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.
Keywords
Non-oxime - Diazinon - Cholinesterase activity - Pralidoxime - Organophosphate - LD50
