Design, synthesis and acaricidal activities of Cyflumetofen analogues based on carbon-silicon isosteric replacement

Article abstract of DOI:10.1016/j.bmc.2020.115509

The application of a carbon-silicon bioisosteric replacement strategy to find new acaricides with improved properties led to the discovery of Sila-Cyflumetofen 6B, a novel and highly potent acaricide. The essential t-butyl group in the beta-ketonitrile ac

Full text of DOI:10.1016/j.bmc.2020.115509

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Design, synthesis and acaricidal activities of Cyflumetofen analogues based
on carbon-silicon isosteric replacement
Cong Zhou, Jiagao Cheng, Ryan Beadle, Fergus G Earley, Zhong Li, Peter
Maienfisch
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S0968-0896(20)30335-7
https://doi.org/10.1016/j.bmc.2020.115509
BMC 115509
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14 April 2020
Please cite this article as: C. Zhou, J. Cheng, R. Beadle, F.G. Earley, Z. Li, P. Maienfisch, Design, synthesis and
acaricidal activities of Cyflumetofen analogues based on carbon-silicon isosteric replacement, Bioorganic &
Medicinal Chemistry (2020), doi: https://doi.org/10.1016/j.bmc.2020.115509
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Design, synthesis and acaricidal activities of Cyflumetofen
analogues based on carbon-silicon isosteric replacement
Cong Zhoua, Jiagao Chenga,*, Ryan Beadleb,d, Fergus G Earleyb, Zhong Lia, Peter
Maienfischa,c,*
aShanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China
University of Science and Technology, Shanghai, 200237, China
bSyngenta Crop Protection AG, Jealott's Hill Research Centre, Bracknell, Berkshire,
UK
cSyngenta Crop Protection AG, Schwarzwaldallee 215, CH-4002 Basel, Switzerland
dCurrent address: Department of Biochemistry, University of York, US
* Corresponding authors:
Peter Maienfisch, E-mail: peter.maienfisch@syngenta.com;
Jiagao Cheng, E-mail: jgcheng@ecust.edu.cn

ABSTRACT
The application of a carbon-silicon bioisosteric replacement strategy to find new
acaricides with improved properties led to the discovery of Sila-Cyflumetofen 6B, a
novel and highly potent acaricide. The essential t-butyl group in the beta-ketonitrile
acaricide Cyflumetofen 6A could be swapped with the bioisosteric trimethyl-silyl group
with retention of high level acaricidal activity and favourable pharmacological
properties. Sila-Cyflumetofen 6B was found to possess similar preferred energy-
minimized conformation and electrostatic potential surface compare to Cyflumetofen
6A. Herein we also report the development and application of the first homology model
of the spider mite mitochondrial electron transport complex II (succinate ubiquinone
oxidoreductase; SQR) and demonstrated that the active metabolite AB-1 of
Cyflumetofen 6A and its sila-analogue Sila-AB-1 bind to the Qp site in same binding
pose and that both compounds form two H-bonds and a cation-π interaction with Trp
165, Tyr 433 and Arg 279, respectively. Furthermore, we also developed a new mode
of action test for spider mite Complex II using cytochrome c as electron acceptor and
blocking its re-oxidation by addition of KCN resulting in a sensitive and convenient
colorimetric assay. This new method avoids the use of non-specific artificial electron
acceptors and allows to measure SQR inhibition in crude extracts of Tetranychus urtice.
In this assay Sila-AB-1, the intrinsically active metabolite of Sila-Cyflumetofen, 6A
exhibited even a somewhat lower IC50 value than the metabolite of Cyflumetofen AB-
1. Synthetic methodologies are described for the preparation of Sila-Cyflumetofen 6B

and its active metabolite Sila-AB-1 which enable an efficient synthesis of these
compounds in only 5 and 4 steps, respectively, from cheap commercial starting
materials. Although the value of carbon-silicon bioisosteric replacements has already
be demonstrated in the past it is to the best of our knowledge the first report of a
successful application in crop protection research in the last two decades.
Keywords:
Discovery of Sila-Cyflumetofen, beta-ketonitrile acaricide, Carbon-silicon
bioisosteric replacement, succinate ubiquinone oxidoreductase, homology model,
spider mite SQR inhibition

1. Introduction
Modern agrochemicals play a vital role in safeguarding and improving the production,
quality, and quantity of food, feed, fiber, and fuel. With the current offerings on
insecticides, herbicides, fungicides and biotechnology products together with
considerable investments in research and development the global agribusiness industry
contributes to growing public expectations for adequate supply of high-quality food and
agricultural sustainability. Despite the current arsenal of insect control agents there is a
clear demand for new innovative, safe and highly effective products mainly due to the
development of resistance to existing active ingredients, pest shifts and the increasing
regulatory requirements.1
Bioisosterism has been demonstrated to be a powerful source of chemical diversity
in biological active molecules design, also has been considered as an effective approach
to solve the challenges that modern agrochemicals are facing.2-10 Furthermore applying
an isosteric replacement strategy maximizes the chances for success in discovering
novel modern agrochemicals. For example, Oxathiapiprolin11-12 is the first highly-
active piperidinyl thiazole isoxazolines fungicides developed by DuPont in 2015. The
original hit leading to Oxathiapiprolin was identified by screening an external
compound library and showed only modest preventative and weak curative fungicidal
activity. A series of isosteric optimization at all parts of the original hit compound, led
to strongly improved biological activity and finally to the discovery of Oxathiapiprolin,
a compound introduced to the marketplace in 2015 and reportedly active at lower
application rates than existing Oomycete products.

