Insect Control: Biological and Synthetic Agents - Index of

62 3: Neonicotinoid Insecticides
several crops. Due to the favorable mammalian safety
characteristics (Matsuda et al., 1998; Yamamoto
et al., 1998; Tomizawa et al., 2000) neonicotinoids
like imidacloprid are also important for the control
of subterranean pests, and for veterinary use
(Mencke and Jeschke, 2002).
3.2. Neonicotinoid History
In the early 1970s, the former Shell Development
Company’s Biological Research Center in Modesto,
California, invented a new class of nitromethylene
heterocyclic compounds capable of acting on the
nAChR. Starting with a random screening to discover
lead structures from university sources, Shell
detected the 2-(dibromo-nitromethyl)-3-methyl pyridine
(SD-031588) (Figure 1) from a pool of chemicals
from Prof. Henry Feuer of Purdue University
(Feuer and Lawrence, 1969), which revealed an unexpected
low-level insecticidal activity against housefly
and pea aphid.
Further structural optimization of this insecticide
lead structure led to the active six-membered
tetrahydro-2-(nitromethylene)-2H-1,3-thiazine, nithiazine
(SD-03565, SKI-71) (Soloway et al., 1978, 1979;
Schroeder and Flattum, 1984; Kollmeyer et al., 1999).
The molecular design by Shell appears rational and
straightforward. The chemistry had been largely concentrated
on the nitromethylene enamine skeleton
(Kagabu, 2003a). Today, this early prototype can be
considered as the first generation of the so-called neonicotinoid
insecticides (Figure 2). Nithiazine showed
higher activity than parathion against housefly adults
(Musca domestica), and 1662 times higher activity
against the target insect, the lepidopteran corn
earworm larvae (Helicoverpa zea), combined with
good systemic behavior in plants and low mammalian
toxicity (Soloway et al., 1978, 1979; Kollmeyer et al.,
1999; Tomizawa and Casida, 2003). However, due to
the photochemically unstable 2-nitromethylene chromophore
(Figure 3) in the field tests, nithiazine was
never commercialized for broad agricultural use
(Soloway et al., 1978, 1979; Kagabu and Medej,
1995; Kagabu, 1997a; Kollmeyer et al., 1999). Alternatively,
photostabilization using the formyl moiety
was not adequate for practical application (Kollmeyer
et al., 1999). Nevertheless, a knock-down fly product
against M. domestica containing nithiazine as
the active ingredient of a housefly trap device for
poultry and animal husbandry has recently been
commercialized (Kollmeyer et al., 1999).
In the early 1980s synthesis work was initiated
at Nihon Tokushu Noyaku Seizo K. K. (presently
Bayer CropScience K. K.) on the basis of this first
remarkable neonicotinoid lead structure and the
unique insecticidal spectrum of activity (Kagabu
et al., 1992; Moriya et al., 1992). Instead of the
lepidopteran larva H. zea, the target insect for
studying structure–activity relationships (SARs) and
optimizing biological activity was the green rice
leafhopper (Nephotettix cincticeps), because it is a
major hemipteran pest of rice in Japan (Kagabu,
1997a). At the beginning of the project, a new
pesticide screening method using rice seedlings was
developed for continuous monitoring of the combined
systemic and contact activities of compounds
over 2 weeks against leafhoppers and planthoppers
(Sone et al., 1995).
The six-membered 2-(nitromethylene)-tetrahydro-
1,3-thiazine ring was replaced with different
N 1 -substituted N-heterocyclic ring systems. Starting
with 1-methyl-2-(nitromethylene)-imidazolidine, it
was found that the activity depends on ring
size (5 > 6 > 7-ring system). The N 1 -benzylated
2-(nitromethylene)-imidazolidine 5-ring was the
most active one. Introduction of substituted benzyl
residues in the 1-position, like the para-chlorobenzyl
moiety, and of nitrogen-containing N-hetarylmethyl
Figure 1 Development of nithiazine (SKI-71) by Shell. (Data from Kollmeyer, W.D., Flattum, R.F., Foster, J.P., Powel, J.E.,
Schroeder, M.E., et al., 1999. Discovery of the nitromethylene heterocycle insecticides. In: Yamamoto, I., Casida, J.E. (Eds.),
Neonicotinoid Insecticides and the Nicotinic Acetylcholine Receptor. Springer, New York, pp. 71–89 and Kagabu, S., 2003a.
Molecular design of neonicotinoids: past, present and future. In: Voss, G., Ramos, G. (Eds.), Chemistry of Crop Protection: Progress
and Prospects in Science and Regulation. Wiley–VCH, New York, pp. 193–212.)