Structure–Activity Relationships of Antiplasmodial Pantothenamide Analogues Reveal a New Way by Which Triazoles Mimic Amide Bonds,ChemMedChem

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Structure–Activity Relationships of Antiplasmodial Pantothenamide Analogues Reveal a New Way by Which Triazoles Mimic Amide Bonds
ChemMedChem ( IF 3.6 ) Pub Date : 2018-11-29 , DOI: 10.1002/cmdc.201800327
Jinming Guan ₁ , Erick T. Tjhin ₂ , Vanessa M. Howieson ₂ , Tanakorn Kittikool ₁ , Christina Spry ₂ , Kevin J. Saliba _{2,

3} , Karine Auclair ₁

Affiliation

Pantothenamides are potent growth inhibitors of the malaria parasite Plasmodium falciparum. Their clinical use is, however, hindered due to the ubiquitous presence of pantetheinases in human serum, which rapidly degrade pantothenamides into pantothenate and the corresponding amine. We previously reported that replacement of the labile amide bond with a triazole ring not only imparts stability toward pantetheinases, but also improves activity against P. falciparum. A small library of new triazole derivatives was synthesized, and their use in establishing structure–activity relationships relevant to antiplasmodial activity of this family of compounds is discussed herein. Overall it was observed that 1,4‐substitution on the triazole ring and use of an unbranched, one‐carbon linker between the pantoyl group and the triazole are optimal for inhibition of intraerythrocytic P. falciparum growth. Our results imply that the triazole ring may mimic the amide bond with an orientation different from what was previously suggested for this amide bioisostere.

中文翻译：

抗疟原体泛酰胺类似物的结构-活性关系揭示了三唑模拟酰胺键的新方法。

泛酰胺是疟原虫恶性疟原虫的有效生长抑制剂。然而，由于泛酸在人血清中的普遍存在而阻碍了它们的临床应用，泛酸迅速将泛酰胺降解为泛酸酯和相应的胺。我们以前曾报道过，用三唑环取代不稳定的酰胺键不仅赋予了泛酸酶以稳定性，而且还提高了对P的活性。 恶性疟。合成了一个新的三唑衍生物的小型文库，并在本文中讨论了它们在建立与该化合物家族的抗血浆活性有关的构效关系中的用途。总的来说，观察到三唑环上的1,4取代以及在泛酰基和三唑之间使用无支链的单碳连接基是抑制红细胞内P的最佳方法。恶性增长。我们的结果表明，三唑环可能以与以前针对该酰胺生物等排体所建议的取向不同的方向模拟酰胺键。

更新日期：2018-11-29

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