Theoretical study on the toxicity of ‘Novichok’ agent candidates

Jeong, Keunhong; Choi, Jun Won

doi:10.1098/rsos.190414

Cited by 38 publications

(26 citation statements)

References 25 publications

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“…The most important application of oximes is their ability to treat OP poisoning by the reactivation of acetylcholinesterase, which is inactivated by the OPs that form the dimethyl-or diethylphosphoryl-acetylcholinesterase complex [24,46]. The current known organophosphates that are used as nerve poisons include sarin, cyclosarin, tabun, VX, Russian VX, Chinese VX, soman and novichok (Figure 5) [47][48][49][50]. A detailed investigation on the OP poisoning and the development of AChE reactivators as antidotes appeared in the literature [51].…”

Section: Oximes As Organophosphate (Op) Poisoning Antidotesmentioning

confidence: 99%

FDA-Approved Oximes and Their Significance in Medicinal Chemistry

2022

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Despite the scientific advancements, organophosphate (OP) poisoning continues to be a major threat to humans, accounting for nearly one million poisoning cases every year leading to at least 20,000 deaths worldwide. Oximes represent the most important class in medicinal chemistry, renowned for their widespread applications as OP antidotes, drugs and intermediates for the synthesis of several pharmacological derivatives. Common oxime based reactivators or nerve antidotes include pralidoxime, obidoxime, HI-6, trimedoxime and methoxime, among which pralidoxime is the only FDA-approved drug. Cephalosporins are β-lactam based antibiotics and serve as widely acclaimed tools in fighting bacterial infections. Oxime based cephalosporins have emerged as an important class of drugs with improved efficacy and a broad spectrum of anti-microbial activity against Gram-positive and Gram-negative pathogens. Among the several oxime based derivatives, cefuroxime, ceftizoxime, cefpodoxime and cefmenoxime are the FDA approved oxime-based antibiotics. Given the pharmacological significance of oximes, in the present paper, we put together all the FDA-approved oximes and discuss their mechanism of action, pharmacokinetics and synthesis.

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Section: Oximes As Organophosphate (Op) Poisoning Antidotesmentioning

confidence: 99%

FDA-Approved Oximes and Their Significance in Medicinal Chemistry

2022

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“…Theoretically, it has been seen that Novichok also binds with acetylcholinesterase (AChE, E.C. 3.1.1.7) and leads to ageing of the enzyme [ 20 , 47 ]. The stereochemistry of nerve agents also determines the extent of reactivation of the AChE [ 11 ].…”

Section: Physiological Effectsmentioning

confidence: 99%

Organophosphorus Nerve Agents: Types, Toxicity, and Treatments

Mukherjee

Gupta

2020

Journal of Toxicology

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Organophosphorus compounds are extensively used worldwide as pesticides which cause great hazards to human health. Nerve agents, a subcategory of the organophosphorus compounds, have been produced and used during wars, and they have also been used in terrorist activities. These compounds possess physiological threats by interacting and inhibiting acetylcholinesterase enzyme which leads to the cholinergic crisis. After a general introduction, this review elucidates the mechanisms underlying cholinergic and noncholinergic effects of organophosphorus compounds. The conceivable treatment strategies for organophosphate poisoning are different types of bioscavengers which include stoichiometric, catalytic, and pseudocatalytic. The current research on the promising treatments specifically the catalytic bioscavengers including several wild-type organophosphate hydrolases such as paraoxonase and phosphotriesterase, phosphotriesterase-like lactonase, methyl parathion hydrolase, organophosphate acid anhydrolase, diisopropyl fluorophosphatase, human triphosphate nucleotidohydrolase, and senescence marker protein has been widely discussed. Organophosphorus compounds are reported to be the nonphysiological substrate for many mammalian organophosphate hydrolysing enzymes; therefore, the efficiency of these enzymes toward these compounds is inadequate. Hence, studies have been conducted to create mutants with an enhanced rate of hydrolysis and high specificity. Several mutants have been created by applying directed molecular evolution and/or targeted mutagenesis, and catalytic efficiency has been characterized. Generally, organophosphorus compounds are chiral in nature. The development of mutant enzymes for providing superior stereoselective degradation of toxic organophosphorus compounds has also been widely accounted for in this review. Existing enzymes have shown limited efficiency; hence, more effective treatment strategies have also been critically analyzed.

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“…17–19 Therefore, if the optimal scaling method is determined according to the calculation conditions, a variety of unknown compounds with the common functional group of the unknown organic compounds to be detected can be created; these can then be used to build a spectral database for the compounds, including the prediction of various properties. 20…”

Section: Introductionmentioning

confidence: 99%