Bioorganic & Medicinal Chemistry Letters
Design, synthesis and structure–activity relationship of indoxacarb
analogs as voltage-gated sodium channel blocker
a,
Wenbo Hao a,b,y, Chunling Fu a,y, Huijuan Yu b, Jian Chen b, Hanhong Xu a, Guang Shao b, , Dingxin Jiang
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a State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Key Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education,
Laboratory of Insect Toxicology, South China Agricultural University, Guangzhou 510642, People’s Republic of China
b School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Indoxacarb, the first commercialized pyrazoline-type sodium-channel blocker, is a commonly used insec-
ticide because of high selectivity. To discover sodium-channel blocker with high insecticidal activity, a
series of novel indoxacarb analogs were designed and synthesized by judicious structural modifications
of the substituent group of C5, C6 in indenone and C04 in benzene ring. Some analogs exhibited significant
insecticidal activities against Spodoptera litura F. and excellent BgNav1-1a channel inhibitory activity. The
structure–activity analysis indicated that the presence of strong electron-withdrawing group and
decreased steric hindrance of indenone ring (R1, R2) in 5- and 6-position could enhance larvicidal activity
and BgNav1-1a channel inhibitory activity.
Received 6 May 2015
Revised 7 August 2015
Accepted 21 August 2015
Available online xxxx
Keywords:
Indoxacarb analogs
Synthesis
Sodium channel blocker
Structure–activity relationships
Ó 2015 Published by Elsevier Ltd.
Highly efficacious insecticides with novel modes of action
which act on unique biochemical target sites are becoming increas-
ingly important in agriculture.1 There is great demand for safer and
more selective insecticides that spare natural enemies and non-
target organisms. The modes of action of the major insecticide
classes and biochemical sites related to insecticide action have
been reviewed.2 Sodium channel is an important target for a vari-
ety of neurotoxic insecticides, including pyrethroids, DDT, isobuty-
lamides, and dihydropyrazoles.3 Indoxacarb, a sodium channel
blocker insecticide (SCBI), was introduced by the E.I. DuPont Com-
pany as a pro-insecticide because of its outstanding field insectici-
dal activity, environmental compatibility, and safety to non-target
organisms.4 It was found to be hydrolyzed by an esterase or ami-
dase into a much more potent N-decarbomethoxyllated (DCJW)
metabolite5 (Fig. 1) that paralyzes insects by blocking action
potential initiation in nerve cells. However, higher animals primar-
ily degrade indoxacarb to inactive metabolites via alternative
route. Therefore, indoxacarb has a selective toxicity toward insect.6
In order to clarify the insecticidal molecular mechanisms and
selective toxicity of indoxacarb, a dock of DCJW in open bacterial
sodium channel NavAb has been built based on the X-ray structure
of the closed bacterial sodium channel NavAb (PDB code 3RVY) and
the open potassium channel Kv1.2 (PDB code 2A79).7 Substituent
R1 or R2 of C5- or C6-position of the indenone ring, 5- or 6-Cl, Br,
OCH2CF3, and CF3 groups render compounds the highest activity.8
However, R1 or R2 substituents such as methyl, methoxy or
large steric hindrance and strong electron-donating groups, are
unfavorable for the sodium channel blocker insecticides (SCBIs)
(data not shown). Probably compound cannot pass through the
open bacterial sodium channel NavAb smoothly to reach the
target site on the receptor protein because of high electronic
density and large steric hindrance of the indenone ring. Therefore,
a series of novel indoxacarb analogs were designed by modifying
the substituent group of C5 and C6 in indenone, C04 in benzene ring
(Scheme 1) to reduce the steric hindrance and electronic density of
the benzo ring. The goal is to develop new pyrazoline type sodium
channel blocker insecticides that are active against indoxacarb
resistant strains, and safe to non-target organisms.
It is worth noting that Claisen condensation (step i) and cycliza-
tion reaction (step ii) are crucial procedures in the total synthetic
routes of the title compounds 7a–n, which is outlined in Scheme 1.
The intermediates 2a–g were synthesized in high yields by stirring
indenone analogs 1a–g with NaH and potassium tert-butylate in
dry dimethyl carbonate (DMC) for 1 h.9 Potassium tert-butylate
played an important role for boosting the reaction. The crude prod-
ucts (2a–g) need to be added in the next step reaction immediately
after preparation because they are oxidized easily when exposed to
air. The intermediates (4a–g) are instable in column chromatogra-
phy with silica gel. After many attempts, we successfully synthe-
sized the target compounds (7a–n) by utilizing phosphorus
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Corresponding authors.
y
The authors contributed equally to the work.
0960-894X/Ó 2015 Published by Elsevier Ltd.