Division of Medicinal & Process Chemistry, Central Drug Research Institute, Lucknow-226001, India.
J Med Chem. 2010 Nov 11;53(21):7587-98. doi: 10.1021/jm100678p.
Keto-trioxanes 7a-d, easily accessible in two steps from allylic alcohols 5a-d, underwent reductive amination with substituted anilines to furnish amino-functionalized trioxanes 8a-i, 9a-i, 10a-i, and 11a-i. All these new trioxanes were assessed for their oral antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice. 2-Naphthalene-based trioxanes 9c and 9i, the most active compounds of the series, provided 100% protection to the malaria-infected mice at 24 mg/kg × 4 days, while the related trioxane 9b and phenanthrene-based trioxane 11e provided a similar level of protection at 48 mg/kg × 4 days. All other trioxanes, except 10c, 10d, and 10g, provided 100% protection at 96 mg/kg × 4 days. In this model, β-arteether provided 100% protection at 48 mg/kg × 4 days and 20% protection at 24 mg/kg × 4 days.
Keto-trioxanes 7a-d 可通过两步从烯丙醇 5a-d 轻松获得，与取代苯胺进行还原胺化，得到氨基功能化的三氧杂环己烷 8a-i、9a-i、10a-i 和 11a-i。所有这些新的三氧杂环己烷都在瑞士小鼠中评估了其对多药耐药性 Plasmodium yoelii nigeriensis 的口服抗疟活性。基于 2-萘的三氧杂环己烷 9c 和 9i 是该系列中最有效的化合物，在 24 mg/kg×4 天时对感染疟疾的小鼠提供了 100%的保护，而相关的三氧杂环己烷 9b 和菲三氧杂环己烷 11e 在 48 mg/kg×4 天时提供了类似水平的保护。除了 10c、10d 和 10g 之外，所有其他三氧杂环己烷在 96 mg/kg×4 天时都提供了 100%的保护。在该模型中，β-青蒿素在 48 mg/kg×4 天时提供了 100%的保护，在 24 mg/kg×4 天时提供了 20%的保护。
