Design of Novel Centrally Active Cholinesterase Reactivators

Project head: Zrinka Kovarik

Croatian-French cooperation programme “Cogito” of the Hubert Curien Partnership

Duration: 2015-2016

Our collaboration and investigation focused on the synthesis of effective reactivators of organophosphorus (OP) compound-inhibited cholinesterases (French group) along with a determination of interaction of cholinesterases with reactivators (Croatian group), all with the goal of developing new antidotes for intoxication with highly-toxic OP compounds. In order to achieve this goal, our
partners from Rouen synthesized seven new oximes while our research included:

  • determination of in silico interactions (molecular modelling) in order to obtain an insight of oxime accommodation in the active site of the enzyme and further structure optimization for effective reactivators in acetylcholinesterase (AChE) inhibited by tabun and VX determination of IC50 values, i.e. reversible inhibition constants for interaction of AChE and butyrylcholinesterase (BChE) with oximes;
  • determination of parameters and reactivation constants for tabun and VX-inhibited AChE and BChE with oximes.

From seven new oximes, three were shown to be exceedingly effective reactivators and we will continue to investigate their efficiency through ex vivo and in vivo testing. The results were presented at two international scientific meetings as two posters and one oral presentation.