Insecticide synergists

Chemists have found numerous industrial applications for 1,2,3-thiadiazole derivatives. In particular, 1,2,3-thiadiazole derivatives have been used as insecticide synergists, herbicides, and polymer compounds. They have also been shown to have sedative, antibacterial, and antibiotic activity. Examples of these compounds were discussed in CHEC(1984) and CHEC-II(1996). 

In crop protection as well, understanding plant metabolism is of paramount importance to increase selectivity and to address resistance of chemical compounds. Moreover, dissipation of a compound in the aquatic ecosystem is very similar to the excretion phenomena of the bodies. An extensive amount of evidence has been accumulated to support the involvement of CYPs in the metabolism and detoxification of herbicides, fungicides and insecticides. The understanding of their biotransformations at the molecular level may be extremely helpful for herbicide- or insecticide-synergistic development. 

In an effort to characterize further the metabolism of DEHP by trout, the effect of the mixed function oxidase inhibitor, piperonyl butoxide, upon the metabolism of DEHP by these trout liver fractions and serum was examined. Because of the use of piperonyl butoxide as an insecticide synergist, it is possible that fish might be exposed to this chemical in the environment. The data in Table VII show that piperonyl butoxide inhibited overall metabolism of DEHP by liver homogenates and microsomes whether NADPH was added or not. The hydrolysis of DEHP by serum was also blocked by piperonyl butoxide and although not shown, this was also the case with liver cytosol. These latter results were surprising because piperonyl butoxide has been known as a mixed function oxidase inhibitor only, and would not be expected... 

The LD5Q values for insecticide + synergist vary less than 2%, whereas LD g values for carbaryl alone differ by more than 100%. 

It should be noted that synergism and potentiation may be defined in the reverse way in some texts, and the term insecticide synergists," as defined here, usually reflects potentiation. The definition used here is the same as that used in pharmacology. 

Jones, D.G. Pipemnvl Burnside The Insecticide Synergist, Academic Press, Inc.. San Diego, CA. 1998. 

The definition of a poison, or toxicant, also involves a qualitative biological aspect because a compound, toxic to one species or genetic strain, may be relatively harmless to another. For example, carbon tetrachloride, a potent hepatotoxicant in many species, is relatively harmless to the chicken. Certain strains of rabbit can eat Belladonna with impunity while others cannot. Compounds may be toxic under some circumstances but not others or, perhaps, toxic in combination with another compound but nontoxic alone. The methylenedioxyphenyl insecticide synergists, such as piperonyl butoxide, are of low toxicity to both insects and mammals when administered alone but are, by virtue of their ability to inhibit xenobiotic-metabolizing enzymes, capable of causing dramatic increases in the toxicity of other compounds. 

Pyrethrins affect nerve membranes by modifying the sodium and potassium channels, resulting in depolarization of the membranes. Formulations of these insecticides frequently contain the insecticide synergist piperonyl butoxide [5- 2-(2-butoxyethoxy) ethoxymethyl -6-propyl-l,3-benzodioxole], which acts to increase the efficacy of the insecticide by inhibiting the cytochrome P450 enzymes responsible for the breakdown of the insecticide. 

Methylenedioxy (Benzodioxole) Ring Cleavage. Methylenedioxy-phenyl compounds, such as safrole or the insecticide synergist, piperonyl butoxide, many of which are effective inhibitors of CYP monooxygenations, are themselves metabolized to catechols. The most probable mechanism appears to be an attack on the methylene carbon, followed by elimination of water to yield a carbene. The highly reactive carbene either reacts with the heme iron to form a CYP-inhibitory complex or breaks down to yield the catechol (Figure 7.8). 

Irreversible inhibition, which is much more important toxicologically, can arise from various causes. In most cases the formation of covalent or other stable bonds or the disruption of the enzyme structure is involved. In these cases the effect cannot be readily reversed in vitro by either dialysis or dilution. The formation of stable inhibitory complexes may involve the prior formation of a reactive intermediate that then interacts with the enzyme. An excellent example of this type of inhibition is the effect of the insecticide synergist piperonyl butoxide (Figure 9.6) on hepatic microsomal monooxygenase activity. This methylenedioxyphenyl compound can form a stable inhibitory complex that blocks CO binding to P450 and also prevents substrate oxidation. This complex results from the formation of a reactive intermediate, which is shown by the fact that the type of inhibition changes from competitive to irreversible as metabolism, in the... 

