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

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

Abstract

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.

Keywords: Antibiotic; Dxr; Mycobacterium tuberculosis; Nonmevalonate pathway.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antitubercular Agents / chemistry*
  • Antitubercular Agents / pharmacology*
  • Drug Resistance, Multiple, Bacterial / drug effects*
  • Drug Resistance, Multiple, Bacterial / physiology
  • Fosfomycin / analogs & derivatives*
  • Fosfomycin / chemistry
  • Fosfomycin / pharmacology
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / physiology
  • Structure-Activity Relationship

Substances

  • Antitubercular Agents
  • Fosfomycin
  • 3-(N-acetyl-N-hydroxy)aminopropylphosphonic acid