LIPOPHILIC ANTIFOLATES AND AIDS OPPORTUNISTIC INFECTIONS

这个延续项目的总体目标是发现新的 抗卡氏肺孢子虫和弓形虫药物 已知的可引起重大发病率和 获得性免疫缺陷综合征患者的死亡率 (艾滋病)。更具体地说，该项目将专注于设计和 几类以前未被研究过的单与环的合成 二环二氨基吡啶类化合物，我们希望它能结合 高效的曲美曲辛(TMQ)和匹立曲辛(PTX)与结合 甲氧苄氨嘧啶(TMP)和乙胺嘧啶(PM)对P. Carinii(Pc)和Tg(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 它们与亚叶酸钙(LV)一起使用以防止血液毒性，而 TMP和PM作为单一药物的相对较低的疗效要求他们 与磺胺类药物和其他经常导致可吸收的药物一起使用 副作用。因此，新的DHFR抑制剂既有效又 有选择性将是非常可取的。建议的合成目标包括 4种一般类型，重点是带有CH2桥或NO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。苯环上的取代基将包括 PTX中的两个MeO基团，TMQ中的三个MeO基团，或一个Cl原子AS 在下午拟研究的2，4-二氨基化合物包括：(A) 吡哆醇[2，3-d]嘧啶类化合物，在C5上带有H或Me，并带有一个小的烷基或 取代苯环C6；(B)吡咯并[2，3-d]嘧啶并a 取代的Phe环不带桥或通过CH2桥连接到C5； (C)含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桥连接到C5；和(D)吡哆醇[2，3- 带有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桥连接到C6。的基本原理是 短桥依赖于公布的卡氏肺孢子虫DHFR 活性中心比哺乳动物DHFR的活性中心更紧密。因为. 这种拓扑结构的差异，在疏水结合上的差异就更大 被认为在卡氏肺孢子虫和哺乳动物酶之间是可能的 当缓蚀剂中适合紧密内侧区域的部分 的活动站点同样紧凑(即更像TMP和PM，而不是 如TMQ或PTX)。放置中长(最高为C8)的基本原理 在Phe环远端的疏水烷氧基是，这可以 在保持活性部位结合选择性的同时提高效力 TMQ和PM的

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.