Organophosphorus compounds and oximes: a critical review

Abstract

Organophosphorus (OP) pesticides and nerve agents still pose a threat to the population. Treatment of OP poisoning is an ongoing challenge and burden for medical services. Standard drug treatment consists of atropine and an oxime as reactivator of OP-inhibited acetylcholinesterase and is virtually unchanged since more than six decades. Established oximes, i.e. pralidoxime, obidoxime, TMB-4, HI-6 and MMB-4, are of insufficient effectiveness in some poisonings and often cover only a limited spectrum of the different nerve agents and pesticides. Moreover, the value of oximes in human OP pesticide poisoning is still disputed. Long-lasting research efforts resulted in the preparation of countless experimental oximes, and more recently non-oxime reactivators, intended to replace or supplement the established and licensed oximes. The progress of this development is slow and none of the novel compounds appears to be suitable for transfer into advanced development or into clinical use. This situation calls for a critical analysis of the value of oximes as mainstay of treatment as well as the potential and limitations of established and novel reactivators. Requirements for a straightforward identification of superior reactivators and their development to licensed drugs need to be addressed as well as options for interim solutions as a chance to improve the therapy of OP poisoning in a foreseeable time frame.

Keywords: Acetylcholinesterase; Nerve agents; Organophosphorus compounds; Oximes; Pesticides; Reactivation.

Fig. 1

Chemical structure of in-service oximes developed in the 1950s and 1960s. Oximes with different counterions, e.g. pralidoxime chloride (2-PAM) and methanesulfonate (P2S) are available and are used in research and clinical practice

Fig. 2

Chemical structure of selected novel oxime and non-oxime reactivators according to de Koning et al. (2011a, b, 2018), Mercey et al. (2011), Radic et al. (2012), Kalisiak et al. (2011), Katz et al. (2015), Santoni et al. (2018)

Fig. 3

Generic structure of organophosphorus compounds with residues R₁ and R₂ and leaving group X. In many OP pesticides the oxygen is replaced by sulfur to reduce mammalian toxicity

Fig. 4

Scheme of reactions between OP and AChE [E] resulting in inhibited AChE [EP]. Post-inhibitory reactions may lead to spontaneously reactivated AChE [E] or to aged AChE [EA]

Fig. 5

Ratio of bimolecular reactivation rate constants k_r2 of obidoxime and 2-PAM for GA tabun, GB sarin, GF cyclosarin, VX, VR Russian VX, CVX Chinese VX, PXE paraoxon-ethyl and PXM paraoxon-methyl

Fig. 6

Reaction scheme for the reactivation of OP-inhibited AChE by oximes. [E] native AChE; [EP] OP-inhibited AChE; [OX] oxime; [EPOX] Michaelis complex; [POX] phosphyloxime; K_D dissociation constant; k_r reactivity constant; k_r2 bimolecular reactivation rate constant

Fig. 7

Reactivation of paraoxon-inhibited human AChE by obidoxime (10 µM) in the presence of paraoxon (0–10 µM) in a dynamic model with online recording of AChE activity (Worek et al. 2015). Calculation gives the theoretical reactivation based on in vitro reactivation constants (Worek et al. 2011a)

Fig. 8

Calculated steady-state AChE activities in the presence of tabun (a, b) or sarin (c, d) and obidoxime (a, c) or 2-PAM (b, d). Calculations are based on experimental reactivation constants of obidoxime (tabun: k_r 0.04 min⁻¹, K_D 97.3 µM; sarin: k_r 0.937 min⁻¹, K_D 31.3 µM) and 2-PAM (tabun: k_r 0.01 min⁻¹, K_D 695 µM; sarin: k_r 0.25 min⁻¹, K_D 27.6 µM) and the bimolecular inhibition rate constants k_i of tabun (7.4 × 10⁶ M⁻¹ min⁻¹) and sarin (2.7 × 10⁷ M⁻¹ min⁻¹) (Worek et al. 2004) and were performed for oxime concentration of 10–200 µM. The dotted horizontal line resembles the cutoff AChE activity (20%). For calculation the equation [E]/[EP + EPOX] = k_r/(k_i × [OP] × (1 + K_D/[OX])) was applied (Eyer 2003)