Discovery of the aryl heterocyclic amine insecticides: synthesis, insecticidal activity, field results, mode of action and bioavailability of a leading field candidate.
BACKGROUND
γ-Amino butyric acid (GABA) antagonists are proven targets for control of lepidopteran and other pests. New heterocyclic compounds with high insecticidal activity were discovered using a competitive-intelligence-inspired scaffold-hopping approach to generate analogs of fipronil, a known GABA antagonist. These novel aryl heterocyclic amines (AHAs) displayed broad-spectrum activity on a number of chewing insect pests.


RESULTS
Through >370 modifications of the core AHA structure, a 7-pyrazolopyridine lead molecule was found to exhibit much improved activity on a number of insect pests. In field trial studies, its performance was 2-4 times lower than commercial standards and also appeared to be species dependent, with good activity seen for larvae of Spodoptera exigua, but inactivity on larvae of Trichoplusia ni.


CONCLUSIONS
An extensive investigational biology effort demonstrated that these AHA analogs appear to have multiple modes of action, including GABA receptor antagonism and mitopotential or uncoupler activity. The limited capability in larvae of T. ni to convert the lead molecule to its associated open form correlates with the low toxicity of the lead molecule in this species. This work has provided information that could aid investigations of novel GABA antagonists. © 2016 Society of Chemical Industry.
Dow AgroSciences, Indianapolis, IN, USA.
William H
WH
Dent
Dow AgroSciences, Indianapolis, IN, USA.
Mark A
MA
Pobanz
Dow AgroSciences, Indianapolis, IN, USA.
Chaoxian
C
Geng
Dow AgroSciences, Indianapolis, IN, USA.
Thomas C
TC
Sparks
Dow AgroSciences, Indianapolis, IN, USA.
Gerald B
GB
Watson
Dow AgroSciences, Indianapolis, IN, USA.
Theodore J
TJ
Letherer
Dow AgroSciences, Indianapolis, IN, USA.
Kenneth W
KW
Beavers
Dow AgroSciences, Indianapolis, IN, USA.
Cathy D
CD
Young
Dow AgroSciences, Indianapolis, IN, USA.
Yelena A
YA
Adelfinskaya
Dow AgroSciences, Indianapolis, IN, USA.
Ronald R
RR
Ross
Dow AgroSciences, Indianapolis, IN, USA.
Greg
G
Whiteker
Dow AgroSciences, Indianapolis, IN, USA.
James
J
Renga
D000588:Amines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D055808:Drug Discovery; D007306:Insecticides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D007814:Larva / Q000187:drug effects; D009036:Moths / Q000187:drug effects* / Q000254:growth & development; D018411:Spodoptera / Q000187:drug effects / Q000254:growth & development
D000588:Amines; D007306:Insecticides
GABA antagonism; insecticidal activity; investigational biology; pyrazolopyridine; pyrazolopyrimidine