Pyrethroid insecticides

Pyrethrins are a family of natural insecticides located in the flower head of Chrysanthemum cinerariifolium. Chemists have modified the original structures and extended their insecticidal properties to the benefit of mankind and under consideration of ecology and ethics in a transdisciplinary research endeavor that has covered almost a century. We expect that this review will allow teachers to produce material in their own language, in the format and at the level they judge most adequate for the message they want to transmit


Insects as pests
Although insects are invaluable in their aptitude to fertilize plants by pollination and to produce, in the case of honey bees, a highly valuable food, a few of them interact with humans either competitively or in other ways. 1 In fact, of 700 000 insect species, a mere hundred can be regarded as pests. 2 They: (i) compete for food (Locusta migratoria the desert locust, Leptinotarsa decemlineata the colorado or potato beetle, Helicoverpa zea, the corn earworm or cotton bollworm, which is a noctuid moth), Cydia pomonella the codling moth), feeding on food crops; (ii) destroy crops and trees threatening human economy [vine (Phylloxera), cotton (Spodoptera littoralis), tobacco (Helioverpa zea), olive trees (Philaenus spumarius, vector of the bacterium Xylella fastidiosa), elms (Scolytis spp. the elm bark beetles)]; (iii) act as vectors for possibly life-threatening diseases such as plague, leishmaniansis especially visceral leishmaniansis (fleas), typhus (lice), malaria, yellow fever, dengue and Zika fever (mosquitoes), lyme disease (ticks), and skin and allergic diseases (mites). 2 As a consequence, men have fought insects from very early times, 1,3 and crop protection can be estimated at the cost of $6 billions/year. 2 Fumigation with sulfur was first used (1000 BC), followed by natural extract of plants (such as pyrethrins, in the Middle Ages, 3,4 Figure 1), inorganic compounds [lead arsenate (PbHAsO4), cryolite (Na3AlF6) and borax (Na2B4O7)], organic compounds (DDT, 1939) 2,5,6 and bacterial, fungal and viral agents as well as DNA insecticides. 3nsecticides should be adapted to the type of insect to fight (flying, crawling, swimming, moving in the soil), the conditions (indoor or outdoor use) and the ambient conditions (temperature, humidity, sunlight) and therefore the choice is context dependent.Anyhow, they should be: (i) highly toxic to the target category of insects (LD50), but should not harm other species such as fish, birds and mammals; (ii) possess a very powerful knock-down effect (KD) 7 that should almost instantaneously paralyze the insects preventing them for example biting other species or to infest fruit with their eggs before dying;

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(iii) stable enough to protect for just the required time, being eco-friendly with the proper remanence; (iv) possess limited soil persistence, except for soil insecticides; (v) unaffected by resistance of insects over the years; (vi) Readily available at low cost None of the different classes of insecticides that have been marketed fulfill those requirements.
Pyrethrins, 8,9 (Figure 1), the active principles of the ground flower-head of some chrysanthemum plants

Development of the pyrethrins and other insecticides
]11 Increasing demand in Europe (1820), in the US (1880) and in Japan (1885) has led to intensive cultivation in Japan, Kenya, Rwanda, Tanzania, China and Papua New Guinea, owing to the suitable climate in those countries, of Chrysanthemum cinerariifolium whose content in active principle is the highest (1.5 % in the ground flower head).Japanese pyrethrum production reached a peak of 13 000 tons/year in 1938 (70% of the world's production at that time) and declined to only 1000 tons in 1965 at the time that synthetic analogs, the pyrethroid family, entered the market. 13,14yrethrum has been used quite early (1890) to produce mosquito-burning sticks active for 1 h, then coils with prolonged burning time (7 h). 11Extraction of the flowers with organic solvents proved to be more efficient with the more benign supercritical carbon dioxide, 15 producing up to 50% of oily pyrethrin extracts devoid of the natural resin present in the powder that possesses allergenic properties, that is used in spray as household insecticide (USA, 1919) or as oil-based preparations (Japan, 1924). 16yrethrum was used to fight a typhus epidemic in Naples in December 1943 but was supplanted by DDT (Figure 2), a more persistent synthetic insecticide, whose properties were discovered by P. Müller, a scientist at the Geigy company who won the Nobel Medicine Prize in 1948 6,17 on the strength of this discovery.
DDT was used to eradicate malaria in Europe (1975) 6,10,18 and would have achieved a similar result in other parts of the world had it not been banished worldwide due to its strong persistence in the environment and its accumulation in the fat of almost all living organisms. 18New insecticides, less persistent than DDT but more stable than pyrethrins, were needed and expected to be produced by structural modifications of the latter.Those however must retain the advantages that pyrethrins already possess over DDT to kill insects at much lower dose (Table 1), to be almost harmless to mammals, and to possess a powerful knock down effect. 6,18ioneer work (1909) by chemists 4,11 led to the isolation by Fujitani 19 of some of the pyrethrins (1a-f) (Figure 1) as the active principle of Chrysanthemumum cinerariifolium.The presence of compounds possessing at least a C=C double bond, a cyclopropane ring and an ester group was suggested by the isolation by Yamamoto of trans-caronic acid (4) (Figure 3) on hydrolysis of this active principle followed by ozone oxidation (1923). 20,21taudinger and Ruzicka 22 proposed the structures of pyrethrin I and II (1a, 1b, Figure 1; 1924, with minor errors in the location of the unsaturations).Laforge 23 discovered the cinerins (1c, 1d, Figure 1; 1945) and Gordins 24 the jasmolins (1e, 1f, Figure 1; 1966).
Finally, the absolute configuration of the carboxyl moieties part of the chrysanthemic acid (2a) (Figure 2, 1954) were elucidated by Crombie, 25 that of the related chrysanthemum acid (2b) (Figure 3, 1955) by Inoue, 26 and that of the natural rethrolones (3a-c) by Katsuda 27 ((S); Figure 3, 1958)  copper bronze but its yield was very low (8%) due to the poor quality of ( 5) and to the heterogeneity of the medium.They were unable however to synthesize the pyrethrolone (3a) since their structural assignment proved later to be incorrect and therefore they never achieved the synthesis of pyrethrin I (1a). 4,8heme 1.First synthesis of ethyl chrysanthemate by Staudinger in 1924.
Since then chemists in academia, research centers and chemical companies have succeeded to design, synthesize and market unnatural semi-synthetic or synthetic analogues the pyrethroids that possess exceptional properties adapted to contextual enviremental (against flying, crawling and soil insects) and economic needs. 14 more detailed account of the biosynthesis of natural pyrethrins in the plants and of the structure and properties of some of the most important commercially available unnatural analogues the pyrethroides, will be presented in Chapter 1, which follows this Introductory section.

Figure 1 .
Figure 1.Natural pyrethrins: their structures, a their relative amount in Chrysanthemum cinerariaefolium.b Their activity (LD50 refers to the lethal dose (LD50), the dose that causes death in 50% of the treated organisms generally expressed as mg of chemical per kg of body weight.c relative knockdown factor.

2a;Figure 3 .
Figure 3. Names and structures of constituents of pyrethrins and of related compounds.
2,3(such as Chrysanthemum cinerariifolium a plant that originates from Dalmatia, now part of Croatia), occupy a special place.

Table 1 .
Lethal doses of different series of insecticides and related selectivity factors