Improved chemical synthesis, identification and evaluation of prospective centrally active oxime antidotes for the treatment of nerve agent exposure

Carlos A. Valdez*, Doris Lam, Victoria Lao, Alagu Subramanian, Heather A. Enright, Michael A. Malfatti, Nicholas A. Be, Mark L. Dreyer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

An improved method for the synthesis of hydroxyiminoacetamide-based oximes, compounds rhat hold great promise as centrally-active nerve agent antidotes, is described. The method involves the coupling of hydroxyiminoacetic acid to various amines in the presence of HOBT or HATU and diisopropylcarbodiimide. The optimized protocol was found to work effectively for the coupling with amines to the activated form of the hydroxyiminoacetic acid with yields ranging between 84 and 90% for primary amines, 65–75% for α-substituted and cyclic amines, while producing decent 41–48% yields for the sterically hindered α,α-substituted amines, that can not be obtained using the previously established method.

Original languageEnglish
Article number133598
JournalTetrahedron
Volume144
DOIs
StatePublished - 7 Sep 2023
Externally publishedYes

Keywords

  • Amide-coupling
  • Blood brain barrier
  • Nerve agent
  • Oximes
  • Reactivators

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