to C6 via a CH2 bridge. The rationale for a short bridge rests on published indications that the P. carinii DHFR active site is more compact than that of mammalian DHFR. Because of this topology difference, a greater difference in hydrophobic binding is thought to be possible between the P. carinii and mammalian enzyme when the portion of the inhibitor that fits into the tight inner region of the active site is likewise compact (i.e., more like TMP and PM than like TMQ or PTX). The rationale for placing midlength (up to C8) hydrophobic alkoxy groups distally in the Phe ring is that this may increases potency while preserving the active-site binding selectivity of TMQ and PM.

该延续项目的总体目标是发现新的 抗卡氏肺囊虫和弓形虫的药物，这两种 已知会导致显着发病率的机会性病原体 获得性免疫缺陷综合征患者的死亡率 （艾滋病）。 更具体地说，该项目将重点关注设计和 合成了几类以前未研究的单和 我们希望将双环二氨基嘧啶衍生物结合起来 曲美曲沙 (TMQ) 和吡曲辛 (PTX) 的高效结合 甲氧苄啶 (TMP) 和乙胺嘧啶 (PM) 对疟原虫的选择性。 carinii (Pc) 和 T. gondii (Tg) 二氢叶酸还原酶 (DHFR) 对比 哺乳动物 DHFR。 TMQ 和 PTX 缺乏选择性，因此需要 它们与亚叶酸 (LV) 一起使用以防止血液毒性，而 TMP 和 PM 的功效相对较低，因为单一药物需要它们 与磺胺类药物和其他经常引起无法耐受的药物一起使用 副作用。 因此，新的 DHFR 抑制剂既有效又 选择性将是非常可取的。 提议的合成目标包括 4 种常规类型，重点关注具有或不具有 CH2 桥的分子 二氨基嘧啶和二氨基嘧啶之间的桥（即零碳桥） 取代的 Phe 部分。 苯环上的取代基包括 两个 MeO 基团（如 PTX）、三个 MeO 基团（如 TMQ）或一个 Cl 原子（如 下午。 要研究的 2,4-二氨基化合物包括： (a) C5 处带有 H 或 Me 以及一个小烷基的吡啶醇[2,3-d]嘧啶或 在C6处被取代的Phe环； (b) 吡咯并[2,3-d]嘧啶 取代的 Phe 环不通过桥或通过 CH2 桥与 C5 连接； (c) 具有 3,4-(MeO)2-5-(C4-8-烷氧基)Phe 或 2-MeO-5-(c4-8-) 的嘧啶 烷氧基)Phe环通过CH2桥连接至C5； (d) 吡啶醇[2,3- d]嘧啶与3,4-(MeO)2-5-(C4-8烷氧基)Phe或2-MeO-5-(c4-8- 烷氧基)Phe环通过CH2桥连接至C6。 理由如下： 短桥依赖于已发表的迹象，即 P. carinii DHFR 活性位点比哺乳动物 DHFR 的活性位点更紧凑。 由于 这种拓扑结构的差异，疏水结合的差异更大 被认为可能存在于 P. carinii 和哺乳动物酶之间 当抑制剂的部分适合紧密的内部区域时 活性位点同样紧凑（即，更像 TMP 和 PM，而不是 例如 TMQ 或 PTX）。 放置中长（最多 C8）的理由 Phe 环远端的疏水性烷氧基是这样的： 提高效力，同时保留活性位点结合选择性 TMQ 和 PM。