Insect Control: Biological and Synthetic Agents - Index of

166 4: Insect Growth- and Development-Disrupting Insecticides
management programs based on their new and selective
mode of action in contrast to broad-spectrum
neurotoxins.
At present, it is believed that chitin synthesis has
by no means been fully exploited as an attractive
target and that opportunities exist to further discover
new CSIs. A better understanding of the biosynthetic
pathway for chitin synthesis and cuticle
deposition, as well as precise mode of action of
CSIs would allow for development of better and
more efficient high throughput assays for discovery
of new and novel CSIs.
4.5. Conclusions and Future Prospects
of Insect Growth- and Development-
Disrupting Insecticides
The three classes of insecticides reviewed in this
chapter are much slower acting than those acting
on neural target sites. The end user has, of course,
been used to seeing insects die within a very short
time following application of neuroactive insecticides.
The discovery and availability of insecticides
that inhibit growth and development of insects
brought a paradigm shift from the faster acting neurotoxic
insecticides. This change has necessitated
educating the distributors and the users on the
mode of action of these new insecticides. The bisacylhydrazine
insecticides are generally faster acting
than the JHA and CSI insecticides. Moreover, an
attractive feature of the bisacylhydrazine insecticides
is their ability to prevent crop damage by inhibition
of feeding within 3–12 h after application.
Of the three classes of insecticides that disrupt
growth and development in insects, the mode of
action of nonsteroidal ecdysone agonist bisacylhydrazine
insecticides is the best understood at the
molecular level. This detailed understanding has
been possible, both with the cloning and expression
of cDNAs encoding EcR and USPs from several
insects, and the availability of stable and easy to
synthesize bisacylhydrazines. Unlike the JHAs and
CSI, the molecular targets for bisacylhydrazine
insecticides are not only known but the interaction
of some of these insecticides with specific amino
acid residues in the ligand binding pocket of the
target ecdysone receptor are also known. Moreover,
reasons for the selective insect toxicity of bisacylhydrazine
insecticides are also well understood. Publication
of the crystal structure of unliganded and
liganded (with ecdysteroid and bisacylhydrazine)
HvEcR/HvUSP, and the discovery of new nonsteroidal
ecdysone agonist chemistries like tetrahydroquinolines,
provides new tools, and suggests
possibilities of discovering new ecdysone agonist
insecticides. It should now be possible to use combinatorial
chemistry approaches, around leads generated
either via in silico screening or rational design
(based on the three-dimensional structures and
interactions of ligand in ligand binding pocket of
EcR), to discover new and novel chemistries that
target EcRs from specific insect orders. The discovery
of additional new, novel, selective, and potent
nonsteroidal ecdysone agonists will create opportunities
to extend their applications in individually or
simultaneously regulating different ecdysone receptor
gene switches in plants and animals. Further,
the discovery of non steroidal ecdysone agonist
bisacylhydrazine insecticides has opened tremendous
opportunities to explore both basic and
applied biology.
The molecular basis of action of JHA and CSI
insecticides is not well understood, although both
classes of chemistries were discovered long before
the bisacylhydrazine insecticides. The discovery
of the JH receptor(s) has been elusive. To complicate
matters further, it is not clear if the JHAs use the
same molecular target/site as the natural JHs do
(Dhadialla et al., 1998). Dhadialla et al. (1998)
alluded to the possibility that the JH receptor
may be a complex of two or more proteins, and
that JH and JHAs could manifest their action
by interacting either with different proteins in the
complex or by interacting at different, but effective,
sites. Consequently, the research to discover new
JH agonist or antagonist chemistries has been
slow. An antagonist of JH (different from a precocene
type of mode of action) that acts either by
inhibiting one of the JH biosynthesis steps or antagonizes
the action of JH at the receptor level would
be useful. With that, it may be possible to have
agonists/antagonists of JH with insect selective
toxicity, as has been possible for the ecdysone
agonists.
Even though the precise mode of action of CSI
insecticides is unknown, many analogs and variants
of the original diflubenzuron, Dimilin Õ , have been
synthesized and registered as insecticides. A better
understanding of the biosynthetic pathway for chitin
synthesis and cuticle deposition, and molecular
characterization of the various enzymes involved, as
well as the precise mode of action of CSIs, would
allow for development of better and more efficient
high-throughput assays for discovery of new and
novel CSIs.
Finally, in spite of their slower speed of kill of
insect pests than the faster acting neurotoxic insecticides,
the three classes of insect growth and
development disrupting insecticides are well suited
for use in insect pest control. They are also suited for