Zacharova Marija K, Tulloch Lindsay B, Gould Eoin R, Fraser Andrew L, King Elizabeth F, Menzies Stefanie K, Smith Terry K, Florence Gordon J
EaStCHEM School of Chemistry and School of Biology Biomedical Science Research Complex University of St Andrews North Haugh St Andrews KY16 9ST UK.
European J Org Chem. 2019 Sep 1;2019(31-32):5434-5440. doi: 10.1002/ejoc.201900541. Epub 2019 May 29.
The protozoan parasites and . are responsible for the severely debilitating neglected Tropical diseases of African sleeping sickness, Chagas disease and leishmaniasis, respectively. As part of our ongoing programme exploring the potential of simplified analogues of the acetogenin chamuvarinin we identified the FoF1-ATP synthase as a target of our earlier triazole analogue series. Using computational docking studies, we hypothesised that the central triazole heterocyclic spacer could be substituted for a central 2,5-substituted furan moiety, thus diversifying the chemical framework for the generation of compounds with greater potency and/or selectivity. Here we report the design, docking, synthesis and biological evaluation of new series of trypanocidal compounds and demonstrate their on-target inhibitory effects. Furthermore, the synthesis of furans by the modular coupling of alkyne- and aldehyde-THPs to bis-THP 1,4-alkyne diols followed by ruthenium/xantphos-catalysed heterocyclisation described here represents the most complex use of this method of heterocyclisation to date.
原生动物寄生虫和……分别导致了非洲昏睡病、恰加斯病和利什曼病这些严重使人衰弱的被忽视的热带疾病。作为我们正在进行的探索产乙酸菌素查穆瓦林宁简化类似物潜力计划的一部分，我们确定F₀F₁ - ATP合酶是我们早期三唑类似物系列的一个靶点。通过计算对接研究，我们推测中心三唑杂环间隔基可以被中心2,5 - 二取代呋喃部分取代，从而使生成具有更高效力和/或选择性的化合物的化学框架多样化。在此我们报告新系列杀锥虫化合物的设计、对接、合成及生物学评价，并展示它们的靶向抑制作用。此外，本文所述通过炔烃 - 和醛 - THP与双 - THP 1,4 - 炔二醇的模块化偶联，随后进行钌/黄原膦催化的杂环化反应来合成呋喃，代表了该杂环化方法迄今为止最复杂的应用。
