Insect Control: Biological and Synthetic Agents - Index of

sampling using forcefield methods (MMFF94s).
The calculated free energies indicate that at room
temperature (RT), the preferred orientation of
the N-nitroimino group is in the trans position;
the Z-isomer with lowest energy is more than
2.6 kcal mol 1 above the optimal E-isomer. NMR
experiments are in agreement that the N-nitroimino
group strongly prefers one orientation only. From
calculations as well as the X-ray structure, one can
see that the three C w N bonds involving atom C5
have some double bond character. It is worth mentioning
that the C5 w N3 bond, which is the only
formal C›N double bond within the N-nitroimino
moiety, is slightly longer than the formal single
bonds C5 w N5 and C5 w N2. This is reflected by the
torsional angles found around the C w N bonds during
conformational analysis; the respective values
are all 180 or 180 . The N-methyl group can
flip easily from the anti position into a syn position.
The energies of the respective clothianidin (TI-435)
conformers, relative to the optimal structure, are
below 1.5 kcal mol 1 . All these findings are in line
with the experimental 13 C NMR spectrum, which
shows a relatively broad singlet at 138.8 ppm for
Figure 8 Digital stereo photomicrograph of a single crystal
of clothianidin (TI-435) grown from methanol/water at room
temperature (Jeschke et al., 2003).
3: Neonicotinoid Insecticides 71
the atom C3. This can already be understood qualitatively
from the conformational arguments, like
rotations of the C w N single bonds and modifications
of the positioning of the CTM moiety (Jeschke
et al., 2003).
3.3.2.4. ( )-N-methyl-N 0 -nitro-N 00 -[(tetrahydro-3furanyl)methyl]guanidine
(dinotefuran, MTI-
446) ( )-Dinotefuran (MTI-446) was discovered
by Mitsui Chemicals Inc., and is highly effective
as an agonist of nAChRs (Zhang et al., 2000). It
has a broad spectrum of activity against insect pests
and has low mammalian toxicity (Kodaka et al.,
1998, 1999a, 1999b; Hirase, 2003). The trade
names for the commercialized product are Starkle Õ
and Albarin Õ . Similar to imidacloprid and clothianidin,
it has a N-nitroguanidine pharmacophore
[ w N w C(N)›N w NO2], but an alicyclic ( )-tetrahydro-
3-furylmethyl (TFM) moiety instead of the halogenated
heteroaromatic CPM or CTM moiety
in the other neonicotinoids. The discovery of
( )-dinotefuran resulted from the idea of incorporating
an N-nitroimino fragment into the structure
of acetylcholine (Kodaka et al., 1998; Wakita et al.,
2003). ( )-Dinotefuran bears a nonaromatic oxygen
atom in the position corresponding to that of
the aromatic nitrogen atom of the other neonicotinoids.
The potencies of ( )-dinotefuran and a competitive
nAChR antagonist (a-bungarotoxin, BGT)
in inhibiting [ 3 H]epibatidine binding to Periplaneta
americana nerve cord membranes were examined
(Mori et al., 2001). ( ) and (þ) Dinotefuran inhibited
[ 3 H]epibatidine binding with IC50 (inhibitory
concentration, where 50% of the tritiated ligand
is displaced in membrane preparations from cockroach
nerve) values of 890 and 856 nM, respectively.
The ( )-enantiomer was about twofold less
effective. In contrast the (þ)-enantiomer was
approximately 50-fold more insecticidal than the
( )-enantiomer of dinotefuran (Table 2).
The SAR between the tetrahydrofuran ring
moiety and the insecticidal activity was investigated
Table 2 Potency of dinotefuran and its isomers in inhibiting [ 3 H]EPI and [ 3 H]a-BGT binding, and their in vivo activities
[ 3 H]EPI binding, IC50 [ 3 H]a-BGT binding, IC50 Knockdown, KD50 Insecticidal activity, LD50
Compound (nM) a
(nM) a
(nmol g 1 ) (nmol g 1 ) a
( )-Dinotefuran 890 (626–1264) 36.1 (24.9–52.2) 0.351 0.173 (0.104–0.287)
(þ)-Dinotefuran 856 (590–1241) 9.58 (6.79–13.52) 0.123 0.0545 (0.0396–0.0792)
( )-Dinotefuran 1890 (1230–2890) 69.8 (47.1–103.4) 6.70 2.67 (1.55–4.69)
a 95% confidence limits in parentheses.
BGT, bungarotoxin; EPI, epibatidine.
Reproduced with permission from Mori, K., Okumoto, T., Kawahara, N., Ozoe, Y., 2001. Interaction of dinotefuran and its analogues
with nicotinic acetylcholine receptors of cockroach nerve cords. Pest Mgt Sci. 58, 190–196.