No abstract

Oximes are a class of compounds normally used to reverse the acetylcholinesterase (AChE) inhibition caused by organophosphates (OPs). Conversely, researches focusing on the possible antioxidant properties of these compounds are lacking in the literature. The aim of this study was to investigate the potential antioxidant and toxic properties of 3-(phenylhydrazono) butan-2-one oxime in mice. In vitro, hydrogen peroxide-induced lipid peroxidation was decreased by low concentrations of the oxime (0.1-1.0 microM); (P < 0.05). Similarly, lipoperoxidation induced by malonate and iron (Fe2+) was significantly decreased by the oxime (0.4-1.0 microM) (P < 0.05). Oxime pre-treatment did not modify the basal peroxidation level nor prevented the induced lipid peroxidation determined ex-vivo. The present results suggest that 3-(phenylhydrazono) butan-2-one oxime could be a good antioxidant compound. The absence of toxicity signs after in vivo administration of 3-(phenylhydrazono) butan-2-one oxime to mice may indicate that it could be a safe drug for further studies.

Methamidophos is one of the most toxic organophosphorus (OP) compounds. It acts via phosphorylation of a serine residue in the active site of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), leading to enzyme inactivation. Different oximes have been developed to reverse this inhibition. Thus, our work aimed to test the protective or reactivation capability of pralidoxime and obidoxime, as well as two new oximes synthesised in our laboratory, on human and rat cholinesterases inhibited by methamidophos. In addition, we performed molecular docking studies in non-aged methamidophos-inhibited AChE to understand the mechanisms involved. Our results suggested that pralidoxime protected and reactivated methamidophos-inhibited rat brain AChE. Regarding human erythrocyte AChE, all oximes tested protected and reactivated the enzyme, with the best reactivation index observed at the concentration of 50 lM. Concerning BChE, butane-2,3-dionethiosemicarbazone oxime (oxime 1) was able to protect and reactivate the methamidophos-inhibited BChE by 45% at 50 lM, whereas 2(3-(phenylhydrazono) butan-2-one oxime (oxime 2) reactivated 28% of BChE activity at 100 lM. The two classical oximes failed to reactivate BChE. The molecular docking study demonstrated that pralidoxime appears to be better positioned in the active site to attack the O-P moiety of the inhibited enzyme, being near the oxyanion hole, whereas our new oximes were stably positioned in the active site in a manner similar to that of obidoxime. In conclusion, our work demonstrated that the newly synthesised oximes were able to reactivate not only human erythrocyte AChE but also human plasma BChE, which could represent an advantage in the treatment of OP compounds poisoning. Acetylcholinesterase (EC 3.1.1.7, AChE) is an enzyme that catalyses the hydrolysis of acetylcholine to choline and acetate. The biological function of this enzyme is to terminate acetylcholine activity in the terminal nervous junction with its effector organs or post-synaptic sites [1]. The mechanism of action of organophosphorus (OP) compounds with anticholin-esterase activity involves the phosphorylation of the serine hydroxyl group in the active site of AChE, leading to an inactive enzyme (AChE-OP) [2]. The inactivation of AChE results in the accumulation of acetylcholine at cholinergic receptor sites, causing a cholinergic crisis that can lead to death [3]. Methamidophos is a potent AChE inhibitor used to control plague of insects on a variety of crops [4] and may present anticholinesterase activity against human cholinesterases [5,6]. In Brazil in particular, methamidophos is commonly used on many crops, including cotton, soybeans and wheat, resulting in food [7] and occupational exposure [8]. A recent study demonstrated that over 90% of small farmers use methamido-phos and nearly 60% of them exhibit typical OP intoxication symptoms [9]. Mechanistically, methamidophos may inhibit AChE by covalently binding a serine residue (Ser203) in the active site, and this moiety could form two dif...

The structure of the title compound, C(12)H(9)N(5)O(4), reveals an almost planar molecule (r.m.s. deviation = 0.061 A), in which the interplanar angle between the phenyl rings is 5.7 (1) degrees and the largest interplanar angle is that between the phenyl ring and the nitro group of one of the 4-nitrophenyl substituents [8.8 (3) degrees ]. The observed molecular conformation suggests a delocalization of pi-electrons extended over the diazoamine group and the terminal aryl substituents. Intermolecular N-H.O interactions between the twofold screw-related molecules give rise to helical chains along the [010] direction. Intermolecular C-H.O interactions then generate sheets of molecules in the (10-1) plane, and these sheets are held together by N.C and O.O pi-pi interactions.