Design, synthesis of novel Triazolones and bis-Triazolones derivatives under ultrasound irradiation and evaluation as potent angiotensin converting enzyme (ACE) inhibitors

Bioorg Chem. 2018 Feb:76:147-153. doi: 10.1016/j.bioorg.2017.11.004. Epub 2017 Nov 17.

Abstract

The condensation of several primary amines and diamines with various N1-ethoxycarbonyles N1-tosylhydrazonates (1a-b), triazolones (2) and bis-triazolone (3) resulted in ethanol under ultrasound irradiation. Compared with the conventional methods, the main advantages of the present procedure are milder conditions, shorter reaction time and higher yields. The newly synthesized compounds were evaluated for angiotensin I-converting enzyme (ACE) inhibition. The results were compared to Captopril as a reference drug. Compounds 3b, 2h, 3a, 2d, and 2f showed not only inhibition activity with IC50 values of 0.162, 0.253, 0.253, 0.281 and 0.382 µM, respectively, but also minimal toxicity. The docking of chemical compounds in the ACE active site showed possible inhibitory effect of all compounds on the catalytic activity of the enzyme, which would satisfactorily explain the anti-hypertensive effect of these compounds.

Keywords: Angiotensin I-converting enzyme (ACE) inhibitory activity; N(1)-ethoxycarbonyles N(1)-tosylhydrazonates; Triazolones; Ultrasound; bis-Triazolones.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / chemical synthesis*
  • Angiotensin-Converting Enzyme Inhibitors / toxicity
  • Animals
  • Antihypertensive Agents / chemical synthesis
  • Antihypertensive Agents / toxicity
  • Catalytic Domain
  • Drug Design*
  • HeLa Cells
  • Humans
  • Molecular Docking Simulation
  • Peptidyl-Dipeptidase A / chemistry
  • Rabbits
  • Triazoles / chemical synthesis*
  • Triazoles / toxicity
  • Ultrasonic Waves

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Antihypertensive Agents
  • Triazoles
  • Peptidyl-Dipeptidase A