Abstract
The lethality of seven 0,0-dimethyl 0-(p-nitrophenyl) phosphorothioates and their corresponding oxons has been determined in adult, male mice. The anticholinesterase potency of the oxons for bovine, erythrocyte acetylcholinesterase has also been determined. The LD50 values in mg/kg were: methylparathion, 33.1; fenitrothion, 988; chlorothion, 794; decapthon, 331, 0,0-dimethyl 0-(3 ethyl-4-nitrophenyl) phosphorothioate, 1396; 0,0-dimethyl 0-(3-isopropyl-4-nitrophenyl) phosphorothioate, 1379, and 0,0-dimethyl 0-(3,5-dimethyl-4-nitropenyl) phosphorothioate, 630. The lethality values for the 0-analogs were: methyl paraoxon, 21.8; fenitrooxon, 120; chloroxon, 280; dicapthoxon, 102; dimethyl-3-ethyl-4-nitrophenyl phosphate, 191; dimethyl-3-isopropyl-4-nitrophenyl phosphate, 321; dimethyl-3,5-dimethyl-4-nitrophenyl phosphate, 630. The pI50 values for inhibition of bovine red blood cell cholinesterase by the oxons were: methyl paraoxon, 7.2; fenitrooxon, 6.2; chlorooxon, 7.0; dicapthoxon, 7.1; dimethyl-3-ethyl-4-nitrophenyl phosphate, 6.0; dimethyl-3-isopropyl-4-nitrophenyl phosphate, 6.0; and dimethyl-3,5-dimethyl-4-nitrophenyl phosphate, 5.4. All the substitutions on the 4-nitrophenyl nucleus decreased toxicity whereas conversion of the phosphorothioates to oxons increased toxicity. The substituted oxons were all less toxic than methyl paraoxon while the substituted phosphorothioates were all less toxic than methyl parathion.
All substitutions on the 3 position of the 4-nitrophenyl ring in the phenyl phosphates decreased anticholinesterase activity. The halogen substitution at positions 2 and 3 produced much less reduction in acetylcholinesterase activity than did alkyl substitution at position 3 or dimethyl substitution at 3 and 5.
Partition coefficients of both the thioates and oxons were determined in four binary solvent systems. The partition coefficients from the octanol/water system were highly correlated with coefficients obtained in the other systems. Therefore data obtained from any solvent pair could be used in the multiple regression analysis for quantitative structure-action relationships.
Multiple regression analysis of the lethality data gave an equation, (1/LD50 = -0.89 -0.35 log P - 0.99 F + 0.5 Es, n-12, r-0.942, s-0.226log P = logarithm of octanol/water partition coefficient. F = Swain and Lupton's field constant, Es = Taft's steric substituent constant, n = number of compounds, r = correlation coefficient, s = standard deviation, in which all coefficients are significantly different from zero, which best describes our data. This equation should serve as a reliable predictor of toxicity in other meta substituted 4-nitrophenyl phosphorothioates or their oxons. The 2-chloro substituted compound (dicapthon) was not included in the regression equation because of the proximity of the ortho position to the reactive site in the molecule.
Hansch analysis of the anticholinesterase results gave an equation, pI50= 7.00 + 0.05 MR + 0.88 Es, n = 6, r = 0.981, s = 0.165, MR = molecular refractivity, which best describes our data. This equation, although it was derived from only six compounds, might be useful in predicting the toxicity of other 3-substituted 4-nitrophenyl phosphates. Again, dicapthoxon, the 2-chloro substituted derivative, was not used in the regression equation.
