<i>N</i>‐acylation of <i>N</i>‐methylcarbamate insecticides and its effect on biological activity

Fraser, J.; Clinch, P. G.; Reay, R. C.

doi:10.1002/jsfa.2740161008

Cited by 25 publications

(9 citation statements)

References 5 publications

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“…In cases where analogous compounds are available for comparison, the dimethylcarbamates, ethylcarbamate, N-acetyl-N-methylcarbamates, and unsubstituted carbamates generally are less active and, frequently, are much less active inhibitors than their respective methylcarbamate analogs. The reduced antiChE activity on forming the N-acetyl derivatives is consistent with published information (Fraser et al, 1965;Lewis, 1967;Reay and Lewis, 1966). Methylcarbamates with various sites of ring hydroxylation vary in potency, as cholinesterase inhibitors, from moderately active to highly active ones.…”

Section: Resultssupporting

confidence: 87%

Oxidation of methyl- and dimethylcarbamate insecticide chemicals by microsomal enzymes and anticholinesterase activity of the metabolites

Oonnithan¹,

Casida²

1968

J. Agric. Food Chem.

101

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Each of the 33 methyl-and dimethylcarbamate insecticide chemicals and related compounds studied is metabolized by the rat liver microsome-reduced nicotinamide-adenine dinucleotide phosphate (NADPH2) system, producing one or more carbamate metabolites in each case. In this system, NADPH2 is required for each of the following types of enzymatic reactions, as demonstrated with the listed carbamates: vV-demethylation (dimetilan, Matacil, Zectran, and 1-naphthyl dimethylcarbamate); conversion of M-methyl to TV-formamide (Zectran) and to /V-hydroxymethyl groups (Banol, Baygon, carbaryl, HRS-1422, Matacil, UC 10854, and Zectran); aromatic ring hydroxylation (Baygon and carbaryl) or formation of a dihydrodihydroxy derivative (carbaryl); O-dealkylation (Baygon); alkyl hydroxylation of an aralkyl substituent (UC 10854); sulfoxidation (Mesurol and Temik). Car-baryl is nroduced on A-demethylation of 1-naphthyl dimethylcarbamate by the microsome-NADPH2tracting with ether, drying the ether extract with anhydrous sodium sulfate, and evaporating the ether under a gentle stream of nitrogen. Nicotinamide-adenine dinucleotide (NAD), its reduced form (NADH2), nicotinamide-adenine dinucleotide phosphate (NADP), its reduced form (NADPH2), and acetylcholine were obtained from Calbiochem., Los Angeles, Calif. Pooled, outdated human blood plasma was used as the enzyme source for the anti-ChE tests. The sources of materials and methods for TLC and for detection and measurement of radioactivity were those already reported (Abdel-Wahab et al., 1966;Oonnithan, 1966;Oonnithan and Casida, 1966). Male albino rats, weighing 150 to 160 grams, were obtained from the Berkeley Pacific Laboratories, Berkeley, Calif.The rat liver homogenates were separated into different fractions in a Servall refrigerated centrifuge (Ivan Sorvall, Norwalk, Conn.) and in a Beckman ultracentrifuge (Model L, Beckman Instruments, Menlo Park, Calif.).The enzyme systems containing the substrates were incubated in a Dubnoff metabolic shaking incubator (Precision Scientific Co., Chicago, 111.). Separation, Detection, and Characterization of Metabolic Products. Thin-layer chromatography was used to separate the carbamates and their metabolic products. For routine analysis, 20 X 20 cm. glass plates coated with silica gel G in0.25-mm. thickness were employed; however, for preparative scale TLC, the coatings were 0.5 mm. thick. Solvent systems used for TLC were (Figure 1); normal manner, and the spots were visualized by chromogenic, radioautographic, or antiChE procedures, and compared in the above described manner.The metabolic products were usually tentatively characterized by cochromatography of the products, as recovered, or of derivatives made from these products (prior to cochromatography). In the latter instances, 1 ml. of an ether solution of the labeled metabolites and/or of known nonlabeled compounds were reacted for 18 hours at 25°C. with one of two reagents: 1 ml. of 2% diazomethane solution in ether, to form the O-methyl ether derivatives;1 ml. of methylisocyanate p...

