Antibacterial and antitubercular activity of fosmidomycin, FR900098, and their lipophilic analogs

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:21

Article

Uh, Eugene¹  Jackson, Emily R.¹  Jose, Geraldine San¹  Maddox, Marcus²  Lee, Robin E.²  Lee, Richard E.²  Boshoff, Helena I.³  Dowd, Cynthia S.¹ 

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

[2] St Jude Childrens Res Hosp, Memphis, TN 38105 USA

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

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

DOI  :  10.1016/j.bmcl.2011.09.123

来源: Elsevier

【 摘 要 】

The nonmevalonate pathway (NMP) of isoprene biosynthesis is an exciting new route toward novel antibiotic development. Inhibitors against several enzymes in this pathway are currently under examination. A significant liability of many of these agents is poor cell penetration. To overcome and improve our understanding of this problem, we have synthesized a series of lipophilic, prodrug analogs of fosmidomycin and FR900098, inhibitors of the NMP enzyme Dxr. Several of these compounds show improved antibacterial activity against a panel of organisms relative to the parent compound, including activity against Mycobacterium tuberculosis (Mtb). Our results show that this strategy can be an effective way for improving whole cell activity of NMP inhibitors. (C) 2011 Elsevier Ltd. All rights reserved.

【 授权许可】

Free