Benzimidazoles and N-phenylcarbamates

We used N. crassa as a model fungus and attempted to elucidate the mechanism of negatively correlated cross resistance between benzimidazoles and N-phenylcarbamates. MBC resistant mutants were isolated from the wild type strain of N. crassa by UV treatment. Selection of the MBC resistant mutants was carried out on medium containing 50ppm MBC. MBC (carbendazim), the degradation product of benomyl and thiophanate-methyl, appears to be the active form in fungi (1). 

Genetic studies of negatively correlated cross resistance between benzimidazoles and N-phenylcarbamates. 

The inherent risk for development of resistance towards phenylpyrroles is considered as medium [39]. No cross-resistance has been reported between phenylpyrroles and products of other chemical classes, including benzimidazoles, dicarboximides, N-phenylcarbamates and anilinopyrimidines for B. cinerea [40]. 

Herbicides that act as inhibitory uncouplers are dinitro-phenols, N-phenylcarbamates, acylanilides, halogenated benzoni-triles, substituted imidazoles, substituted benzimidazoles, bromofenoxim, substituted 2,6-dinitroanilines, pyridinols, and substituted 1,2,4-thiadiazoles (2). 

Leroux and Gredt reported that benzimidazole-resistant strains of Botrytis cinerea and Penicillium expansum exhibited negatively correlated cross resistance to herbicidal N-phenylcarbamates such as barban, chlorpropham, and chlorbufam (10, 11, 12). Based on their observation, Sumitomo scientists evaluated many examples of N-phenylcarbamates to search for compounds with potent fungitoxicity and no phytotoxicity. This effort was eventually successful, leading to new fungicides such as MDPC ( , 21 ) and diethofencarb (14, 23, 24) (Figure 2). 

Some years ago, two groups of compounds, i.e. If-phenylcarbamates and N-phenylformamidoximes were synthesized in Japan and their specific antifungal activity against benzimidazole-resistant strains was reported ( 2, 3J. In France, where benzimidazole-resistant strains of the gray mold Botrvtis cinerea predominate in some areas, a N-phenylcarbamate compound diethofencarb is already in use as a mixture with a benzimidazole fungicide carbendazim. 

Leroux and Gredt (46) described the enhanced sensitivity of benzimidazole-resistant biotypes of Penicillium expansum and Botrytis cinerea to several N-phenylcarbamate herbicides. Following this lead, methyl 3,5-dichlorophenylcarbamate and isopropyl... 

Zoxamide (1) [3,5-dichloro-N-(3-chloro-l-ethyl-l-methyl-2-oxopropyl)-4-methyl-benzamide, RH-7281, Fig. 16.1.1] was discovered and commercialized by Rohm and Haas Company in 2001 for control of Oomycete pathogens [1], and is now marketed by Dow AgroSciences LLC. The primary markets for zoxamide are late blight on potatoes and downy mildews on vines and vegetables. Inhibitors of microtubule assembly that have been used as fungicides include the benzimidazole (BZ) and thiophanate fungicides such as carbendazim and thiophanate-methyl, the N-phenylcarbamate (NPC) diethofencarb, and the antibiotic griseofulvin. Zoxamide represents the first inhibitor of microtubule assembly to be used commercially for control of Oomycetes. 

L. C. Davidse, H. Ishii, Biochemical and molecular aspects of the mechanism of action of benzimidazoles, N-phenylcarbamates and N-phenyl-formamidoximes and the mechanism of resistance to these compoimds in fimgi, in Modem Selective Fungicides -Properties, Applications, Mechanisms of Action, H. Lyr (Ed.), Gustav Fischer Verlag, Jena, 1995, pp. 305-322. 

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. 

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