Benzoylphenyl ureas

An early representative to the benzoylphenyl ureas includes difiubenzuron, discovered by Philips-Duphar B.V. as an inhibitor of chitin synthesis, and commercialized in 1977 for control of lepidopteran and coleopteran pests in fruit, cotton. 

Teflubenzuron was introduced in 1986 by ACC (now BASF) into parts of Europe and Africa for control of lepidopteran pests in fruits, citrus, vegetables and cotton. It also has mosquito larvacide activity and is currently being investigated for use as a feed treatment for sea lice on flsh grown in captivity [60]. 

Hexaflumuron, originally developed by Dow as an insecticide for control of Lepidoptera, Coleoptera, Homoptera, and dipera pests on cotton, top fruit and potatoes, was first introduced into Latin America in 1987. It was later registered in the USA in 1995 as the first reduced risk pesticide for use as part of a termite bait matrix system called Sentricon [59, 61-65]. Hexaflumuron has since been replaced with another benzoylphenyl urea, noviflumuron, which is more potent 

Lufeneron from Ciba-Geigy is the current market leader of the benzoylphenyl ureas [72]. It has been used in Europe and Japan on cotton and vegetables and markets are increasing in Latin America and South Korea. Its major application has been in the animal health market for the control of fleas on domestic dogs, cats and other animals [73-76]. It is also currently being developed as a bait for termite control [72]. 

Bistrifluron (DBI-3204) is a benzoylphenyl urea, recently introduced by Dongbu Hannong of Korea, that is active against whiteflies Triakurodes vaporar-iorum and Bemisia tahaci) and Lepidoptera pests (e.g., Spodoptera eocigua, and Plu-tella xylostella) [77]. This compound has also shown promise for use as a bait for the control of ants and cockroaches in domestic environments [78]. 

---

Anti-cancer properties of diflubenzuron require elucidation. The indication that one or more hydroxylated forms of diflubenzuron can regulate growth of mouse tumor cells provides a basis for further studies to identify and isolate the most active analog of this compound, and it suggests that other benzoylphenyl ureas may have similar properties (Jenkins et al. 1986). 

MTD and MTD approaches will be discussed and compared using QSAR of insecticidal benzoylphenyl-ureas, DDT-type analogs and benzylchrysanthemates, herbicidal benzonitriles and nitrophenols, and plant-growth regulating phenoxypropionic acids. 

These results give some insight in the scope and limitations of the MTD, MTD and STERIMOL parameters. Let us first compare the MTD and MTD methods. In the example of the benzyl chrysanthemates the regression equations have only steric terms, sothat there is no difference between the two methods in principle. In the case of the benzoylphenyl ureas the intercorrelation between the MTD values and the other parameters is very low, so it is understandable that there is hardly any difference. But in the four other studies there was much more intercorrelation between the MTD values on the one hand and the electronic and/or hydrophobic parameters on the other hand, and in these cases the MTD method gives slightly better results. Our preliminary conclusion from the examples discussed, is that the MTD is the preferable one, both from fundamental and... 

Benzoylphenyl urea. Substitution at the anilide portion of the molecule, particularly at the 4 position, has resulted in a variety of different commercial benzoylphenyl urea insecticides diflubenzuron (Dimilin ), with chlorine at the 4 position of the anilide, provides one of the earliest examples [153], The trifluoromethyl-containing benzoylphenyl ureas flufenoxuron and bistrifluron were discussed in Section 2.1.1.2, and chlorfluazuron was discussed in Section 2.1.2.2. Tefluben-zuron (Nemolt ) is used for the control of lepidoptera, coleoptera, diptera, and hemiptera larvae on vines, pome fruit, cabbages, vegetables, and cotton. 

Fig. 36. Influence of fluorine on soil stability of benzoylphenyl urea insecticides.

Benzoylphenyl Ureas—A New Group of Larvicides Interfering with Chitin Deposition... 

The high insecticidal activity of Du 19111 against the larval stages of several lepidopterous, coleopterous and dipterous insects and its unique mode of action prompted us to synthetise several hundreds of benzoylphenyl ureas and to evaluate their insecticidal potency in laboratory tests and small scale field trials (4, >, j6). These and other studies led to the ultimate choice of diflubenzuron (il) as the optimal derivative for further development. 

After the discovery of Du 19111, many hundreds of related benzoylphenyl ureas were synthetized and screened with respect to larvicidal activity. 

