engleski

Profiling imidazolium and benzimidazolium oximes as antidotes in organophosphorus compound poisoning

Organophosphorus compounds (OP) used as pesticides account for more than 3 000 000 accidental or deliberate cases of poisoning registered per year worldwide. Furthermore, OPs developed as nerve agents (soman, sarin, tabun, VX) still present a threat in terrorist attacks and conflicts, such as in the recent case of Syria. The main targets of OP compounds are cholinesterases (ChEs) of the central and peripheral nervous system: acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BChE, EC 3.1.1.8). Upon exposure, OP compounds covalently bind to the specific active site serine after which physiological activity of these enzymes is permanently lost. The antidotal property of the oximes is attributed to their ability to reactivate ChEs inhibited by OPs and thus restore vital functions and reduce the severe consequences for an organism. In the search for more efficient oximes, a better understanding of their interactions with ChEs presents an important step considering the strict criteria set for their in vivo applications. For this purpose, we investigated a set of imidazolium and benzimidazolium oximes, presenting a structural shift from the oximes currently used in medical practice. A comprehensive analysis was performed defining all relevant kinetic parameters of reactivation as well as interactions with uninhibited ChEs. Several oximes were pointed out as leads in the development of new antidotes especially in the case of OP-inhibited BChE reactivation. Experimental data were correlated with computational studies including QSAR analysis. We were able to thoroughly describe the characteristic of novel oximes that contribute to favourable interactions with ChEs and should be the basis for further structure refinement. Furthermore, novel oximes were characterised for their cytotoxic profiles on a set of cell lines in order to elucidate all unwanted effects in vivo before investigating their further development as potential pharmaceuticals.

reactivation ; kinetic parameters ; QSAR analysis

nije evidentirano