Re-engineering aryl methylcarbamates to confer high selectivity for inhibition of Anopheles gambiae versus human acetylcholinesterase

Bioorg Med Chem Lett. 2012 Jul 15;22(14):4593-8. doi: 10.1016/j.bmcl.2012.05.103. Epub 2012 Jun 6.

Abstract

To identify potential human-safe insecticides against the malaria mosquito we undertook an investigation of the structure-activity relationship of aryl methylcarbamates inhibitors of acetylcholinesterase (AChE). Compounds bearing a β-branched 2-alkoxy or 2-thioalkyl group were found to possess good selectivity for inhibition of Anopheles gambiae AChE over human AChE; up to 530-fold selectivity was achieved with carbamate 11d. A 3D QSAR model is presented that is reasonably consistent with log inhibition selectivity of 34 carbamates. Toxicity of these compounds to live Anopheles gambiae was demonstrated using both tarsal contact (filter paper) and topical application protocols.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Animals
  • Anopheles / drug effects
  • Anopheles / enzymology*
  • Carbamates
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / pharmacology
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Quantitative Structure-Activity Relationship

Substances

  • Carbamates
  • Cholinesterase Inhibitors
  • methyl carbamate
  • Acetylcholinesterase