These efforts were guided by the study of quantitative structure-activity relationships (QSAR) following the Hansch approach. In this method linear free-energy related and other electronic, hydrophobic, and steric substituent constants are used for a quantitative analysis of the possible ways in which substituents may modulate bioactivity in a congeneric series. In the QSAR studies of benzoylphenyl ureas the electronic Hammett a-constants and the hydro-phobic Hansch n-constants were used. To measure the steric influences, steric substituent constants of a new type (B1,B2,B3,B4, and L) were applied which had recently been introduced by us and which give improved correlations in comparison with the steric Es constants used in the literature hitherto (21, 22). The constants B- toBj are measures of the widths of substituents in four rectangular directions. The L-constant accounts for the length of a substituent ... 

QSAR for the larvicidal effects of benzoylphenyl ureas on Pieris brassicae and Aedes aegypti larvae were studied for the following subseries ... 

However, at this stage the results of another area of our research of the benzoylphenyl ureas, i.e. the environmental studies, were going to have a vital influence on the further selection of the best compound. A preliminary study with a radioactive preparation of the "parent" compound Du 191 11> labeled with at the carbonyl group of the benzoyl... 

It was also found that 2,6-dichlorobenzamide was the principal labeled metabolite. Now there are several possible routes for the hydrolysis of the benzoylphenyl ureas, as is illustrated in Figure 2, where route A would lead to ortho-substituted benzoic acids and jD-chloro-phenyl urea while routes 2 and 3 would both result in ortho-substituted benzamides and p-Cl-aniline as the primary conversion products. Evidently routes 2 or 3 were the preferred ones in the case of PH 6O-38 with X = Cl (28). 

We knew that a shift of at least one chlorine atom from the ortho-position to the meta- or para-position resulted in much more soil-degradable benzamides but this could not be applied here, because we had learned from other QSAR studies with the benzoylphenyl ureas mentioned earlier that the 2,6-position of the(chlorine)substituents was essential for a high larvicidal activity. 

The similarities in the influences of the different parameters in the two subseries suggested that the optimum compound for development should still contain the p-Cl-aniline moiety, so that diflubenzuron was ultimately selected as the final benzoylphenyl urea derivative to be developed as a new selective insecticide. 

In the introduction it was stated that the disturbances of the endocuticular matrix of Pieris brassicae larvae by the parent benzoylphenyl urea compound Du 19111 were caused by an influence on chitin formation, thus assigning to the benzoylphenyl ureas an insecticidal position equivalent to that of the fungicidal polyoxins. In the last part of this paper we shall try to adduce arguments supporting that statement. 

Summarizing, diflubenzuron features mentioned in the introduction of this paper can be completed as follows The new insecticide has favourable environmental properties because it is non-persistent in soils and it has a low biological magnification. It is stable on plants and in insects, hence it has a long residual activity. It represents the best choice from the series of the benzoylphenyl ureas. It is a reversible inhibitor of chitin synthesis in insects, probably by blocking chitin synthetase. 

Dlflubenzuron. The benzoylphenyl urea Insect growth regulators, for example, pose a formidable residue analysis problem. The compounds are nonvolatile and thus must be derivatized for GC analysis by a rather arduous chemical procedure. The immunoassay developed in this laboratory is much more sensitive and reproducible at a fraction of the cost and can be used to analyze the more difficult matrices such as milk. For instance, a sensitivity of 1 ppb is routinely obtained when milk is added directly to the assay ( .). A series of partition steps can also be added to further clean dlflubenzuron milk extracts yielding a sensitivity in the low ppt range (4). However this increase in sensitivity may not be needed since methods in current use provide a detection limit of only 10-50 ppb. 

Oberlander, H. and Silhacek, D.L., New perspectives on the mode of action of benzoylphenyl urea insecticides, in Insecticides with novel modes of action, Ishaaya, I. and Degheele, D., Eds., Berlin Springer-Verlag, 1998, p. 92. 

Hajjar, N.P. and Casida, J.E. 1978. Insecticidal benzoylphenyl ureas. Structure-activity relationships as chitin synthesis inhibitors. Science, 200, 1499-1500. 

Nakagawa et al. (1984) found that the oxidative metabolism of benzoylphenyl-urea insectiddes, a factor significant in determining the activity, is favoured by electron-donating substituents at the anilide moiety. However, when the metabolic factor is eliminated, the activity is enhanced by electron-withdrawing and hydrophobic substituents and lowered by bulky groups. 

---