Synthesis of natural flutimide and analogous fully substituted pyrazine-2,6-diones, endonuclease inhibitors of influenza virus
Synthesis of natural flutimide and analogous fully substituted pyrazine-2,6-diones, endonuclease inhibitors of influenza virus
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DOI：
10.1021/jo015665d
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发表时间：
2001-08-10
影响因子：
3.6
通讯作者：
Tomassini, JE
中科院分区：
文献类型：
--
作者：
Singh, SB;Tomassini, JE
氟替米特是一种完全取代的1-羟基-3H-吡嗪-2，6-二酮，是从Delitschia一新种中分离得到的真菌代谢产物。cofertaspora。已显示其选择性抑制流感病毒A的帽依赖性核酸内切酶活性。这种活性的抑制是治疗流感感染的治疗剂的潜在开发的目标。本文报道了以L-亮氨酸为起始原料合成氟替米特的收敛全合成法。合成方法已经扩展到包括合成专门设计的氟替米特的芳族类似物，其中一些表现出大于7倍的活性改善，最有效的化合物是在3 H-吡嗪-2，6-二酮的C-5处具有对-氟苄叉或对-甲氧基苄叉取代的化合物，并且分别显示出0.9和0.8 μ M的IC 50值。这些类似物的合成设计，合成和生物活性的基本原理的细节进行了描述。
Flutimide, a fully substituted 1-hydroxy-3H-pyrazine-2,6-dione, is a fungal metabolite isolated from a new species of Delitschia. cofertaspora. It has been shown to selectively inhibit cap-dependent endonuclease activity of influenza virus A. The inhibition of this activity is a target for the potential development of a therapeutic agent to treat influenza infections. A convergent total synthesis of flutimide starting from L-leucine has been described. The synthetic methodology has been extended to include the synthesis of specifically designed aromatic analogues of flutimide, some of which exhibited greater than 7-fold improvement in activity, The most potent compounds were those with p-fluorobenzylidene or p-methoxybenzylidene substitutions at C-5 of 3H-pyrazine-2,6-dione and showed IC50 values of 0.9 and 0.8 muM, respectively. The details of the rationale for the synthetic design, syntheses, and biological activities of these analogues are described.