Aryl-N-methylcarbamates

Pussemier et al. (1989) found that log Koc for 12 aryl N-methylcarbamates correlated significantly to a linear combination of two parameters, % hydrophobic effect (calculated from RP-HPLC measurements) and 8 Hildebrand solubility parameter. The authors also used data for 16 phenylureas and 13 anilides from Briggs (1981) and obtained similar results. 

Katagi, T. Theoretical studies on the photo-Fries rearrangement of O-aryl N-methylcarbamates. Nippon Noyaku Gakkaishi 1991, 16, 57-62. Grimme, S. MO theoretical investigation on the photodissociation of carbon-oxygen bonds in aromatic compounds. Chem. Phys. 1992,163, 313-330. 

Several aryl N-methylcarbamates have been developed in which a nitrogen-containing side chain is attached to the phenyl group. Typical representatives of this class are 3,5-dimethyl-4-dimethylaminophenyl N-methylcarbamatc (mexacarbate,... 

Inhibition of AChE preparations from S- and R-strains of green rice leafhopper by aryl N-methylcarbamates (n 20) and aryl oxadiazolones (n = 81) were evaluated with pI50 as the end-point. Regression against binding and reactivity descriptors was used to explore differences in mechanistic behavior. 

Early studies of the relation of aryl N-methylcarbamate structure with activity and enzyme inhibition were first reported in 1966 and showed rather simple dependence on substituent effects for limited sets of compounds (4, 5) The apparent simplicity was partly due to the fact that QSAR techniques were still in the first decade of development. The true complexity of carbamate inhibition is revealed in later studies by Fujita and co-workers on brown plant-hopper AChE (6, 7), and by Hansch and co-workers on housefly head AChE (8). The latter study shows that 12 significant factors are required to correlate the pI50 data for a set of 269 carbamates. 

TABLE 1. Anti-AChe activity of aryl N-methylcarbamates on... 

Oral toxicity of aryl N-methylcarbamates to the rat indicate a complexity similar to that observed against the housefly (10) and brown planthopper (11,12). Complex ortho-effects and strong H-bond-Ing for some substituents combine to modify toxicity. The major mechanistic step In carbamate poisoning is strong binding to an AChE site. The parallel factors Involved for Insects and animals are consistent with death due to AChE Inhibition. 

Carbamates are substituted esters of carbamic acid (NH2COOH) with aliphatic or aromatic substituents on the oxygen and nitrogen atoms. Carbamate insecticides have an aryl or oxime N-methylcarbamate structure, and their mode of action is based on the inhibition of the enzyme acethylcholine esterase (1). However, this inhibition is reversible, and recovery from sublethal doses occurs rapidly. Some carbamate fungicides have a dithio, bisdithio, or benzimidazole carbamate basic structure, and dithiocarbamate fungicides inhibit the enzyme aldehyde deshydro-genase (2). The herbicides have an /V-alkylthiocarbamate or A-phenylcarbamate structure and interfere with photosynthetic activity or affect meristematic activity or lipid metabolism (3). Representative structures of carbamate pesticides are shown in Fig. 1. 

Of the N-alkylcarbamates only the aryl esters of N-alkylcarbamic acid possess herbicidal activity. The herbicidal activity of N-alkylcarbamic acid alkylesters and of the heterocyclic derivatives of N-alkylcarbamic add is mentioned only in the patents literature, but these latter derivatives have not found agricultural application. Examples are the N-dimethylcarbamic acid enol esters proposed by Whetstone and Kuddema (1959) and the N-methylcarbamic add pyridine esters proposed by Johnston (1964). 

The results of a comparative metabolism study of an aryl-sulfenyl derivative of carbofuran [2,2-dimethy1-2,3-dihydro-benzofuranyl-7 -methyl-N-(2-toluenesulfenyl)carbamate] in the house fly and white mouse Indicated the selective action of this compound to be a consequence of different metabolic pathways in insects and mammals (12). The arylsulfenyl group on the carbamate moiety allows the mammal to carry out metabolic reactions leading to less toxic products which are rapidly conjugated, while the toxic parent methylcarbamate is formed in the insect. 

The discovery of the Improved toxicological properties of the aryl- and alkylsulfenyl derivatives of methylcarbamate insecticides stimulated examination of other types of derivatives containing an N-S linkage. In most of the cases where highest insecticidal activity is found, the methylcarbamate nitrogen is attached to a sulfur atom which is attached to another nitrogen atom, as shown in the general structure below. 

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