Bioorganic & Medicinal Chemistry Letters
Synthesis and fungicidal activities of novel
benzothiophene-substituted oxime ether strobilurins
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Song Tu , Ya-Qiang Xie, Si-Zhe Gui, Li-Yi Ye, Zi-Long Huang, Yi-Bing Huang, Li-Ming Che
Department of Chemical and Biochemical Engineering, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, 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:
Twenty-one novel benzothiophene-substituted oxime ether strobilurins, which employed a benzothio-
phene group to stabilise the E-styryl group in Enoxastrobin (an unsaturated oxime strobilurin fungicide
developed by Shenyang Research Institute of Chemical Industry, China) were designed and synthesised.
The biological assay indicated that most compounds exhibited good or excellent fungicidal activities,
especially against Colletotrichum lagenarium and Puccinia sorghi Schw. In addition, methyl 3-methoxy-
propenoate oxime ethers and N-methoxy-carbamic acid methyl esters exhibited good in vivo fungicidal
activities against Erysiphe graminis, Colletotrichum lagenarium and Puccinia sorghi Schw. under the tested
concentrations. Notably, (E,E)-methyl 3-methoxy-2-(2-((((6-chloro-1-(1H-benzo[b]thien-2-yl)ethyli-
dene)amino)oxy)methyl)phenyl)propenoate (5E) exhibited more potent in vivo fungicidal activities
against nearly all of the tested fungi at a concentration of 0.39 mg/L compared to Enoxastrobin.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 28 January 2014
Revised 6 March 2014
Accepted 8 March 2014
Available online 26 March 2014
Keywords:
Benzothiophene
Oxime ether
Strobilurins
Fungicide
Fungicidal activities
Strobilurins are naturally occurring derivatives of b-methoxyac-
rylic acid that comprise an important class of agricultural fungi-
cides.1–4 However, these compounds are natural, and they could
not be used directly due to insufficient photochemical stability
and volatility.2,5 To date, several chemists have published synthetic
analogues of strobilurin A (Fig. 1) to stabilise the triene structure of
the compound.6–14
Compounds I (Fig. 1), which were discovered by the Rohm and
Haas Company [the 4-Cl-substituted derivatives of compounds I
were developed by Shenyang Research Institute of Chemical Indus-
try and named Enoxastrobin (Fig. 1)10], contain an unsaturated
oxime ether group and exhibit effective fungicidal activities.7 In
addition, novel arylcyclopropyl oxime ether compounds II
(Fig. 1), which replace the E-styryl group in compounds I with a
trans-arylcyclopropyl group, have been reported. These com-
pounds exhibit excellent fungicidal activities.8 In our previous
study, we synthesised a series of novel indene–substituted oxime
ethers III (Fig. 1) to study the structure–activity relationships of
this type of compound.12,15 A benzopentatomic ring structure
was used to stabilise the E-styryl group in Enoxastrobin. Most of
the indene–substituted oxime ethers (III) exhibited effective fungi-
cidal activity. In addition, the fungicidal activities of some com-
pounds (III) were better than those of Enoxastrobin.
discovery.16–21 The heterocyclic scaffold of a crop protection agent
often has a positive effect on its synthetic accessibility and its
physicochemical properties, driving values, such as lipophilicity
and solubility toward the optimal balanced range for uptake and
bioavailability.16 Heterocycles are deemed to be perfect bioisoster-
es of other carba- or heterocyclic rings as well as of several differ-
ent functional groups which deliver equal or even better biological
efficacy through their similarity in structural shape and electronic
distribution.16,20 In addition, the substitution of a heteroaryl group
(i.e., pyridine or furane) with one of the aryl residues of the com-
pound results in increased biological activity.21 More importantly,
environmental compatibility of the synthesised organic com-
pounds is enhanced when heteroatoms are introduced into the car-
ba-rings.16,19,20
Based on these facts, a series of novel benzothiophene-substi-
tuted oxime ethers 5 (Fig. 1) utilising a benzothiophene group as
a bioisostere to replace the E-styryl group in Enoxastrobin was syn-
thesised in this Letter. The target compounds (5) were predicted to
retain or further enhance their biological activity and simulta-
neously improve their environmental compatibility. The struc-
ture–activity relationship of this type of compound was also
studied. The biological assay indicated that most compounds (5)
maintained or enhanced their fungicidal activities compared to
Enoxastrobin.
Many heterocyclic compounds have shown good insecticidal or
fungicidal activities, increasing their importance in pesticide
The synthetic route for the target compounds is outlined in
Scheme 1, and the reaction yields were not optimised.
The 2-(ethylthio)-benzaldehyde intermediates (2) were
⇑
Corresponding author. Tel./fax: +86 592 2183751.
prepared according to a previously published protocol.22 the
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.