In continuation of our pharmacomodulation work on the nitroimidazooxazole series, we report the synthesis of new 5-substituted 6-nitroimidazooxazole derivatives. Our aim was to evaluate how functionalization of the 5-position of the 6-nitroimidazooxazole scaffold affects antileishmanial and antitrypanosomal in vitro activities. Twenty-one original compounds were synthesized and evaluated for their in vitro antileishmanial (L. donovani) and antitrypanosomal (T. cruzi) properties. Pallado-catalyzed cross-coupling reactions were used to introduce an aryl or ethynyl aryl substituent in 5-position from a 5-brominated-6-nitroimidazooxazole starting product. Unfortunately, the first series of compounds bearing an aryl group in 5-position presented limited in vitro activities against L. donovani and T. cruzi, with IC50 > 10 μM (vs 0.18 μM and 2.31 μM for the reference drugs amphotericin B and benznidazole respectively). Interestingly, the second series of compounds bearing an ethynyl aryl substituent in 5-position showed more promising, particularly against T. cruzi. Compounds 6a, 6b, 6c, 6g and 6h had better activity than the reference drug benznidazole (0.92 μM ≤ IC50 ≤ 2.18 μM vs IC50 = 2.31 μM), whereas the non-functionalized 2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b]oxazole 2 was not active against T. cruzi (IC50 > 10 μM).

中文翻译：

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新型 5-取代 6-硝基咪唑并恶唑作为抗动质体药物的合成和体外评价。

在我们对 nitroimidazooxazole 系列的药物调节工作的继续中，我们报告了新的 5-取代 6-nitroimidazooxazole 衍生物的合成。我们的目的是评估 6-硝基咪唑并恶唑支架的 5 位功能化如何影响抗利什曼原虫和抗锥虫体外活性。合成了 21 种原始化合物，并评估了它们的体外抗利什曼原虫 (L. donovani) 和抗锥虫 (T. cruzi) 特性。Pallado 催化的交叉偶联反应用于从 5-溴化-6-硝基咪唑恶唑起始产物的 5 位引入芳基或乙炔基芳基取代基。不幸的是，第一批在 5 位带有芳基的化合物对多氏乳杆菌和克氏锥虫的体外活性有限，IC50 > 10 μM（对比 0.18 μM 和 2. 参考药物两性霉素 B 和苯并硝唑分别为 31 μM）。有趣的是，在 5 位带有乙炔基芳基取代基的第二系列化合物显示出更有前途，特别是针对 T. cruzi。化合物 6a、6b、6c、6g 和 6h 比参考药物苯并硝唑具有更好的活性（0.92 μM ≤ IC50 ≤ 2.18 μM vs IC50 = 2.31 μM），而非功能化的 2-methyl-6-nitro-2,3-二氢咪唑 [2,1-b]恶唑 2 对克氏锥虫没有活性 (IC50 > 10 μM)。