Insect Control: Biological and Synthetic Agents - Index of

36 2: Indoxacarb and the Sodium Channel Blocker Insecticides
creates the possibility of useful invertebrate control
agents as well as the development of additional tools
for understanding ion channel function.
The identification of the Na þ channel blocker
insecticides (SCBIs) represents such a discovery.
These compounds all act at a unique site in insect
voltage-gated Na þ channels, which may correspond
to the local anesthetic/anticonvulsant site. Our
knowledge of the mode of action of indoxacarb
derives largely from studies on the pyrazoline (also
known as dihydropyrazole) forerunners of this family,
carried out in the 1980s at the Rohm and Haas
Company (Salgado, 1990, 1992). Pyrazolines were
found to paralyze insects by blocking action potential
initiation in nerve cells. The mechanism of this
block was due to a voltage-dependent blocking
action on voltage-gated Na þ channels. This mechanism
is also observed with many therapeutically
useful local anesthetic, antiarrhythmic, and anticonvulsant
drugs. The bioactivated form of
indoxacarb, N-decarbomethoxylated DPX-MP062
(DCMP), also works in this manner. Indoxacarb’s
selective toxicity towards pest insects is due to its
rapid bioactivation to the active metabolite DCMP,
while higher animals primarily degrade indoxacarb
to inactive metabolites via alternate routes.
This article will trace the chemical evolution of
these compounds and their physiological activity in
invertebrates, which eventually led to the commercial
introduction of a member of this class, indoxacarb
(Harder et al., 1996; Wing et al., 2000). The unique
metabolic, insecticidal, and pest management control
properties of indoxacarb will also be discussed.
2.2. Chemistry of the Na +
Channel Blockers
2.2.1. Chemical Evolution and Structure–Activity
of the Na + Channel Blocker Insecticides
The first insecticidal pyrazoline Na þ channel blockers
were reported in patents from Philips-Duphar in
Figure 1 Structures of original pyrazoline Na þ channel blockers.
1973 and are represented by PH 60–41 (Mulder and
Wellinga, 1973) (Figure 1). These compounds were
reported to have high levels of efficacy against
coleopteran and lepidopteran pests. In 1985, Rohm
and Haas reported pyrazolines such as RH-3421
with ester substituents on the pyrazoline 4-position
( Jacobson, 1985). These compounds were later
reported to have high insecticidal efficacy, low
mammalian toxicity, and a rapid rate of dissipation
in the environment (Jacobson, 1989). Subsequent
work by DuPont on the SCBIs resulted in the discovery
of several classes of related structures, all
with similarly high levels of insecticidal activity
(Figure 2). It was found that transposition of the
N1 and C3 atoms in the pyrazoline core gave active
compounds (compound B). Conformationally constrained
pyrazolines, resulting from bridging the
pyrazoline C4 postion with the C3 aryl substituent
(forming indazoles and oxaindazoles) (compound
CinFigure 2), were also highly active. Semicarbazones
D are also insecticidal; these compounds are
structurally similar to pyrazolines, but with the C5
carbon removed. Expanding the pyrazoline ring by
one carbon gave highly active pyridazine compounds
(compound E). Substituting oxygen or nitrogen for
the C5 pyridazine atom gives oxadiazines and
triazines, also with high insecticidal activity (compound
F). Indoxacarb is, in fact, a representative of
the oxadiazine subclass of SCBIs.
The insecticidal structure–activity relationships for
the oxadiazines are summarized in Figure 3. For substituent
R1, 4- or 5-Cl, Br, OCH2CF3,andCF3 groups
gave compounds with the highest activity. In the R2
position, 4-halo-phenyl and CO2Me were the most
active substituents. For groups at R3, 4-OCF3, 4-CF3,
and 4-Br were best for activity. For the substituents on
nitrogen (R4), CO 2CH 3 and COCH 3 were the most
active, followed by H, Me, and Et.
2.2.2. Chemistry and Properties of Indoxacarb
Indoxacarb is synthesized as described in McCann
et al. (2001, 2002) and Shapiro et al. (2002). Its