Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity

Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17564-9. doi: 10.1073/pnas.1302664110. Epub 2013 Oct 7.


Metronidazole and other 5-nitroimidazoles (5-NI) are among the most effective antimicrobials available against many important anaerobic pathogens, but evolving resistance is threatening their long-term clinical utility. The common 5-NIs were developed decades ago, yet little 5-NI drug development has since taken place, leaving the true potential of this important drug class unexplored. Here we report on a unique approach to the modular synthesis of diversified 5-NIs for broad exploration of their antimicrobial potential. Many of the more than 650 synthesized compounds, carrying structurally diverse functional groups, have vastly improved activity against a range of microbes, including the pathogenic protozoa Giardia lamblia and Trichomonas vaginalis, and the bacterial pathogens Helicobacter pylori, Clostridium difficile, and Bacteroides fragilis. Furthermore, they can overcome different forms of drug resistance, and are active and nontoxic in animal infection models. These findings provide impetus to the development of structurally diverse, next-generation 5-NI drugs as agents in the antimicrobial armamentarium, thus ensuring their future viability as primary therapeutic agents against many clinically important infections.

Keywords: antibiotics; infectious diseases; medicinal chemistry.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Infective Agents / chemistry*
  • Anti-Infective Agents / pharmacology*
  • Bacteroides fragilis / drug effects
  • Cell Survival / drug effects
  • Clostridioides difficile / drug effects
  • Combinatorial Chemistry Techniques
  • Giardia lamblia / drug effects
  • Giardiasis / drug therapy
  • Giardiasis / parasitology
  • HeLa Cells
  • Helicobacter pylori / drug effects
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Nitroimidazoles / chemistry*
  • Nitroimidazoles / pharmacology*
  • Structure-Activity Relationship
  • Treatment Outcome
  • Trichomonas vaginalis / drug effects


  • Anti-Infective Agents
  • Nitroimidazoles
  • 4-nitroimidazole