Decreasing the toxicity of paraquat through the complexation with sodium salicylate: Stoichiometric analysis

Abstract

Over the last decades, paraquat (1,1′-dimethyl-4,4′-bipyridilium dichloride; PQ) has been involved in numerous fatalities especially attributed to suicide attempts. Previously, it was shown that salicylates, namely sodium salicylate (NaSAL) and lysine acetylsalicylate (LAS) may form complexes with PQ, which may contribute to prevent its toxicity. The direct chemical reactivity between PQ and NaSAL was previously studied by liquid chromatography/electrospray ionization/mass spectrometry/mass spectrometry, showing the formation of complexes, though reported data was not fully conclusive. In the present study, the structure of the complex of PQ with NaSAL is fully characterized by crystallography. It was observed that PQ is complexed with 4 NaSAL molecules. Since formulations containing PQ and salicylates have been proposed, these results point that the stoichiometry of 1:4 (PQ:salicylates) should be considered to optimize prevention of PQ-mediated toxic effects.

Introduction

Paraquat (1,1′-dimethyl-4,4′-bipyridilium dichloride; PQ) is a highly toxic compound implicated in suicide attempts (Baltazar et al., 2014a, Dinis-Oliveira et al., 2006, Dinis-Oliveira et al., 2008a). Therapies currently used have failed to successfully treat PQ poisoned patients. During the last years, our research group has been focusing attention to the development of PQ antidotes. Sodium salicylate (NaSAL) and lysine acetylsalicylate (LAS) have been shown to have a multifactorial protection mechanisms against PQ-induced toxicity, due to its ability to modulate inflammatory signaling systems, to prevent oxidative stress and to its capacity to complex with PQ (Baltazar et al., 2014a, Baltazar et al., 2014b, Baltazar et al., 2011, Dinis-Oliveira et al., 2009a). More recently, it was shown that a new formulation of PQ containing LAS significantly decreased mammalian toxicity while maintaining effective herbicidal activity (Baltazar et al., 2014a, Baltazar et al., 2014b). Silverman et al. (2005) proved that the addition of NaSAL to PQ spray solutions significantly decreased herbicidal activity, which corroborates that an effective formulation must have LAS and not NaSAL.

The direct chemical reactivity between PQ and NaSAL was firstly discovered in 2008 (Dinis-Oliveira et al., 2008b). It was shown that PQ and NaSAL react immediately forming stable charge-transfer (CT) complexes. Liquid chromatography/electrospray ionization/mass spectrometry/mass spectrometry (LC/ESI/MS/MS) allowed obtaining a hypothetic stoichiometry of the CT complexes of 1:2, 1:3, 1:4, 1:6, 1:8 (PQ:NaSAL) but reported data was not fully conclusive.

The aim of the present work was to fully characterize the structure of the complex of PQ and NaSAL by crystallography and to evaluate the best chemical stoichiometry between these compounds. Results can offer data of the best stoichiometry to be considered in the development of PQ formulations containing salicylates.