Structure-activity relationship study of novel iminothiadiazolo-pyrimidinone antimicrobial agents

J Antibiot (Tokyo). 2013 Nov;66(11):663-7. doi: 10.1038/ja.2013.69. Epub 2013 Jul 3.

Abstract

An iminothiadiazolo-pyrimidinone derivative, 0002-04-KK, harboring a furan moiety, acts as an antimicrobial agent with a minimum inhibitory concentration (MIC) against Staphylococcus aureus of 25 μg ml(-1). Several derivatives of 0002-04-KK were synthesized and among them 0026-59-KK, harboring a nitrofuran moiety, had the most potent antimicrobial activity with an MIC of 6 μg ml(-1). Both 0002-04-KK and 0026-59-KK inhibited the biosynthesis of DNA, RNA and proteins. Peptidoglycan biosynthesis was inhibited by 0026-59-KK, and slightly inhibited by 0002-04-KK. Derivative 0002-04-KK showed bactericidal activity in contrast to the bacteriostatic activity of 0002-04-KK. Derivative 0002-04-KK had less toxicity in silkworms (lethal dose fifty (LD50): >230 μg g(-1)) than 0002-04-KK (LD50: 100 μg g(-1)). The bactericidal activity against S. aureus was because of the nitrofuran moiety. These findings suggest that iminothiadiazolo-pyrimidinone compounds could be used as lead molecules to develop antimicrobial agents.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Infective Agents / chemistry
  • Anti-Infective Agents / pharmacology*
  • Bacteria / drug effects*
  • Bacterial Proteins / biosynthesis
  • Bacterial Proteins / drug effects
  • Bombyx / drug effects
  • DNA, Bacterial / biosynthesis
  • DNA, Bacterial / drug effects
  • Fungi / drug effects*
  • Lethal Dose 50
  • Microbial Sensitivity Tests
  • Peptidoglycan / biosynthesis
  • Peptidoglycan / drug effects
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology*
  • Pyrimidinones / toxicity
  • RNA, Bacterial / biosynthesis
  • RNA, Bacterial / drug effects
  • Staphylococcus aureus / drug effects*
  • Structure-Activity Relationship
  • Toxicity Tests / methods

Substances

  • Anti-Infective Agents
  • Bacterial Proteins
  • DNA, Bacterial
  • Peptidoglycan
  • Pyrimidinones
  • RNA, Bacterial