Pyrethroids, structure

Gray, A.J. 1985. Pyrethroid structure-toxicity relationships in mammals. Neuro toxicology 6 127-137. 

An important characteristic of the pyrethroid-generated tail current is that its amplitude and duration are independent. The current amplitude is dependent only on the proportion of sodium channels modified, and hence shows a saturable relationship with pyrethroid concentration or dose. The current duration however is dependent only on the pyrethroid structure some pyrethroids, such as permethrin holding the channel open for a few milliseconds and others, such as deltamethrin, holding it open for tens of milliseconds. Individual pyrethroids thus generate a characteristic time constant for prolongation of the sodium channel tail current that is virtually independent of dose. 

Another aspect of conformational flexibility in general though is the effect this may have on the properties which are computed in order to describe molecular structures. As an example of this, consider the pyrethroid structure shown in Figure 8.3. There are five flexible torsion angles in the two side chains of the cyclopropane ring, although torsion 3 is effectively fixed as it has some double bond character in resonance with the carbonyl oxygen. 

From these different pyrethroid structures around 41% contain no halogen substituents, whereas around 59% are halogen substituted. Generally, 43% of pyrethroids containing fluorine/chlorine are the most important 26% of pyrethroids contain only chlorine, 13% fluorine, around 9% bromine and around 2% are fluorine/bromine substituted. 

K. Naumaim, Synthetic Pyrethroid Insecticides Structures and Properties, Sptinger-Verlag, Berlin, 1990. 

Many pesticides are not as novel as they may seem. Some, such as the pyre-throid and neonicotinoid insecticides, are modeled on natural insecticides. Synthetic pyrethroids are related to the natural pyrethrins (see Chapter 12), whereas the neo-nicotinoids share structural features with nicotine. In both cases, the synthetic compounds have the same mode of action as the natural products they resemble. Also, the synthetic pyrethroids are subject to similar mechanisms of metabolic detoxication as natural pyrethrins (Chapter 12). More widely, many detoxication mechanisms are relatively nonspecific, operating against a wide range of compounds that... 

The structures of some pyrethroid insecticides are shown in Figure 12.1. They are all lipophilic esters showing some structural resemblance to the natural pyrethrins. They can all exist in a number of different enantiomeric forms. Permethrin, cypermethrin, and deltamethrin, for example, all have three asymmetric carbon atoms... 

Figure 8 Structure of immunogen haptens for pyrethroids with spacer arm attachment at the a-position of the alcohol moiety. Since the whole pyrethroid molecule is available for recognition by the antibody, assays resulting from these immunogens were selective for the parent pyrethroids...

Figure 9 Structure of the immunogen hapten used to generate antibodies for a type I pyrethroid class-selective assay. Pyrethroids lacking an a-cyano group are generally termed type I. This hapten exposed the features most common to type I pyrethroids, the phenoxybenzyl group, the cyclopropyl group and the lack of a cyano group, resulting in antibodies that recognized permethrin, phenothrin, resmethrin and bioresmethrin, but not cypermethrin...

Casida, J.E. and LJ. Lawrence. 1985. Structure-activity correlations for interactions of bicyclophosphorus esters and some polychlorocycloalkane and pyrethroid insecticides with the brain-specific t-butylcyclo-phosphorothionate receptor. Environ. Health Perspec. 61 123-132. 

Doherty, J.D., K. Nishimura, N. Kurihara, and T. Fujita. 1986. Quantitative structure-activity studies of substituted benzyl chrysanthemates. 9. Calcium uptake inhibition in crayfish nerve cord and lobster axon homogenates in vitro by synthetic pyrethroids. Pestic. Biochem. Physiol. 25 295-305. 

Glickman, A.H. and J.E. Casida. 1982. Species and structural variations affecting pyrethroid neurotoxicity. Neurobehav. Toxicol. Teratol. 4 793-799. 

Verschoyle, R.D. and W.N. Aldridge. 1980. Structure-activity relationships of some pyrethroids in rats. Arch. Toxicol. 45 325-329. 

Vijverberg, H.P.M., G.S.F. Ruigt, and J.V.D. Bercken. 1982. Structure-related effects of pyrethroid insecticides on the lateral-line sense organ and on peripheral nerves of the clawed frog, Xenopus laevis. Pestic. Biochem. Physiol. 18 315-324. 

As described in the section on Cross-resistance in this chapter, it was found that some insect species showed extremely low cross-resistance to three ingredients, pyrethrins as well as d-allethrin and prallethrin, although they developed resistance to photostable synthetic pyrethroids. The latter two compounds of d-allethrin and prallethrin have quite similar chemical structures and the same configuration as cinerin I (an ingredient of pyrethrins). It is considered preferable to develop pyrethroids retaining the characteristics of natural pyrethrins and household insecticides containing them in the perspectives of safety and low cross-resistance. 

Figure 7 shows the course of development of various synthetic pyrethroids developed by retaining chrysanthemic acid as the acid moiety and modifying the alcohol moiety. Numerous useful compounds with favorable characteristics have been derived from the structural modification of natural cinerin I (7). These underlined compounds have been put into practical use as active ingredients, mainly for household insecticides. 

The main application fields of pyrethrins are limited to indoor use because of their instability to heat, light, and oxygen. Since the absolute configuration of the six insecticidal components of pyrethrins were elucidated in 1958, various researches on structural modifications have been carried out actively in many countries for more than half a century, leading to the development of a variety of photostable pyrethroids. As a result, they have been widely put into outdoor use for agriculture, forestry, animal health, termite control, and so on. 

Allethrin, the first synthetic pyrethroid, is a compound which is the closest in structure to cinerin I. Pyrethroids developed subsequently are mostly esters of chrysanthemic acid, and cinerin II analogs, i.e., esters of chrysanthemum acid have not been industrialized. 

Cross-resistance to pyrethroids for outdoor use has developed markedly in M. domestica, mosquitoes, cockroaches, and so on however, it has also been found that natural pyrethrins as well as d-allethrin and prallethrin (ETOC ), which have very similar chemical structures and the same configuration as natural pyrethrins, show an extremely low degree of cross-resistance development by these highly-resis-tant sanitary pests compared to photostable pyrethroids. Many novel synthetic pyrethroids recently developed as household insecticides have tended to pursue efficacy improvements in terms of rapid knock-down effects, residual efficacy or volatility. 

Natural pyrethrins are a neurotoxin and repel, knock down, and kill by contact with insects at a low concentration. On the other hand, they have ideal features for household insecticides because of their quite low dermal and oral toxicides to warm-blooded animals. Neither plants other than pyrethrum nor synthetic insecticides have been reported to have such properties. Numerous synthetic pyrethroids have been developed by chemists since the complicated chemical structure of natural pyrethrins was elucidated in the middle of the twentieth century. Allethrin was the first synthetic pyrethroid put into practical use. 

Matsuo N (1993) Structure of pyrethroids and their development, vol 18, The 2nd series of pharmaceutical research and development. Hirokawa Publishing Co, Tokyo, pp 494-515... 

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