Design, synthesis and biological evaluation of bisabolangelone oxime derivatives as potassium-competitive acid blockers (P-CABs)

Bioorg Med Chem Lett. 2016 May 1;26(9):2268-72. doi: 10.1016/j.bmcl.2016.03.051. Epub 2016 Mar 14.

Abstract

With the aim of searching novel P-CABs, seven bisabolangelone oxime derivatives were designed, synthesized, characterized and evaluated the H(+),K(+)-ATPase inhibitory activities guided by computer aided drug design methods. The binding free energy calculations were in good agreement with the experiment results with the correlation coefficient R of -0.9104 between ΔGbind and pIC50 of ligands. Compound 5 exhibited the best inhibitory activity (pIC50=6.36) and most favorable binding free energy (ΔGbind=-47.67 kcal/mol) than other derivatives. The binding sites of these compounds were found to be the hydrophobic substituted groups with the Cys813 residue by the decomposed binding free energy analysis.

Keywords: Bisabolangelone; Drug rational design; H(+),K(+)-ATPase inhibitory activities; P-CABs; Synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Design
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / pharmacology*
  • H(+)-K(+)-Exchanging ATPase / drug effects*
  • Oximes / chemistry
  • Potassium / metabolism*
  • Sesquiterpenes / chemistry
  • Sesquiterpenes / pharmacology*

Substances

  • Enzyme Inhibitors
  • Oximes
  • Sesquiterpenes
  • bisabolangelone
  • H(+)-K(+)-Exchanging ATPase
  • Potassium