LIPOPHILIC ANTIFOLATES AND AIDS OPPORTUNISTIC INFECTIONS

这个延续项目的总体目标是发现新的 针对卡氏肺孢子虫和刚地弓形虫的药物， 已知可导致显著发病率的机会致病菌， 获得性免疫缺陷综合征患者的死亡率 （艾滋病）。 更具体地说，该项目将侧重于设计和 合成了几类以前未研究的单-和 双环二氨基嘧啶衍生物，我们希望将联合收割机 曲美曲嗪（TMQ）和吡曲辛（PTX）的高效力， 甲氧苄啶（TMP）和乙胺嘧啶（PM）对P. carinii（Pc）和T.弓形虫（Tg）二氢叶酸还原酶（DHFR）与 哺乳动物DHFR。 TMQ和PTX缺乏选择性要求 它们与亚叶酸（LV）一起使用以防止血液毒性，而 TMP和PM作为单一药剂的相对低的功效要求它们 与磺胺类药物和其他药物一起使用， 副作用. 因此，新的DHFR抑制剂既有效， 选择性将是高度期望的。 拟议的合成目标包括 4种一般类型，重点是具有CH 2桥或不具有CH 2桥的分子 桥（即，零碳桥）之间的二氨基嘧啶和 取代的Phe部分。 苯环上的取代基将包括 两个MeO基团（如PTX中）、三个MeO基团（如TMQ中）或一个Cl原子（如 在PM。 待研究的2，4-二氨基化合物包括：（a） 在C5具有H或Me和小烷基的吡啶并[2，3-d]嘧啶，或 （B）吡咯并[2，3-d]嘧啶，其具有 取代的Phe环不通过桥或通过CH 2桥连接到C5; (c)嘧啶与3，4-（MeO）2-5-（C4-8-烷氧基）Phe或2-MeO-5-（C4 - 8-烷氧基）Phe反应， （d）吡啶并[2，3-b]吡啶并[2 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的反应 烷氧基）Phe环通过CH 2桥连接至C6。 的基本原理 短桥依赖于已发表的迹象表明，卡氏肺吸虫DHFR 活性位点比哺乳动物DHFR更紧凑。 因为 这种拓扑结构的差异， 卡氏肺孢子虫和哺乳动物的酶之间 当安装到紧密内部区域中的抑制器部分 活性部位的表面同样是紧凑的（即，更像TMP和PM， 如TMQ或PTX）。 放置中等长度（最大C8）的依据 Phe环中远端的疏水烷氧基的重要性在于，这可以 在保持活性位点结合选择性的同时增加效力 TMQ和PM。

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.