Bioorganic & Medicinal Chemistry Letters
Design, synthesis, and fungicidal activities of imino diacid analogs of
valine amide fungicides
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Man Sun, Hui-Hui Yang, Lei Tian, Jian-Qiang Li, Wei-Guang Zhao
State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The novel imino diacid analogs of valine amides were synthesized via several steps, including the protec-
tion, amidation, deprotection, and amino alkylation of valine, with the resulting structures confirmed by
1H and 13C NMR and HRMS. Bioassays showed that some of these compounds exhibited good fungicidal
activity. Notably, isopropyl 2-((1-((1-(3-fluorophenyl)ethyl)amino)-3-methyl-1-oxobutan-2-yl)amino)
Received 23 July 2015
Revised 28 October 2015
Accepted 29 October 2015
Available online 30 October 2015
propanoate 5i displayed significant levels of control, at 50%, against Erysiphe graminis at 3.9 lM as well
as a level of potency very similar to the reference azoxystrobin, which gave 60% activity at this concen-
tration. The present work demonstrates that imino diacid analogs of valine amides could be potentially
useful key compounds for the development of novel fungicides against wheat powdery mildew.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Imino diacid
Valine amide
Synthesis
Fungicidal activity
Environmental problems caused by traditional pesticides,
because of their nonbiodegradable properties and residues in soil,
water resources, and crops, have been a concern for both scientists
and the public in recent years.1 Results from studies of environ-
mental friendly and biodegradable pesticides can be used to reduce
environmental problems while maintaining crop yields. Amino
acids play central roles both as building blocks of peptides and pro-
teins and as important constituents of biologically active com-
pounds, such as drugs and agrochemicals.2 They are also an
excellent alternative to synthetic pesticides as a means for reduc-
ing negative chemical impacts on human health and the environ-
ment. Peptide drugs have also been successfully applied in
treating certain human diseases. Currently, peptide/protein drugs
constitute more than 10% of the ethical drug market.3 However,
only a few amino-acid-containing pesticides have progressed
through development for marketing as commercial products.
Glyphosate is the most important and famous amino-acid-
containing pesticide. Iprovalicarb is a member of the valinamide
carbamate fungicides4, which are one of three subclasses of
carboxylic acid amide (CAA) fungicides.5 In 1998, iprovalicarb
was the first commercial amino-acid-containing fungicide to be
introduced. Until now, three valinamide carbamates, including
benthiavalicarb,6 iprovalicarb, and valiphenal,7 have been com-
mercialized for the control of oomycete diseases (Fig. 1).
tobacco, and grape downy mildew.5 Valinamide carbamate fungi-
cides exhibit high activity against most foliar oomycete plant
pathogens, such as Plasmopara viticola in grapes, Phytophthora
infestans in potatoes and tomatoes, and Pseudoperonospora cubensis
in cucurbits.
In our previous study, we reported the synthesis and evaluation
of the fungicidal activities of
a series of CAA derivatives.
N-Benzhydryl valinamide carbamate derivatives exhibited excel-
lent fungicidal activity in vitro against Phytophthora capsici and
Pseudoperonospora cubensis.8 However, this carbamate might be
too easily naturally degraded. And it was also reported that two
atom spacer in the field of mandelamides (CAA fungicides) gave
excellent fungicidal results.9 With this in mind, a series of dipep-
tidomimetics, imino diacid analogs of valine amides, was designed
by adding methylene groups between the carbamate nitrogen
atom and carbonyl group to find novel compounds with high
fungicidal activities (Fig. 2).
Herein, a series of novel imino diacid analogs of valine amide
fungicides was synthesized and their fungicidal activities were
evaluated. The results revealed that these compounds displayed
promising fungicidal activity against wheat powdery mildew but
not against oomycete plant pathogens. This means that these com-
pounds might have different mechanism of fungicide action from
CAA fungicides. As powdery mildew is a serious fungal disease that
affects a wide range of plants, causing yield losses up to 45 percent,
the potential for application of the present compounds against this
disease is encouraging.
Oomycetes can cause several destructive diseases in a range of
important crop plants, such as late blight on potatoes, blue mold on
Compounds 5a–o and 6a–o were synthesized as shown in
Scheme 1. Imino diacid analogs of valine amides were synthesized
⇑
Corresponding author. Tel./fax: +86 22 23504279.
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
Sun, Man
