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Investigation of antioxidant potential of pyridinium oximes with halogen moiety and its relevance to therapeutic application

Pyridinium oximes are an essential part of antidotal therapy used in organophosphorous (OP) compounds poisoning. Through reactivation of phosphorylated acetylcholinesterase (AChE) oximes ameliorate symptoms arising from acute OP poisoning. However, survivors of OP exposures often have delayed neurologic symptoms of memory loss and cognitive dysfunction. It was shown that oxidative stress mediates secondary OP injury so long-term neurological consequences may be amendable to antioxidant therapy. Pyridiunium oximes have incorporated iminium and oxime moieties that are electron-affinic which enables them various physiological properties and might contribute to their overall therapeutic efficacy. The antioxidant activity of novel pyridinium oximes with the addition of chlorine or fluorine atoms was evaluated using DPPH (2, 2-diphenyl-1- picrylhydrazyl) and FRAP (ferric reducing antioxidant power) assays and compared to their non-halogenated analogues, standard pyridinium oximes and standard antioxidants. According to calculated EC50 values (the concentration of a compound necessary to decrease the initial concentration of DPPH radicals by 50 %), di- fluorinated oximes exhibited the best radical scavenging activity, with the strongest effect being observed for oxime 7b (EC50 250 µM). In case of chlorinated oximes, mono-chlorinated oximes showed better DPPH radical scavenging activity than di-chlorinated. Standard oximes and nonhalogenated analogues showed weak scavenging capacity (EC50 1.05 – 2.99 mM). In addition, FRAP assay highlighted di-fluorinated analogue 7b as the oxime with the highest antioxidant activity in terms of its reducing capacity (FRAP value 1.6 mM). Generally, a trend of higher reduction capacity of fluorinated oximes compared to chlorinated and non-halogenated analogues was observed. Both assays clearly indicated that 7b possesses an antioxidant potential probably due to the radical stabilizing effect of fluorine substituents associated with the resonance delocalization of the unpaired electron. Therefore, a multi-purpose (reactivation and antioxidant) activity of studied oximes could contribute to the entire therapeutic outcome in OP poisoning.

Antidote ; Antioxidant potential ; Pyridinium oximes

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