Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Flemingovo Nám. 2, 166 10 Prague 6, Czech Republic.
Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Flemingovo Nám. 2, 166 10 Prague 6, Czech Republic.
Nitric Oxide. 2017 Jul 1;67:53-57. doi: 10.1016/j.niox.2017.05.001. Epub 2017 May 5.
As a part of our extensive structure-activity relationship study of anti-inflammatory heterocycles, a novel series of 67 polysubstituted 2-aminopyrimidines was prepared bearing one (at the C-4 position of the pyrimidine ring) or two (in the C-4 and C-6 positions) (hetero)aryl substituents attached directly through the C-C bond. The key synthetic steps involved either Suzuki-Miyaura or Stille cross-coupling reactions carried out on easily available 4,6-dichloropyrimidines. All prepared compounds, except one, were able to inhibit immune-activated production of nitric oxide (NO) significantly. Moreover, several compounds were found to be low micromolar dual inhibitors of NO and prostaglandin E (PGE) production. Although the exact mode of action of the prepared compounds remains to be elucidated, non-toxic dual inhibitors of NO and PGE production may have great therapeutic benefit in treatment of various inflammation diseases and deserve further preclinical evaluation.
作为我们广泛的抗炎杂环结构-活性关系研究的一部分，我们合成了一系列新型的 67 个多取代的 2-氨基嘧啶，它们在嘧啶环的 C-4 位（或嘧啶环的 C-4 位和 C-6 位）直接通过 C-C 键连接有一个（或两个）（杂）芳基取代基。关键的合成步骤涉及在易得的 4,6-二氯嘧啶上进行 Suzuki-Miyaura 或 Stille 交叉偶联反应。除了一个化合物之外，所有制备的化合物都能够显著抑制免疫激活产生的一氧化氮（NO）。此外，发现一些化合物是低微摩尔水平的一氧化氮和前列腺素 E（PGE）产生的双重抑制剂。虽然所制备的化合物的确切作用模式仍有待阐明，但具有良好治疗效果的非毒性双重一氧化氮和 PGE 产生抑制剂可能在治疗各种炎症疾病方面具有巨大的益处，值得进一步进行临床前评估。
