Singh Chandan, Verma Ved Prakash, Naikade Niraj Krishna, Singh Ajit Shankar, Hassam Mohammad, Puri Sunil K
Division of Medicinal and Process Chemistry and Division of Parasitology, Central Drug Research Institute, Lucknow-226001, India.
J Med Chem. 2008 Dec 11;51(23):7581-92. doi: 10.1021/jm801006v.
A new series of bis-1,2,4-trioxanes 12a-h, 13a-h, and 14a-h and tris-1,2,4-trioxanes 12i-14i were prepared and evaluated against multidrug-resistant Plasmodium yoelii in Swiss mice by oral route. Cyclopentane-based bis-trioxanes 12a, 12b, 12f-h and cyclohexane-based bis-trioxanes 13a, 13f, and 13g showed promising activity. All the tris-1,2,4-trioxanes were found to be inactive. Bis-trioxane 12a, the most active compound of the series, provided 100% and 80% protection to infected mice at 48 and 24 mg/kg x 4 days, respectively. Clinically useful drug beta-arteether provided 100% and 20% protection at similar doses.
制备了一系列新的双 - 1,2,4 - 三恶烷12a - h、13a - h和14a - h以及三 - 1,2,4 - 三恶烷12i - 14i，并通过口服途径在瑞士小鼠体内针对多重耐药约氏疟原虫进行了评估。基于环戊烷的双三恶烷12a、12b、12f - h以及基于环己烷的双三恶烷13a、13f和13g显示出有前景的活性。所有三 - 1,2,4 - 三恶烷均无活性。该系列中活性最强的化合物双三恶烷12a，在48mg/kg×4天和24mg/kg×4天时，分别为感染小鼠提供了100%和80%的保护。临床有用药物蒿甲醚在相似剂量下提供了100%和20%的保护。
