Zhao H, Neamati N, Sunder S, Hong H, Wang S, Milne G W, Pommier Y, Burke T R
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Med Chem. 1997 Mar 14;40(6):937-41. doi: 10.1021/jm960755+.
Inhibitors of HIV integrase are currently being sought as potential new therapeutics for the treatment of AIDS. A large number of inhibitors discovered to date contain the o-bis-hydroxy catechol structure. In an effort to discover structural leads for the development of new HIV integrase inhibitors which do not rely on this potentially cytotoxic catechol substructure, NSC 310217 was identified using a three-point pharmacophore search based on its assigned structure N-(2-hydroxybenzoyl)-N-(2-hydroxy-3-phenoxypropyl)hydrazine (1). When a sample of NSC 310217 was obtained from the NCI repository, it was shown to exhibit potent inhibition of HIV-1 integrase (3'-processing IC50 = 0.6 microgram/mL). In work reported herein, we demonstrate that NSC 310217, rather than containing 1, which has no inhibitory potency against HIV-1 integrase, is comprised of roughly a 1:1 mixture of N-(2-hydroxybenzoyl)-N'-(2-hydroxy-3-phenoxypropyl)hydrazine (6) and N,N'-bis-salicylhydrazine 7, with all inhibitory potency residing with compound 7(IC50 = 0.7 microM for strand transfer). In subsequent structure-activity studies on 7, it is shown that removing a single amide carbonyl (compound 14, IC50 = 5.2 microM) or replacing one aromatic ring system with a naphthyl ring (compound 19, IC50 = 1.1 microM) can be accomplished with little loss of inhibitory potency. Additionally, replacing a single hydroxyl with a sulfhydryl (compound 23, IC50 = 5.8 microM) results in only moderate loss of potency. All other modifications examined, including the replacement of a single hydroxyl with an amino group (compound 22), resulted in complete loss of potency. Being potent, structurally simple, and non-catechol-containing, compounds such as 7 and 14 may provide useful leads for the development of a new class of HIV integrase inhibitor.
目前正在寻找HIV整合酶抑制剂作为治疗艾滋病的潜在新疗法。迄今为止发现的大量抑制剂都含有邻二羟基儿茶酚结构。为了发现不依赖于这种潜在细胞毒性儿茶酚亚结构的新型HIV整合酶抑制剂的结构先导物，基于其指定结构N-(2-羟基苯甲酰基)-N-(2-羟基-3-苯氧基丙基)肼(1)，通过三点药效团搜索确定了NSC 310217。当从美国国立癌症研究所（NCI）储存库获得NSC 310217样品时，它显示出对HIV-1整合酶的强效抑制作用(3'-加工IC50 = 0.6微克/毫升)。在本文报道的工作中，我们证明NSC 310217并非含有对HIV-1整合酶无抑制活性的1，而是由N-(2-羟基苯甲酰基)-N'-(2-羟基-3-苯氧基丙基)肼(6)和N,N'-双水杨酰肼7大致1:1的混合物组成，所有抑制活性都存在于化合物7中(链转移IC50 = 0.7微摩尔)。在随后对7的构效关系研究中表明，去除单个酰胺羰基(化合物14，IC50 = 5.2微摩尔)或用萘环取代一个芳环系统(化合物19，IC50 = 1.1微摩尔)时，抑制活性损失很小。此外，用巯基取代单个羟基(化合物23，IC50 = 5.8微摩尔)只会导致活性适度损失。所研究的所有其他修饰，包括用氨基取代单个羟基(化合物22)，都导致活性完全丧失。像7和14这样的化合物具有强效、结构简单且不含儿茶酚的特点，可能为开发新型HIV整合酶抑制剂提供有用的先导物。
