Chapter 38
1,2-Diacyl-1-alkylhydrazines A New Class of Insect Growth Regulators
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Adam Chi-Tung Hsu Rohm and Haas Company, 727 Norristown Road, Spring House, PA 19477
For the last two decades, in order to develop insecticides with selective toxicity, efforts to identify mimics (agonists) of 20-hydroxyecdysone, the insect molting hormone, have always led to the use of ecdysteroids or closely related steroidal analogs which are not commercially cost-effective. Recently, a new class of insect growth regulators, the 1,2-diacyl-1-alkylhydrazines, has been discovered and shown to be the first nonsteroidal agonists of 20-hydroxyecdysone. R Ο j A - C - N H — N - C —Β
ο R = bulky alkyl or substituted alkyl A and Β = aryl, alkyl, etc. The discovery, synthesis, biological activity, and the mode of action of this new class of compounds are presented. Insect pests, bacteria, fungi, viruses, and weeds have long been troublesome to man. To develop effective methods for controlling them is always a challenging task for us. In the last 10 years, the need for new insecticides with selective toxicity has become recognized because of the increasing problems of insect resistance, toxicity of conventional insecticides, and environmental hazards.
0097-6156/91/0443-0478$06.00/0 © 1991 American Chemical Society
Baker et al.; Synthesis and Chemistry of Agrochemicals II ACS Symposium Series; American Chemical Society: Washington, DC, 1991.
Downloaded by CALIFORNIA INST OF TECHNOLOGY on December 10, 2017 | http://pubs.acs.org Publication Date: December 7, 1991 | doi: 10.1021/bk-1991-0443.ch038
38. HSU
479
l 2-DiacyUl-alkylhydrazines y
Conventional insecticides, such as organochlorines, organophosphates, carbamates, and synthetic pyrethroids, have played dominant roles in crop protection and in controlling diseases transmitted by harmful insects. Today, they are still our major tools for the control of insect problems affecting agriculture and public health. However, there are two major difficulties in using these insecticides. They are not selective; they are toxic not only to the pests, but in most cases also to beneficial insects, wildlife, or man, because these insecticides act similarly toward target and nontarget organisms. The second difficulty is that insects are rapidly developing resistance to conventional insecticides including the recently developed synthetic pyrethroids. To combat these problems, scientists have sought to develop a new class of insecticides, the insect growth regulators, that works via a more insect specific mode of action. The benzoylphenylureas, for instance, selectively inhibit cuticle biosynthesis in target insects and cause the death at the time of the next molt (1). Perhaps the most intriguing insect growth regulators, however, are those which cause insect death by interfering with unique hormonally controlled processes. Two hormones known to regulate insect metamorphosis and development are the juvenile hormones and 20-hydroxyecdysone. Juvenile hormone inhibits progress toward the adult form and 20hydroxyecdysone is the driving force for molting. For 20 years juvenile hormone agonists have been the subject of intensive chemical research providing several new insecticides, including methoprene and kinoprene (2).
Juvenile Hormone : J H I
20-Hydroxyecdysone
In contrast, no insecticide has been developed to interfere specifically with the process associated with the steroidal insect molting hormone, 20-hydroxyecdysone. Although active ecdysteroids can be obtained from plant and animal sources (a), the main reason for the failure to develop them as insecticides has been that (a) their structures are too complex to produce economically, (b) their hydrophilic nature prohibits their penetration into insect cuticle, and (c) insects have powerful mechanisms to eliminate ecdysones between molts. One approach to solve these problems is to synthesize a simple molecule which can mimic ecdysone, but with appropriate chemical and transport properties, and acceptable metabolic stability.
Baker et al.; Synthesis and Chemistry of Agrochemicals II ACS Symposium Series; American Chemical Society: Washington, DC, 1991.
480
SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π
A new class of insect growth regulators, the 1,2-diacyl-l-alkylhydrazines, has been discovered and shown to be the first nonsteroidal mimics of 20-hydroxyecdysone. They may represent a major new method of controlling insect pests.
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Discovery Synthesis It is a fact that "serendipity" still dominates the discovery of an entirely new class of pesticides, especially one with novel mode of action. The reason is simply because our ability to design compounds to affect enzymes, receptors, or other biochemical targets is still very limited. Modern molecular modeling techniques and the computer-aided study of quantitative structure activity relationship are mainly for the optimization of an original lead (4). The discovery of 1,2-diacyl-l-alkylhydrazines can be traced back to an initial effort aimed at the synthesis of 1-alkyl benzhydrazidoyl chlorides, l c (Table I). Table I: Biological Activity of Hydrazidoyl Chlorides CI A-C=N-NH-R 1
la lb lc
1 A Phenyl Alkyl Phenyl
R Phenyl Phenyl Alkyl
Biological Activity Insecticide, Anthelmintic Insecticide, Herbicide Unknown
1-Phenyl hydrazidoyl chlorides, l a and l b , had been studied extensively by Upjohn Company as insecticides (£) and herbicides (£), but, at the time nothing had been reported about the biological activity of lc. The original plan was to synthesize 2 i n two steps from t-butylhydrazine and 4-chlorobenzoyl chloride as follow: Ο Cl-^^-C-Cl
