Biochemical Modes of Action

Based on the structure of dioxapyrrolomycin and related compounds, it was postulated that the insecticidal activity of these compounds was due to the uncoupling of oxidative phosphorylation. This was subsequently confirmed through mouse-liver mitochondrial assays [6]. 

Uncoupling activity is dependent on two physicochemical parameters (1) lipo-philicity (log P) that allows the molecule to move across the mitochondrial membrane [7, 8] and (2) acidity (pXa) that allows the molecule to disrupt the proton gradient necessary for the conversion of ADP into ATP [7-9]. Studies have shown that a log P of 6.0 + 1 and a pXa range of 7.0-7.9 are necessary for optimal insecticidal activity [10]. 

Further support for the pro-insecticide concept was found using Colorado potato beetles that had been pretreated with piperonyl butoxide (PBO), an inhibitor of MFOs. In this study, chlorfenapyr (2) gave complete control at a dose rate of 10 ppm on the untreated insects. Treatment of the insects with PBO reduced the level of control to 10% [12]. 

The N-ethoxymethyl group provided the best balance between metabolic activation while avoiding phytotoxic effects seen for the parent, 3. 

The use of the benzoyl chloride (or benzoic acid) opens manufacturing opportunities that would be limited by previous routes. Also, new intermediates such as imidoyl chlorides or amides containing fiuoroalkyl groups are made available for biological screening. 

---

The biochemical mode of action of the aminoglycosides as antibacterials has long been a topic of great interest. Early experiments carried out soon after the introduction of streptomycin suggested a variety of modes of action, but these conclusions were based largely on symptomatic analyses of antibiotic-treated bacterial cultures. One important experiment done in 1948 showed that streptomycin blocks enzyme indnction in susceptible bacteria this was the closest that anyone came to identifying the mechanism of action at the time. 

From J.R. Corbett, K. Wright and R.C. Baillie, The Biochemical Mode of Action of Pesticides, Academic Press, London, 1984)... 

Several compounds are used as insecticides where little is known about their biochemical mode of action or whether they are general toxicants. Some have been around for many years, some are of natural origin and others are living organisms that predate on insects. 

The biochemical mode of action has been studied by several authors (16, 18). It appears that metalaxyl inhibits RNA synthesis by Interference with template-bound and a -amanitin-insensitive RNA polymerase action (15). 

Early observations indicated that a profound difference does exist between the biochemical modes of action of triorganotin and -lead compounds on the one hand and diorganotin and -lead compounds on the other. Whereas the latter compounds are antagonized by thiol compounds, in particular by the dithiol compound 2,3-dimercaptopropanol (BAL), no single antagonist is known of the triorganotin and -lead compounds. 

The main actions of prolactin in mammals are concerned with the mammary gland (see below). Lactogenic and mammogenic actions are also shown by several other hormones, including the placental lactogens found in man and many other mammalian species [5-7]. The physiological role of these placental hormones has not been fully established, but it does seem likely that their biochemical mode of action will prove to be similar in some respects to that of prolactin. Their structural relationships to GH and prolactin are discussed in Chapter 13. 

Biochemical mode of action of prolactin on the mammary gland... 

The main actions of prolactin in female mammals involve stimulation of mammary growth and function, and it is in this area that the bulk of work on the biochemical mode of action of the hormone has been concentrated. 

R. K. Jansson R. A. Dybas, Avermectins Biochemical Mode of Action, Biological Activity and Agricultural Importance. In Insecticides with Novel Mode of Action I. Ishaaya, D. Degheele, Eds. Springer Berlin, 1998 pp 152-170. 

Figure 7.2 Diagram of a nerve cell and a cholinergic synapse. (From Corbett, J.R., Wright, K., and Baillie, A.C., Eds., The Biochemical Mode of Action of Pesticides, 2nd ed., Academic Press, New York, 1984. With permission.)...

Figure 7.4 A typical action potential, (a) Rising phase Na+ ions are flowing into the axon from outside (b) Falling phase Na+ permeability has now dropped but permeability to K+ has increased and K+ ions are moving out of the axon (c) Positive phase this is due to maintained high K+ permeability (d) Negative after-potential local high K+ outside the axon gives net K+ influx, which delays equilibration. (Adapted from Corbett, J.R., Wright, K., and Baillie, A.C., The Biochemical Mode of Action of Pesticides, 2nd ed., Academic Press, New York, 1984. With permission.)...

The elucidation of the primary site and biochemical mode of action of inhibitors is often difficult and not necessarily associated with the mechanism of resistance in field isolates. Nevertheless, information on the mechanism of resistance can provide evidence to determine the site of action. Therefore, the classification of fungicides is based on crossresistance reactions rather than chemical similarities of structures or proposed modes of action (Table 1). Based on available information in the literature, three categories of inhibitor classes can be made Classes with known mode of action and known mechanism of resistance, classes with proposed mode of action and unknown mode of resistance but wide-spread field resistance, and classes in which resistance is claimed to occur in the field but both mode of action and resistance are not known. 

D-penicillamine is a non-physiological amino acid. It is a dimethyl derivative of cysteine, which is a structural component of many proteins. Metabohcally, penicillamine is relatively stable. In addition to the amino group (-NH2) and the carboxyl group (—COOH), it contains a sulphhydryl group (-SH) as a further reactive centre. The underlying biochemical modes of action are ... 

The selective toxicity of sulfonylureas to certain weeds without damage to the cereal crop arises from their rapid metabolism in the crop plant to inactive compounds, whereas in sensitive weeds the metabolism is much slower. The very high herbicidal activity suggests a specific biochemical mode of action, which is concluded to be the inhibition of plant cell division. Sulfonylureas block the enzyme acetolacetate synthase (ALS), which catalyses the biosynthesis of the essential branched chain amino acids valine, leucine and isoleucine. 

Biochemical Mode of Action of Pesticides, 2nd ed. Academic Press London, 1984. 

Corbett, J.R. "The Biochemical Mode of Action of Pesticides" Academic Press New York, 1974, p. 189. 

Here, too, a better knowledge of their biochemical modes of action and of pest vulnerability and defenses will be indispensible. However these goals can be fully realized only if there is greater investment in research into pesticidal mechanisms and responses in target and non-target species. 

---