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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:24

Article

Jackson, Emily R.¹  San Jose, Geraldine¹  Brothers, Robert C.¹  Edelstein, Emma K.¹  Sheldon, Zachary¹  Haymond, Amanda^2,3  Johny, Chinchu^2,3  Boshoff, Helena I.⁴  Couch, Robin D.^2,3  Dowd, Cynthia S.¹ 

[1] George Washington Univ, Dept Chem, Washington, DC 20052 USA

[2] George Mason Univ, Dept Chem & Biochem, Manassas, VA 20110 USA

[3] George Mason Univ, Natl Ctr Biodef & Infect Dis, Manassas, VA 20110 USA

[4] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA

关键词: Mycobacterium tuberculosis;    Nonmevalonate pathway;    Dxr;    Antibiotic;   

DOI  :  10.1016/j.bmcl.2013.11.067

来源: Elsevier

【 摘 要 】

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 mu M against Mtb Dxr. The pivaloyl ester of 22, compound 26, has an MIC of 9.4 mu g/mL, representing a significant improvement in antitubercular potency in this class of compounds. (C) 2013 Elsevier Ltd. All rights reserved.

【 授权许可】

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