The efficacy of 2-formyl benzoic acid in reactivating diazinon inhibited murine cholinesterase.

Abstract

Oximes, as classical acetylcholinesterase (AChE) reactivators, have some pharmacokinetics/pharmacodynamics disadvantages. During the synthesis of non-oxime compounds, we encountered the compound 2-formylbenzoic acid (2-FBA) with promising in vitro and in vivo cholinesterase (ChE) reactivating properties in the acute exposure to diazinon (DZN). For in vitro experiments, the healthy mice serum and brain homogenate were freshly prepared and exposed to DZN (160 µg/mL). After 10 minutes, 2-FBA was added to the poisoned samples, and ChE activity was measured afterward. For the in vivo assay, the mice were poisoned with DZN subcutaneous (SC) injection (50 mg/kg), and after 1 hour, either 2-FBA or Pralidoxime (2-PAM) was injected intravenously (IV). After 3 h, ChE activity was measured in the serum and brain homogenate samples. The LD50 (IV) for 2-FBA in mice was measured as well. 2-FBA effectively reactivated the inhibited ChE in serum and brain homogenate samples in vitro. In the in vivo experiments, while 2-FBA could significantly reactivate the brain ChE even better than 2-PAM, they failed to reactivate the serum ChE by single IV injection. LD50 of 2-FBA was calculated to be 963 mg/kg. There were no general toxicity signs in any treatment groups. The in silico results support the potential ability of 2-FBA efficacy via possibly Witting reaction mechanism. Our findings indicate that 2-FBA seems to be a suitable non-oxime candidate for AChE reactivation with minimal side effects. Further toxicokinetic studies on this compound are strongly recommended to be performed before conducting the clinical trial in humans.