Agrochemical Discovery - ACS Publications - American Chemical

Chapter 1

Modern Agrochemical Discovery 1

Don R. Baker and Noriharu Ken Umetsu

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Downloaded by UNITED ARAB EMIRATES UNIV on August 27, 2016 | http://pubs.acs.org Publication Date: December 28, 2000 | doi: 10.1021/bk-2001-0774.ch001

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Berkeley Discovery, 15 Muth Drive, Orinda, CA 94563 Otsuka Chemical Company, 3-2-27 Ote-dori, Chuo-ku, Osaka 541-0021, Japan

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The requirements for modern agrochemicals seem almost impossible to satisfy. The public demands materials that are very safe both to humans and the environment. This requires low toxicity to a wide range of non-target species and at the same time short persistence and low residues in crops and water. Farmers want agrochemicals which are active across a wide range of target species and last long enough in the environment to maintain control for that extended period they require. At the same time the compounds have to be safe to workers in the fields and economical to use. It is with this apparent dichotomy, that the 2nd Pan-Pacific Conference on Pesticide Science was held in Honolulu, Hawaii on October 24-27, 1999. (1,2) This conference was a joint effort between the Agrochemicals Division of the American Chemical Society and the Pesticide Science Society of Japan. This present chapter and book provides an examination of this important field of scientific endeavor.

© 2001 American Chemical Society

Baker and Umetsu; Agrochemical Discovery ACS Symposium Series; American Chemical Society: Washington, DC, 2000.

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Introduction The agrochemical community sits at the center of a major world problem: How do we continue to feed the ever-increasing world population? The ultimate fate of civilization rests on how this problem is worked out (3,4) For many parts of the world this problem is already reaching critical proportions with billions suffering. Most of the agrochemical production and research communities are not located in these underfed countries. This major problem confronting the world should give encouragement to proceed with the timeconsuming, costly research needed for new necessary products and methods of agriculture. Means must continue to be found to continue to find ways to provide safe, economical, and effective products to aid the production of both major and minor crops. (5-9) Fortunately, a few organizations continue to see the importance of providing new better and more effective products for the lesser markets for agrochemical agents and means. We must continue to look for new products which possess greater improvement in mammalian toxicity and environmental safety at lower and lower rates in the environment (10) For this the heart of any discovery program begins with reliable and efficient assays that predict the ability of a chemical to protect a field crop. (11)

Insect Control Today we are seeing many kinds of insects that are little affected by a host of insect control agents. Almost every crop known to man has one or more insect predators. Each of these take their toll in the quantity and quality of the food and fiber products which come from our farming efforts. Lepidopterous insects continue to be one of the major predators on our food and fiber crops. Genetically modified crops such as corn and cotton offer new means of controlling Lepidoptera. Here genes of Bacillus thuringensis (Bt) are expressed in the crop plant. The Bt toxin is a small protein which acts as a stomach poison on the insect. As with many past selective insect control agents, resistance is beginning to emerge with Bt This points out the importance of finding new safe, effective insect control methods. Also conservation steps are necessary in order to preserve the effectiveness of compounds or methods where resistance can develop. In those insects where the life cycle is short there seems to be a propensity for the easy development of resistance to insect control agents. Several generations can take place in a single season. This seems to be the case with mosquitoes. Many places in the world have mosquito populations that are resistant to man's most effective control schemes. Many serious public health



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problems, such as malaria, encephalitis, yellow fever, and dengue fever find mosquitoes as disease vectors. Approximately 40% of the world's population lives in areas of malaria risk. Here there are 300 to 500 million cases annually and of these 1.5 to 2.7 million die of malaria each year. Of these deaths, 90% occur in Africa. Each year there are 30 million cases of dengue fever with at least 25,000 deaths. As yet there is no vaccine for dengue fever. Its main vector is Aedes aegypti and its subspecies. Recently a predator, misocyclops, a small shrimplike creature (also called the one-eyed shrimp) was found in Vietnam and where it was propagated this mosquito vector was greatly controlled (12) Unfortunately, the many areas where mosquitoes are disease vectors are also places which can ill afford or in many cases have little means to control those diseases born by mosquitoes. Another public health menace is Chagas Disease, which has a vector in the night biting kissing bug. About 16 to 18 million people are infected each year. Most of the 50,000 deaths each year occur in Mexico, and Central and South America. Some cases are starting to appear as the kissing bug finds its way into the southern United States. Because of world travel we are now seeing the appearance of these diseases in the developed countries of the world (13) This points to the continuing need for efforts to find new methods for controlling insects for both agriculture and public health. Mode of action studies are important in the development of new insect control agents which offer sufficient selectivity in toxicology tests. A section of this current work has chapters which explore this important adjunct to the development of new insect control agents.

Herbicides Only the major crops can afford the luxury of modern agrochemical research. Herbicide research and development into new means of weed control research is limited to corn, soybeans, rice and perhaps wheat. Other crops offer only small markets for new products. The large chemical manufacturers are selling off their minor products which were once used in the smaller agrochemical markets. Because of registration and re-registration costs many of the minor products are no longer available. New weed pressures are developing in many of these areas where older off-patent products are being used Resistance is also becoming a problem with herbicides that have a single site for their mode of action. Resistance has been quick to develop in many important weeds by the Acetolactate synthase (ALS) inhibiting sulfonyl ureas



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and imidazolinones. (14) In all cases studied, the mechanism of resistance has been due to selection of an altered form of the ALS enzyme. These herbicides are exciting because of their wide use at low concentration and their inherent safety. Management of ALS resistance has been through use of other mode of action herbicides in rotation with the ALS controlling compounds. Mode of action studies are important to the development of new herbicides. Much has happened in the last few years in understanding how xenobiotic compounds affect biological systems. (15) Herbicides which affect enzymes peculiar to plants often offer toxicity characteristics favorable to further development. (16) The current search for new control agents usually involves mode of action studies to determine which lead compounds or enzyme systems should be explored more extensively. Plant biotechnology offers important opportunities to improve food production methods. (17) Several major products have been approved for use in several countries. This current work explores this type of effort as one of its major section of chapters.

