Triazole inhibitors of Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase.
Triazole inhibitors of Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase.
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DOI：
10.1021/jm900410u
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发表时间：
2009-08-13
影响因子：
7.3
通讯作者：
Cuny GD
中科院分区：
文献类型：
--
作者：
Maurya SK;Gollapalli DR;Kirubakaran S;Zhang M;Johnson CR;Benjamin NN;Hedstrom L;Cuny GD
小隐孢子虫是一种重要的人类病原体和潜在的生物恐怖分子。这种原生动物寄生虫无法回收鸟嘌呤或鸟苷，因此依赖肌苷 5'-单磷酸脱氢酶 (IMPDH) 进行鸟嘌呤核苷酸的生物合成，从而生存。由于微小隐孢子虫 IMPDH 与宿主对应物高度不同，因此选择性抑制剂有可能用于治疗隐孢子虫病，同时对其哺乳动物宿主的影响最小。描述了一系列含有 1,2,3-三唑的醚 CpIMPDH 抑制剂。结构-活性关系研究表明，(R)-对映体比(S)-对映体活性明显更高，醚的α位上需要一个小烷基。悬垂苯环的3-和/或4-位上的吸电子基团是最好的，并且含有喹啉的抑制剂向喹啉-N-氧化物的转化在存在和不存在牛血清白蛋白的情况下都保留了抑制活性。 1,2,3-三唑 CpIMPDH 抑制剂为阐明 IMPDH 在微小隐孢子虫中的作用提供了新工具，并可能作为治疗隐孢子虫病的潜在疗法。
Cryptosporidium parvum is an important human pathogen and potential bioterrorism agent. This protozoan parasite cannot salvage guanine or guanosine and therefore relies on inosine 5′-monophosphate dehydrogenase (IMPDH) for biosynthesis of guanine nucleotides and hence for survival. Since C. parvum IMPDH is highly divergent from the host counterpart, selective inhibitors could potentially be used to treat cryptosporidiosis with minimal effects on its mammalian host. A series of 1,2,3-triazole containing ether CpIMPDH inhibitors are described. A structure-activity relationship study revealed that a small alkyl group on the alpha-position of the ether was required with the (R)-enantiomer significantly more active than the (S)-enantiomer. Electron-withdrawing groups in the 3- and/or 4-positions of the pendent phenyl ring were best and conversion of the quinoline containing inhibitors to quinoline-N-oxides retained inhibitory activity both in the presence and absence of bovine serum albumin. The 1,2,3-triazole CpIMPDH inhibitors provide new tools for elucidating the role of IMPDH in C. parvum and may serve as potential therapeutics for treating cryptosporidiosis.
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影响因子：
15
作者：
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通讯作者：
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影响因子：
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通讯作者：
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