Zusammenfassung
Die Tödlichkeit von sieben 0,0-Dimethyl 0-(p-nitrophenyl) Phosphorothioates und ihrer zutreffenden Oxone wurde festgestellt in erwachsenen männlichen Mäusen. Die Anticholinesterase-Kräftigkeit der Oxone für Ochsen-Rinder, erythrozyte Acetylcholinesterase wurde ebenfalls festgestellt. Die LD50-Werte in mg/kg waren: Methylparathion, 33,1; Fenitrothion, 988; Chlorothion, 794; Dicapthon, 331; 0,0-Dimethyl 0-(3 ethyl-4-nitrophenyl) Phosphorothioat, 1396; 0,0-Dimethyl 0-(3-isopropyl-4-nitrophenyl) Phosphorothioat, 1397; und 0,0-Dimethyl 0-(3,5-dimethyl-4-nitrophenyl) Phosphorothioat, 630. Die Tödlichkeitwerte für die 0-Ähnlichkeiten waren: Methylparaoxon 21,8; Fenitrooxon, 120; Chloroxon, 280; Dicapthoxon, 102; Dimethyl-3-ethyl-4-nitrophenyl Phosphat, 191; Dimethyl-3-isopropyl-4-nitrophenyl Phosphat, 321; Dimethyl-3,5-dimethyl-4-nitrophenyl Phosphat, 630. Die pI50-Werte für Behinderung der Ochsen-Rinder rote Blutzellen-Cholinesterase bei den Oxonen waren: Methylparaoxon, 7,2; Fenitrooxon, 6,2; Chlorooxon, 7,0; Dicapthoxon, 7,1; Dimethyl-3-ethyl-4-nitrophenyl Phosphat, 6,0; Dimethyl-3-isopropyl-4-nitrophenyl Phosphat, 6,0 und Dimethyl-3,5-dimethyl-4-nitrophenyl Phosphat, 5,4. Alle Ersetzungen des 4-Nitrophenyl-Kernes verminderten die Vergiftungsfähigkeit, während Umstellung der Phosphorothioate für Oxone die Vergiftungsfähigkeit vermehrte. Die ersetzenden Oxone waren in jedem Fall weniger giftig als Methylparaoxon, während die ersetzenden Phosphorothioate in jedem Falle weniger giftig waren als Methylparathion.
Alle Ersetzungen an der 3. Stellung des 4-Nitrophenyl-Ringes in den Phenylphosphaten verminderten die Anticholinesterasewirkung. Die Ersetzung des Halogens an den Stellungen 2 und 3 brachte viel weniger Verminderung in der Acetylcholinesterasetätigkeit mit sich als die Alkylersetzung an Stellung 3 oder Dimethylersetzung an 3 und 5.
Teilungskoeffizienten der Thioates und der Oxone wurden festgestellt in vier zweiteiligen flüssigen Systemen. Die Teilungskoeffizienten von dem Octanol/Wasser-System wurden in engste Wechselbeziehung gebracht mit den Koeffizienten der anderen Systeme. Deshalb können die Resultate von jedem gültigen Paar in der vielfachen Regressionsanalyse für quantitative Aufbauwirkung Beziehungen benützt werden.
Vielfache Regressionsanalyse der Tödlichkeitsresultate ergab eine Gleichung, 1/LD50 = -0,89 -0,35 log P - 0,99 F + 0,5 Es, n = 12, r = 0,942, s = 0,226, log P = Logarithmus des Octanol/Wasserkoeffizienten, F = Swain und Lupton, s = Feldkonstante, Es = Taft, s = sterische, ersetzende Konstante, n = Normabweichung, in welcher alle Koeffizienten beträchtlich von Null differenzieren, welche unsere Resultate am besten beschreiben. Diese Gleichung sollte als eine zuverlässige Vorhersage der Giftigkeit in anderen Meta ersetzten, 4-Nitrophenyl Phosphorothioate oder ihrer Oxone dienen. Das 2-Chloro-ersetzte Präparat (Dicapthon) war nicht in der Rückfallgleichung eingeschlossen, wegen der Nähe der Ortho-Stellung zu der gegenwirkenden Lage in den Molekülen.
Hansch-Analysen der anticholinesterasen Resultate ergab eine Gleichung, pI50= 7,00 + 0,05 MR + 0,88 Es, n = 6, r = 0,981, s = 0,165, MR = molekulare Abbrechung, diese Gleichung beschreibt unsere Resultate am besten. Diese Gleichung, obwohl sie nur von sechs Präparaten herkommt, sollte nützlich sein im Vorhersagen der Giftigkeit anderer 3-ersetzten 4-Nitrophenyl-Phosphate. Ich wiederhole, Dicapthoxon, das 2-Chloro-ersetzte Abgeleitete wurde nicht in der Rückfallgleichung benützt.
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Mundy, R.L., Bowman, M.C., Farmer, J.H. et al. Quantitative structure activity study of a series of substituted 0,0-dimethyl 0-(p-nitrophenyl) phosphorothioates and 0-analogs. Arch. Toxicol. 41, 111–123 (1978). https://doi.org/10.1007/BF00302523
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DOI: https://doi.org/10.1007/BF00302523