Insect Control: Biological and Synthetic Agents - Index of

modification, resulting in a slight decrease (spinosyns
A to B, spinosyns H to R, spinosyn L to N) or a
modest increase in activity (spinosyn J to M). An
increase in alkyl size for one of the positions on the
forosamine nitrogen (i.e., ethyl and n-propyl; compounds
64 and 65) has little effect on H. virescens
activity, while further increases in bulk greatly
reduce activity (compounds 66 and 67). In contrast,
T. urticae activity is only increased by these
same modifications as is, to a lesser degree, activity
against A. gossypii (Table 3). Replacement of the
forosamine N,N-dimethylamine moiety with a
hydroxyl (compound 68), reduces activity against
H. virescens larvae while, apparently (response can
be variable), increasing aphid activity (Table 3).
Loss of the entire forosamine moiety results
in major loss of activity (Sparks et al., 1999)
(Table 2) with only a small improvement noted by
replacement with an acetate (C17-acetate, compound
79) group. Substitution of the forosamine
with N,N-dimethylaminoacyl esters (compounds
80–82) only partially restores activity (Kirst et al.,
2002b) (Table 3). N-methylamino piperazinylacetate
(compound 83) or N,N-dimethylaminopiperidinylacetate
esters (compound 84) at C17 go
further towards restoring activity against H. virescens
and Stomoxys calcitrans, but still fall far short
of the activity observed with forosamine (spinosyn,
compound 1) (Kirst et al., 2002b) (Table 3). A similar
trend is observed with S. calcitrans (stable fly). Thus,
for the lepidopterans, the above modifications to
the forosamine do not lead to improvements in activity.
In contrast, both aphid and mite activity were
improved by replacement of the forosamine N-methyl
groups with larger alkyl groups (compounds 64–67).
6.7.3. Modification or Replacement of the
Tri-O-Methyl-Rhamnose Sugar
6: The Spinosyns: Chemistry, Biochemistry, Mode of Action, and Resistance 237
While many of the early synthetic modifications
to the spinosyn structure were insecticidal, all of
the early spinosoids were typified by a somewhat
reduced or most often an almost total lack of
H. virescens activity compared to spinosyn A. However,
an exception was found in the form of the desmethoxy
(2 0 -H or 3 0 -H) analogs of spinosyns H/Q
and J, respectively (compounds 35, 36 and 43)
(Table 3). These ‘‘desmethoxy’’ analogs were found
to be as active against H. virescens larvae or slightly
more so, than spinosyn A (Creemer et al., 2000; Kirst
et al., 2002b) (Table 2). These modifications constituted
the first clear indication that spinosoids at
least matching the activity of the most active of the
natural spinosyns (i.e., spinosyn A) were possible.
Concurrent with the synthetic efforts, several
computer-aided modeling and design (CAMD)
approaches were examined in an attempt to identify
potential synthetic directions for improved analogs.
Included among the computer modeling approaches
initially used were comparative molecular field
analysis (CoMFA) and Hansch-style quantitative
structure–activity relationships (QSAR) (Crouse
and Sparks, 1998). However, the large molecular
size and complex structure rendered the available
computing power insufficient to the task for these
more conventional methodologies and generally
made QSAR difficult. However, where conventional
CAMD techniques were not successful, the application
of artificial neural networks to spinosyn QSAR
(Sparks et al., 2000a) identified new directions that
led to, as one example, new modified-rhamnose
spinosoids. These latter compounds were in many
cases far more active than spinosyn A against pest
lepidopterans (Crouse and Sparks, 1998; Sparks
et al., 2000a, 2001; Anzeveno and Green, 2002).
As shown by the activity of the 2 0 ,3 0 ,4 0 -demethyl
analogs from the mutant strains, O-demethylation
generally leads to less active compounds compared
to spinosyn A (Table 2). Loss of the rhamnose also
leads to a large reduction in activity (Table 2). The
first spinosoids possessing any kind of improvement
in lepidopteran activity over spinosyn A were (as
noted above) the des-methoxy (2 0 -H (compounds
35 and 36), or 3 0 -H (compound 43) analogs of spinosyns
H/Q and J, respectively (Table 3). For the 2 0 -
substituted spinosoids, the 2 0 -des-methoxy analog
(compound 35) along with the 2 0 -O-ethyl (compound
37) and 2 0 -O-n-propyl (compound 39) represent
the most active of the 2 0 -substitution-based
analogs, which are as active or very slightly more so
than spinosyn A. Likewise, modifications of the
4 0 -position of the rhamnose (e.g., compound 60) results
in no real activity improvement over spinosyn A,
with the exception of the 4 0 -des-methyoxy analog
(compound 59), which generally remains equivalent
or nearly so, to spinosyn K (4 0 -O-demethyl, compound
23) (Table 3). Thus, in general, modifications
to the 2 0 -or4 0 -positions do little to improve activity
compared to spinosyn A.
Unlike the 2 0 -and4 0 -positions (e.g., compounds 37
and 60), a genuine improvement in H. virescens activity
was found to be associated with an increased
size of the alkoxy groups on the rhamnose at the 3 0 -
position (compounds 46–52) (Sparks et al., 2000a).
At the 3 0 -position, the activity optimum is between
two to three carbons. Further increases in bulk or
length resulted in a loss of activity (Sparks et al.,
2000a, 2001; Crouse et al., 2001). The introduction
of unsaturation into these short alkyl chains (e.g.,
compounds 47, 53, 54) was generally neutral in
effect, while branching was detrimental (compounds