Abstract
Nerve agents and oxon forms of organophosphorus pesticides act as strong irreversible inhibitors of two cholinesterases in the human body: acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BChE; EC 3.1.1.8), and are therefore highly toxic compounds. For the recovery of inhibited AChE, antidotes from the group of pyridinium or bispyridinium aldoxime reactivators (pralidoxime, obidoxime, HI-6) are used in combination with anticholinergics and anticonvulsives. Therapeutic efficacy of reactivators (called “oximes”) depends on their chemical structure and also the type of organophosphorus inhibitor. Three novel oximes (K131, K142, K153) with an oxime group in position four of the pyridinium ring were designed and then tested for their potency to reactivate human (Homo sapiens sapiens) AChE (HssACHE) and BChE (HssBChE) inhibited by the pesticide paraoxon (diethyl 4-nitrophenyl phosphate). According to the obtained results, none of the prepared oximes were able to satisfactorily reactivate paraoxon-inhibited cholinesterases. On the contrary, extraordinary activity of obidoxime in the case of paraoxon-inhibited HssAChE reactivation was confirmed. Additional docking studies pointed to possible explanations for these results.
Highlights
Cholinesterase reactivators are generally used as a part of the antidotal therapy against
We believe that this happens because the cavity of HssBChE is larger than HssAChE and does not present residues to help molecules, such as the oximes under study here, to adopt the near attack attack conformation conformation (NAC)
In order to improve the scaffold of the new oximes studied here and for designing more effective ones,We we reported believe that their hydrophobic moieties by adding more aromatic theincreasing synthesis the andbulkiness in vitro of evaluation of three novel bisquaternary aldoximes as rings would help to explore more interactions withinhibited the residues of the hydrophobic pocketsfailed of both potential reactivators for HssAChE
Summary
Cholinesterase reactivators are generally used as a part of the antidotal therapy against pesticide inhibited by organophosphorus (OP) compounds via breaking down the bond between inhibitor and nerve agent poisonings [1]. They reactivate human acetylcholinesterase (HssAChE) inhibited by and enzyme [2]. HssAChE [6].orDue to this, searching for oximes able to reactivate inhibitedand by all pesticides nerve agents [5] This fact is caused by differences in HssBChE structure is needed. We have 23 structurally different oximes,the which were originally developed for HssAChE reactivation, as HssBChE resulted, the maximal activity was obtained for K117.
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