Insect Control: Biological and Synthetic Agents - Index of

238 6: The Spinosyns: Chemistry, Biochemistry, Mode of Action, and Resistance
49 and 50) (Table 3). The 3 0 -O-vinyl analog (compound
47) could represent a very active configuration,
but stability issues resulted in erratic results
(Crouse et al., 2001). Other modifications to the
alkyl chains (halogenation, introduction of another
oxygen, etc.) were generally not as effective as the
simple alkyl chains (compounds 55 and 57) (Crouse
et al., 2001) (Table 3). While the optimum in 3 0 -Oalkyl
chain length for lepidopterous larvae such as
H. virescens (Crouse et al., 2001), beet armyworm
(Spodoptera exigua) and cabbage looper (Trichoplusia
ni) (data not shown) is between two and
three carbons (e.g., compounds 46, 48, 53 and 54),
the optimum for aphids such as A. gossypii extends
to four carbons (compound 51) (Crouse et al., 2001)
(Table 3). Unlike either aphids or lepidopterans,
the longer chain 3 0 -O-alkyl groups (C2–C4) (compounds
46, 48, and 51, respectively) were essentially
equivalent in activity for T. urticae (Table 3) and
were only modestly more active than spinosyn A.
Interestingly, the 2 0 ,3 0 ,4 0 -tri-O-ethyl analog
(compound 62) is essentially as potent against
H. virescens larvae, A. gossypii, and T. urticae as
the 3 0 -O-ethyl derivative (compound 46) (Table 3),
further supporting the importance of the 3 0 -position
of the rhamnose to insecticidal activity.
In addition to modifications to the tri-O-methylrhamnose
moiety, the effects of rhamnose replacement
with other sugar and nonsugar moieties were
also investigated (Anzeveno and Green, 2002).
These studies demonstrated that very little change
around the rhamnose moiety is tolerated. Replacement
sugars such as d-rhamnose, the b-anomeric
rhamnose, furanose, and forosaminyl analogs (not
shown) were much less active or inactive against
H. virescens larvae and T. urticae (Anzeveno and
Green, 2002). In contrast, removal of the methyl
group at the 6 0 -position (l-lyxose analog, compound
85) had little effect on activity relative to
spinosyn A, while addition of hydroxy to the
6 0 -methyl group (l-mannose, compound 86)
provided a very significant improvement in activity
over spinosyn A (Anzeveno and Green, 2002), nearly
equaling that of the 3 0 -O-ethyl analog (compound
46). Replacement of the tri-O-methylrhamnose
with nonsugar moieties such as simple alkyl groups
or methoxy-substituted benzoyl groups (compounds
not shown) all were found to be inactive (Anzeveno
and Green, 2002).
6.7.4. Quantitative Structure–Activity
Relationships and the Spinosyns
The above examples (see Sections 6.7.1–6.7.3) clearly
demonstrate that very significant improvements in
activity of the spinosyns are possible, both in terms
of potency towards a particular pest or group of
insect pests and greater spectrum. These improvements,
especially those involving rhamnose ring
modifications, were facilitated through the
application of both classical and less conventional
CAMD techniques early in the project. The QSAR
analysis of the spinosyns conducted using artificial
neural networks directly led to the identification and
synthesis of far more potent spinosoids than had
been seen up to that time (Sparks et al., 2000a,
2001; Anzeveno and Green, 2002). The analysis
identified several potential modifications to
improve activity, including the lengthened alkyl
groups on the rhamnose, and also pinpointed the
3 0 -position as the most important for activity (Sparks
et al., 2000a, 2001). While the neural net-based
QSAR was able to identify useful targets for synthesis,
understanding the physicochemical basis
for the improved activity is not a question easily
addressed with neural nets (Sparks et al., 2001).
Thus, more classical approaches have also been
employed. Hansch-style multiple regression analysis
(Kubinyi, 1993) of the spinosyns and spinosoids
was able to establish some relationships between
insecticidal activity against H. virescens larvae and
several physicochemical parameters.
Among the spinosyns, the biological response of
H. virescens larvae was best described by the three
whole-molecule parameters, CLogP, Mopac dipole
(dipole moment of the whole spinosyn molecule),
and HOMO (highest occupied molecular orbital)
(Sparks et al., 2000b):
Log Hv LC50 ¼ 2:18 CLogP þ 0:61 Mopac dipole
þ 2:89 HOMO þ 33:74
r 2 ¼ 0:824; s ¼ 0:372; F ¼