Organic Chemistry Division II, Indian Institute of Chemical Technology, Uppal Road Tarnaka, Hyderabad 500607, India.
Bioorg Med Chem Lett. 2012 Sep 15;22(18):6010-5. doi: 10.1016/j.bmcl.2012.05.019. Epub 2012 May 11.
Twenty-six 2-pyridone derivatives (8a-8z), which are structurally analogous to amrinone and milrinone two important cardiotonic drugs, are synthesized and characterized. The synthesis of 2-pyridone derivatives involves addition, followed by cyclization between Baylis-Hillman acetates (7a-7k) and enamino esters or nitriles (3a-3e). Thus synthesized pyridones were subjected to PDE3 inhibitory activity, 14 pyridones were found to be hits out of 26 pyridones synthesized and out of 14 hits, there are 5 pyridones found to be lead compounds having excellent PDE3 inhibitory activity. Further we have carried out computational analysis to understand protein/enzyme and 2-pyridone derivative interactions to identify amino acid residues involved in the vicinity of binding and compared with milrinone drug.
合成并表征了 26 种 2-吡啶酮衍生物（8a-8z），这些化合物与氨力农和米力农两种重要的强心药物在结构上相似。2-吡啶酮衍生物的合成涉及到 Baylis-Hillman 乙酸盐（7a-7k）与烯胺酯或腈（3a-3e）之间的加成，随后环化。因此，合成的吡啶酮进行了 PDE3 抑制活性测试，在 26 种合成的吡啶酮中发现有 14 种是命中化合物，在这 14 种命中化合物中，有 5 种吡啶酮被发现是具有优异 PDE3 抑制活性的先导化合物。此外，我们还进行了计算分析，以了解蛋白质/酶和 2-吡啶酮衍生物的相互作用，以确定结合附近涉及的氨基酸残基，并与米力农药物进行比较。