Although 1,2,3-benzothiadiazoIes are not themselves insecticides, together with carbaryl, several are excellent insecticide synergists against the house fly (76MI42401). Many 1,2,3-benzothiadiazole derivatives were found to be inhibitors of mammalian and insect... 

Although examples are known in which synergistic interactions take place at the receptor site, the majority of such interactions appear to involve the inhibition of xenobiotic-metabolizing enzymes. Two examples involve the insecticide synergists, particularly the methylenedioxyphenyl synergists, and the potentiation of the insecticide malathion by a large number of other organophosphate compounds. 

Another class of cytochrome P-450 inhibitors, compounds with a monosubstituted acetylenic function, are well known for their potential as insecticide synergists (21) and some have already been reported to be active as JH biosynthesis inhibitors as well (19, 22). Ortiz de Montellano and Kunze (23) have shown that many ethynyl substrates cause the destruction of rat hepatic cytochrome P-450, when the prosthetic heme is alkylated during attempted metabolism of the triple bond. Such suicide substrates must bind to the enzyme and be catalytically acceptable thereby offering a potential for selectivity. In fact, selectivity of suicide substrates for particular molecular forms (isozymes) of hepatic... 

Precocene II (1) and 7-hydroxy-4-methylcoumarin were obtained from Aldrich. Acetylenic MF analog (2) was synthesized according to (27). CGA 167126 (3) was a gift from Ciba-Geigy. Insecticide synergist (.4) 2,4,5-trTchlorophenyl 2-propynyl ether was obtained from Hoffmann-La Roche. 7-Methoxy-4-methylcoumarln was obtained from Calbiochem. 

Inhibition of JH III biosynthesis In vitro. All three acetylenic compounds were significantly better Inhibitors of JH biosynthesis than precocene II under similar Incubation conditions (Fig. 4). Compound 2 was the best Inhibitor tested here, with an I50 of 16 pM, more than 25 times better than precocene II. Whether this better performance as an Inhibitor Is due to a closer structural analogy with the natural substrate of the epoxidase or whether it Is a consequence of the presumed difference In the mode of action (Irreversible Inhibition of the epoxidase for cytotoxicity of precocene epoxide eventually resulting In decreased JH biosynthetic rate for 1) Is not presently known. The Insecticide synergist (4) proved to be about 7 times better than precocene II. Its activity as an inhibitor of JH biosynthesis by D. punctata CA is similar to that of 3 and the methylenedioxyphenyl analog of JH (Ro 20-3600). 

Figure 5. Accumulation of methyl farnesoate in corpora allata inhibited by the acetylenic insecticide synergist (4).

B-Bernard, C. and Philogene, B.J.R., Insecticide synergists Role, importance, and perspectives, /. Toxicol. Environ. Health, 38,199,1993. 

Casida, J.E., Mixed-function oxidase involvement in the biochemistry of insecticide synergists, /. Agric. Food Client., 18, 753,1970. 

Hodgson, E. and Levi., P.E., Interactions of piperonyl butoxide with cytochrome P450, in Piperonyl butoxide, the insecticide synergist, Jones, D.G., Ed., San Diego Academic Press, 1998, p. 41. 

Sun, Y.P. and Johnson, E.R., Synergistic and antagonistic actions of insecticide-synergist combinations and their mode of action, /. Agric. Food Chem., 8, 261,1960. 

Chemical/Pharmaceutical/Other Class Methyl-enedioxyphenyl insecticide synergist Chemical Structure ... 

Jones DG (1998) Piperonyl Butoxide - The Insecticide Synergist. San Diego, CA Academic Press. 

A Brief History of the Development of Piperonyl Butoxide as an Insecticide Synergist... 

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