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Section: Resultssupporting

confidence: 87%

Oxidation of methyl- and dimethylcarbamate insecticide chemicals by microsomal enzymes and anticholinesterase activity of the metabolites

Oonnithan¹,

Casida²

1968

J. Agric. Food Chem.

101

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“…Carbamylcarbonyl-1 C-A-acetyl Zectran and (dimethylamino)-14C-A-acetyl Zectran were synthesized by procedures adapted from Fraser, Clinch, and Reay (1965). Purity of these compounds was previously established ).…”

Section: Methodsmentioning

confidence: 99%

Metabolic pathways affecting toxicity of N-acetyl Zectran

Miskus¹,

Andrews²,

Look³

1969

J. Agric. Food Chem.

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“…The first group of compounds of this type were the N-acylated methylcarbamate derivatives (4,5) which were reported to be good insecticides but less toxic to mammals. The N-acyl-N-methylcarbamate derivatives also were appreciably less effective as anticholinesterases, leading to the conclusion that the original methylcarbamate was responsible for intoxication in the insect after in vivo formation from the N-acyl derivative (6).…”

Section: Derivatized Carbamatesmentioning

confidence: 99%

Sulfur in Propesticide Action

Fukuto¹,

Fahmy²

1981

ACS Symposium Series

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It is well known that phosphorothionate insecticides such as parathion (O,O-diethyl O-p-nitrophenyl phosphorothioate) and malathion [O,O-dimethyl S-(1,2-dicarbethoxy)ethyl phosphorodithioate] are intrinsically poor inhibitors of acetylcholinesterase and in vivo activationto the respective anticholinesterases paraoxon and malaoxon is required before animals exposed to the phosphorothionates are intoxicated. Since metabolic activation is essential to the biological activity of these thiono sulfur-containing organophosphorus insecticides, compounds of this type may be considered as propesticides or, more specifically, proinsecticides.The introduction of a thiono sulfur in an organophosphorus insecticide has advantages and disadvantages. From a favorable viewpoint, compared to phosphate esters, the phosphorothionates are generally more stable to hydrolysis and, therefore, may have greater insecticidal activity. Perhaps the most important contribution which a thiono sulfur atom may make is the "delay factor" provided by P=S to P=0 activation. This factor gives mammal s the opportunity to detoxify the toxicant, and in many cases the phosphorothionate is substantially less toxic to warmblooded animals than the corresponding phosphate ester. A classical example of the "delay factor" is found in the safe organophosphorus insecticide malathion for which it was demonstrated over two decades ago that slow in vivo oxidation to the anticholinesterase malaoxon provided the opportunity for detoxifying enzymes in mammals, most likely a carboxylesterase, to degrade malathion to nontoxic metabolic products (_1). The mouse LD50 of purified malathion is 3,200 mg/kg C2), compared to 75 mg/kg for malaoxon (_1) .Among the different classes of organic insecticides in use today, the methylcarbamate esters rank at or near the top in acute mammalian toxicity and in many cases the methylcarbamates are as toxic to mammals as they are to insects (_3) . For

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N‐acylation of N‐methylcarbamate insecticides and its effect on biological activity

Cited by 25 publications

References 5 publications

Oxidation of methyl- and dimethylcarbamate insecticide chemicals by microsomal enzymes and anticholinesterase activity of the metabolites

Oxidation of methyl- and dimethylcarbamate insecticide chemicals by microsomal enzymes and anticholinesterase activity of the metabolites

Metabolic pathways affecting toxicity of N-acetyl Zectran

Sulfur in Propesticide Action

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