Fungicides Fungicides fit alongside insecticides and herbicides in the production of agricultural products. Without modern fungicides many of our agricultural products would be much more expensive to grow. Certain growth conditions predispose many crops to fungal attack. In general terms there are two types of fungicides, protectant fungicides and systemic fungicides. The systemic fungicides are ones where the compound moves through the outer tissues of the plant into the phloem or xylem of the plant. Systemic fungicides usually have only one mode of action in the fungi at a site not usually found in plants or animals. Systemic fungicides are usually subject to resistance development due to the fact that fungi can rapidly reproduce and rapidly adapt to the presence of the fungicide. (18) Protectant fungicides usually do not penetrate any great distance into the plant. Here they remain on the outer surface of the plant giving protection from fungal attack Many of the common protectant fungicides such as captan have their mode of action on more than one site in the fungal cell. This multiplicity makes it more difficult for the organism to develop resistance to the fungicide. At the same time, because of the compound's interaction with more than one site, there may be toxicology issues where animal or plant sites are effected


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1. Abstracts, 2 Pan-Pacific Conference on Pesticide Science, Honolulu, Hawaii; October 24-27, 1999; 61 pages. 2. Final Program,2 Pan-Pacific Conference on Pesticide Science, Honolulu, Hawaii; October 24-27, 1999; 8 pages. 3. Klasen, W., in Eighth International Congress of Pesticide Chemistry, Options 2000; Ragsdale, Ν. N.; Kearny, P. C. ; Plimmer, J. R. , Eds; ACS Conference Proceedings Series, Washington, D. C., 1995; pp 1-32. 4. Fedoroff, V., "Food for a Hungry World: We Must Find Ways to Increase Agricultural Productivity", The Chronicle of Higher Education 1997, 43, Number 41, pp B4-B5. 5. Baker, D. R.; Fenyes, J. G.; Basarab; G. S.: Hunt, D.A.,Eds.,Synthesis and Chemistry of Agrochemicals V, ACS Symposium Series #686. American Chemical Society, Washington D. C.: 1998, 340 pp. 6. Baker, D. R.; Fenyes, J. G.; Basarab, G. S. Eds., Synthesis and Chemistry of Agrochemicals IV, ACS Symposium Series #584. American Chemical Society, Washington D. C.: 1995, 490 pp. 7. Baker, D. R.; Fenyes, J. G.; Steffens, J. J., Eds., Synthesis and Chemistry of Agrochemicals III, ACS Symposium Series #504. American Chemical Society, Washington D. C.: 1992, 468 pp. 8. Baker, D. R.; Fenyes, J. G.; Moberg, W. K., Eds., Synthesis and Chemistry of Agrochemicals II, ACS Symposium Series #443. American Chemical Society, Washington D. C.: 1991, 609 pp. 9. Baker, D. R.; Fenyes, J. G.; Moberg, W. K.; Cross, B., Eds., Synthesis and Chemistry of Agrochemicals, ACS Symposium Series #355. American Chemical Society, Washington D. C.: 1987, 474 pp. 10. Umetsu, Ν. K.; Pesticides and Human Health - To Investigate the Safety of Agrochemicals. Japan Plant Protection Association, 1998 (in Japanese). 11. Basarab, G. S.; Baker, D. R.; Fenyes, J. G. Bioassays in the Discovery Process of Agrochemicals. Synthesis and Chemistry of Agrochemicals IV, ACS Symposium Series, #584, American Chemical Society, Washington, D. C. pp. 1-14, (1995). 12. Hewetson, Μ . , "Dengue Fever Management," Radio National - Earthbeat (Australia); February 20, 1999. 13. Pray, W. S.; US Pharmacist, 21 (6): 18, 20-22, 24, 27; 1996 Jacobson Pubublishers. 14. Powles, S. B.; Holtum, J.A.M.; Herbicide Resistance in Plants Biology and Biochemistry; CRC Press, Boca Raton, FL,1994, 368 pp.


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15. Pike, D. R.; Hagar, Α.; MeGlamery, M . ; How Herbicides Work, University of Illinois. Extension, Dept. of Crop Sciences; 1998; Available on the Internet. 16. Schmidt, R. R.: HRAC Classification of Herbicides according to Mode of Action.; Brighton Crop Protection Conference - Weeds; pp 1133-1140, 1997 17. Economics of Innovation and New Technology; Harwood Academic, The Gordon and Breach Pub. Group, ISSN: 1043-8599; 6 issues per volume. 18. McGrath, M . T.; Zitter, T. A "Managing Fungicide Resistance for Powdery Mildew, Gummy Stem Blight, and Downey Mildew;" Capitol Vegetable News; July 1996; Available on the Internet.


Agrochemical Discovery - ACS Publications - American Chemical

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