Insect Control: Biological and Synthetic Agents - Index of

Figure 9 Stable conformations and predicted properties of
binding site: imidacloprid (white), nitenpyram (blue), acetamiprid
(red). (Adapted from Akazawa et al., 2000.)
Figure 10 Alignment of DFT/BP/SVP/COSMO optimized geometries
of imidacloprid, clothianidin, dinotefuran, and acetamiprid.
The alignment was done by minimization of the mutual
spatial distance of three pharmacophoric points, namely (i) the
positively charged carbon atom connected to the ›N w NO2 and
›N w CN moiety, respectively, (ii) the nitro/cyano groups themselves,
and (iii) the nitrogens of the aromatic rings and the
oxygen of the tetrahydrofuran ring.
Figure 10 shows atom-based aligments of imidacloprid,
clothianidin, dinotefuran and acetamiprid.
The aligment shown does not necessarily reflect the
active conformation. However, the following arguments
hold true for each of these family of conformers.
The ion pairs of the aromatic nitrogen atoms
in imidacloprid, clothianidin, and acetamiprid point
in the same direction, and that this is also true for one
of the two ion pairs of oxygen in dinotefuran. The
tetrahydrofuryl ring of dinotefuran is more or less
perpendicular to the heteroaromatic ring systems of
the other neonicotinoids.
3: Neonicotinoid Insecticides 73
Visual inspection of the nucleophilic Fukui
functions (Figure 11) shows that the tetrahydrofuryl
ring of dinotefuran differs dramatically from the
other neonicotinoids under investigation. While
the latter all show some large contributions at the
aromatic moiety, the tetrahydrofuryl moiety seems
to be much less attractive for nucleophilic attack.
3.3.3.2. Isosteric alternatives to the heterocyclic
N-substituents The nitrogen-containing hetarylmethyl
group as N-substituent (CPM, CTM) has
a remarkably strong influence on the insecticidal
activity. X-ray crystal structure analysis of imidacloprid
and related neonicotinoids indicated that distances
between the van der Waals surface of the
CPM nitrogen and the atomic center of the pharmacophoric
nitrogen are 5.45–6.06 A ˚ (Tomizawa et al.,
2000). This range coincides with the distance between
the ammonium nitrogen and carbonyl oxygen
of acetylcholine, and between the nitrogen atoms
of (S)-nicotine (Kagabu, 1997a). Alternatively, the
CPM and CTM moieties were assumed to be able
to participate in hydrogen bonding, like the pyridine
ring of (S)-nicotine, and that this is important
for the insecticidal activity. The CTM substituent
generally confers higher potency in the clothianidin
and N-desmethyl-thiamethoxam series than the CPM
moiety in the imidacloprid, thiacloprid, acetamiprid,
and nitenpyram series (Zhang et al., 2000). Surprisingly,
replacing both CPM and CTM by an oxygencontaining
five-membered heterocycle resulted in a
novel N-substituent TFM, that led to the development
of the insecticide ( )-dinotefuran. It was found
that the TFM structure can be taken as an isoster of
the CPM and CTM moiety (Kagabu et al., 2002). In
an attempt to understand this, the hydrogen bonding
regions of CPM, CTM, and TFM were projected
onto their respective Connolly surfaces (Jeschke et al.,
2002) (Figure 12).
3.3.3.3. Bioisosteric pharmacophors The particularly
high potency of the neonicotinoids bearing
N-nitroimino, N-cyanoimino, or nitromethylene
moieties, which have a negative electrostatic potential,
implies a positive electrostatic potential for
the corresponding insect nAChR recognition site
(Nakayama and Sukekawa, 1998). Therefore, considerable
attention has been given to the possible
involvement of the pharmacophoric nitrogen in neonicotinoid
action. In order to understand better the
structural requirements, binding activity was analyzed
using CoMFA (Akamatsu et al., 1997). SAR
analyses have also been performed for in vitro activities
(Nishimura et al., 1994). In particular, 3D QSAR