Investigation of 4-amino-5-alkynylpyrimidine-2(1H)-ones as anti-mycobacterial agents

Bioorg Med Chem. 2016 Apr 15;24(8):1771-7. doi: 10.1016/j.bmc.2016.03.003. Epub 2016 Mar 3.

Abstract

In vitro anti-mycobacterial activities of novel 4-amino-5-alkynylpyrimidine-2(1H)-ones were investigated. 4-Amino-5-heptynylpyrimidine-2(1H)-one (3) and 4-amino-5-(2-phenylethynyl)pyrimidine-2(1H)-one (7) displayed potent in vitro activity against Mycobacterium bovis and Mycobacterium tuberculosis. Compounds 3 and 7 were also assessed for their in vivo activity in BALB/c mice infected with M. tuberculosis (H37Ra). Both compounds showed promising in vivo efficacy at a dose of 25 mg/kg for 2 weeks. Importantly, compounds 3 and 7 interacted synergistically with the front-line anti-tuberculosis drug isoniazid in vitro and in vivo. These results suggest that this class of compounds has strong anti-mycobacterial potential.

Keywords: Anti-mycobacterial agent; Heterocycles; Pyrimidines; Tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / therapeutic use
  • Dose-Response Relationship, Drug
  • Female
  • Mice
  • Mice, Inbred BALB C
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Mycobacterium bovis / drug effects*
  • Mycobacterium tuberculosis / drug effects*
  • Pyrimidinones / administration & dosage
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology*
  • Pyrimidinones / therapeutic use
  • Structure-Activity Relationship
  • Tuberculosis / drug therapy*
  • Tuberculosis / microbiology*

Substances

  • 4-amino-5-(2-phenylethynyl)pyrimidine-2(1H)-one
  • 4-amino-5-heptynylpyrimidine-2(1H)-one
  • Anti-Bacterial Agents
  • Pyrimidinones