The effect of chain length and unsaturation on Mtb Dxr inhibition and antitubercular killing activity of FR900098 analogs.
The effect of chain length and unsaturation on Mtb Dxr inhibition and antitubercular killing activity of FR900098 analogs.
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DOI：
10.1016/j.bmcl.2013.11.067
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发表时间：
2014-01-15
影响因子：
2.7
通讯作者：
Dowd, Cynthia S.
中科院分区：
文献类型：
--
作者：
Jackson, Emily R.;San Jose, Geraldine;Brothers, Robert C.;Edelstein, Emma K.;Sheldon, Zachary;Haymond, Amanda;Johny, Chinchu;Boshoff, Helena I.;Couch, Robin D.;Dowd, Cynthia S.
异戊二烯生物合成的非甲羟戊酸途径（NMP）的抑制已被研究为具有新作用机制的新抗生素的来源。Dxr是NMP酶中研究得最好的，并且有几份报告描述了有效的Dxr抑制剂。这些化合物中的许多在结构上与天然产物磷咪霉素和FR 900098相关，各自带有逆羟肟酸酯和膦酸酯基团。我们合成了一系列化合物，其中2至5个亚甲基单元将这些基团分开，以检查什么样的接头长度是最佳的，并测试了对Mtb Dxr的抑制。我们合成了这些化合物的乙酯和新戊酰酯以增加亲脂性并改善对Mtb生长的抑制。我们的研究结果表明，丙基或丙烯基连接链是最佳的。丙烯基类似物22对Mtb Dxr的IC 50为1.07 μM。22的新戊酰基酯，化合物26，具有9.4 μg/mL的MIC，代表这类化合物的抗结核效力的显著改善。
Inhibition of the nonmevalonate pathway (NMP) of isoprene biosynthesis has been examined as a source of new antibiotics with novel mechanisms of action. Dxr is the best studied of the NMP enzymes and several reports have described potent Dxr inhibitors. Many of these compounds are structurally related to natural products fosmidomycin and FR900098, each bearing retrohydroxamate and phosphonate groups. We synthesized a series of compounds with two to five methylene units separating these groups to examine what linker length was optimal and tested for inhibition against Mtb Dxr. We synthesized ethyl and pivaloyl esters of these compounds to increase lipophilicity and improve inhibition of Mtb growth. Our results show that propyl or propenyl linker chains are optimal. Propenyl analog 22 has an IC50 of 1.07 μM against Mtb Dxr. The pivaloyl ester of 22, compound 26, has an MIC of 9.4 μg/mL, representing a significant improvement in antitubercular potency in this class of compounds.
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影响因子：
1.9
作者：
Rohmer, Michel
通讯作者：
Rohmer, Michel
DOI：
10.1080/10426509808032465
发表时间：
1998-02-01
影响因子：
1.3
作者：
Villemin, D;Simeon, F;Jaffres, PA
通讯作者：
Jaffres, PA
影响因子：
2.1
作者：
Balczewski, P;Pietrzykowski, WM
通讯作者：
Pietrzykowski, WM
影响因子：
7.3
作者：
Jansson, Anna M.;Wieckowska, Anna;Mowbray, Sherry L.
通讯作者：
Mowbray, Sherry L.
影响因子：
7.3
作者：
Verbrugghen, Thomas;Vandurm, Pierre;Van Calenbergh, Serge
通讯作者：
Van Calenbergh, Serge