FR900098 类似物的链长和不饱和度对 Mtb Dxr 抑制和抗结核杀菌活性的影响。

The effect of chain length and unsaturation on Mtb Dxr inhibition and antitubercular killing activity of FR900098 analogs.

机构信息

Department of Chemistry, George Washington University, 725 21st Street NW, Corcoran 107, Washington, DC 20052, United States.

Department of Chemistry and Biochemistry and the National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA 20110, United States.

出版信息

Bioorg Med Chem Lett. 2014 Jan 15;24(2):649-53. doi: 10.1016/j.bmcl.2013.11.067. Epub 2013 Dec 4.

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.

抑制异戊二烯生物合成的非甲羟戊酸途径 (NMP) 已被视为具有新型作用机制的新型抗生素的来源。Dxr 是 NMP 酶中研究最充分的酶，已有几篇报道描述了有效的 Dxr 抑制剂。这些化合物中的许多与天然产物福米地霉素和 FR900098 结构上相关，每个都带有 retrohydroxamate 和膦酸酯基团。我们合成了一系列具有两个到五个亚甲基单元的化合物，以研究最佳的连接体长度，并测试了它们对结核分枝杆菌 Dxr 的抑制作用。我们合成了这些化合物的乙基和特戊酰酯，以增加亲脂性并改善对结核分枝杆菌生长的抑制作用。我们的结果表明，丙基或丙烯基连接链是最佳的。丙烯基类似物 22 对 Mtb Dxr 的 IC50 为 1.07 μM。22 的特戊酰酯化合物 26 的 MIC 为 9.4 μg/mL，代表此类化合物抗结核效力的显著提高。