Rational design, synthesis and evaluation of “smart”, uncharged bis‐oxime antidotes of OP inhibited human acetylcholinesterase

Abstract

Organophosphate (OP) intoxications from nerve agent and OP pesticide exposure are treated by outdated, questionably efficient pyridinium aldoxime‐based therapies. Pyridinium cations hamper central nervous system (CNS) uptake, while structural diversity of OPs prevents efficient reactivation of OP inhibited acetylcholinesterase (AChE). Improvements must include much better reactivation of AChE in the CNS. We present here seven novel uncharged bis‐oximes created from our X‐ray structures of an uncharged monoxime, RS194B, reversibly bound to human AChE (hAChE). Bis‐oxime protonation results in equilibration between up to sixteen distinct ionization forms, including uncharged forms capable of diffusing into CNS and multiple zwitterionic forms optimal for reactivation reactions. Conformationally diverse zwitterions acting as structural variants of the compound significantly improved in vitro reactivation of diverse OP‐hAChEs. The enhanced reactivation orientation for one of the bis‐oximes was confirmed by X‐ray structure. Our novel, CNS directed bis‐oximes represent a promising class of “smart”, accelerated antidotes against OP intoxication.Support or Funding InformationThis research was supported by the CounterACT Program, National Institutes of Health Office of the Director (NIH OD), and the National Institute of Neurological Disorders and Stroke (NINDS), [Grant Numbers U01 NS083451 and R21 NS098998] and by the UCSD Academic Senate grant BG084144.