Although the carbon-silicon bioisosteric replacement strategy received increasing
attention in pharmaceutical research in the last two decades,13-20 this discovery strategy
was employed to a much lesser extend in crop protection research despite past research
successes leading to the fungicide Flusilazole21-23 and the insecticide Silafluofen2-3, 24
–
products entering the market places in the late 1980s and early 1990s. Both carbon and
silicon are elements in Group IV of the periodic table. They share the ability to form
four covalent, tetrahedrally disposed bonds which makes silicon the ideal bioisosteric
replacement for carbon.25-26 Silicon-containing bioactive molecules designed by the
strategy of carbon-silicon replacement enables to modify physicochemical properties,
biological activity profile and target selectivity.15, 27-28
Cyflumetofen (6A), is a novel beta-ketonitrile acaricide discovered and developed
by Otsuka. The compound provides excellent control of mites and has been currently
marketed in many countries around the world.29-30 Cyflumetofen (6A) exhibits
excellent and highly selective efficacy against a variety of mites whereas having no
effect on non-targeted organisms potentially due to the procide structure.29-31
Cyflumetofen (6A) is activated by de-esterification and spontaneous decarboxylation
leading to AB-1 as main metabolite and active principle which interacts with the
mitochondrial electron transport complex II.30, 32
Mitochondrial electron transport complex II or succinate ubiquinone oxidoreductase
(SQR) is an important target for acaricides and fungicides. In the last decade other novel
acaricides such as Cyenopyrafen33-35 and Pyflubumide36-37 were developed targeting
SQR. SQR has also been identified as one of the most significant targets for the

discovery of new fungicides.38-41 Succinate dehydrogenase inhibitors (SDHI) provide
broad spectrum fungicidal activities and are important tools in disease control as the
numerous Complex II market products of high commercial value demonstrate. Though
great achievements have been made in revealing the function and structure of SQR,
neither the crystal structure of SQR from spider mites has been detected nor the binding
mode of Complex II acaricides in a target species been elucidated, and therefore further
research on novel acaricides is restrained.
During the optimization of Cyflumetofen (6A), it was found that tert-butyl at para-
position leads to the best activity.29 In our research strategy aiming to discover novel
acaricides with improved properties we considered the bioisosteric replacement of
carbon by silicon as a promising approach. Many options were considered for the
introduction of a silicon-containing substituent or for the integration of silicon into the
molecular skeleton of Cyflumetofen (6A) and have ultimately selected Sila-
Cyflumetofen (6B) as highly interesting target compound. The replacement of the tert-
butyl group by the bioisosteric trimethysilyl moiety was expected to lead potentially to
favourable changes in ligand-receptor interactions and of the pharmacology and
pharmacodynamic properties by influencing the molecular conformation, electron
distribution and physicochemical properties.14, 42-45 Furthermore the introduction of
silicon motifs in existing products also offers opportunities for the generation of new
intellectual property (IP).14, 25
In this paper we report our discovery of the silicon-containing Cyflumetofen
analogue 6B as a potent new acaricide and describe its synthesis, biological activity,

physicochemical properties, enzyme inhibition and its potential surfaces. Furthermore,
we discuss the binding modes within SQR in spider mites and differences between
Cyflumetofen (6A) and its sila-analogue (6B) attributed to the carbon-silicon
replacement.
2. Results and discussion
2.1 Synthetic Chemistry
Sila-Cyflumetofen 6B was synthesized in 5 steps as shown in scheme 1. Key steps
involved the synthesis of 4-trimethylsilyl-phenylacetonitril 3B from 1,4-
dibromobenzene 1 by n-BuLi mediated introduction of the trimethylsilyl group
followed by Pd-catalized C-C bond formation reaction.46 Later steps followed synthetic
methodology used for the synthesis of Cyflumetofen (Scheme 1).47 The build blocks
5A and 5B were synthetized by reactions of the phenylacetonitrils 3A and 3B,
respectively, with diethyl carbonate and subsequent trans-esterification catalyzed by
concentrated sulfuric acid. Finally, the benzoyl moiety in the target compounds 6A and
6B was introduced by reacting 5A and 5B with 2-trifluoromethylbenzoyl chloride.
According to the reaction conditions and yields, we found that the trimethysilyl-
substituent did not alter the reactivities remarkably compared to the tert-butyl-
substituted analogues.
Cyflumetofen 6A and Sila-Cyflumetofen 6B are proinsecticides31 which after
hydrolytical or enzymatic activation are converted to the intrinsic active metabolites
AB-1 and its sila-analogue Sila-AB-1, respectively. These two compounds were

synthesized as shown in scheme 2 in order to investigate the intrinsic activity.
Treatment of phenyl acetonitriles 4A and 4B in the presence of NaH in refluxing
tetrahydrofuran with ethyl 2-(trifluoromethyl)benzoate 8 afforded AB-1 and Sila-AB-
1, respectively, in good yields (Scheme 2).48-50 NMR analysis revealed that AB-1 and
Sila-AB-1, respectively, exist in both tautomeric forms at room temperature. In order
to further confirm the structures of AB-1 and Sila-AB-1 their acylated derivatives 9A
and 9B were prepared by treatment with pivaloyl chloride and triethylamine in
dichloromethane and characterized.33, 51-52
Scheme 1:
NC
Br
Br
a
b
Si
Cl
+
NC
COONa
+
Si
Si
Br
1
3B
2
O
O
X
NC
NC
O
O
NC
O
O
CN
O
e
c
d
O
O
X
X
F3C
X
3A X=C
3B X=Si
5A X=C
5B X=Si
6A X=C
6B X=Si
4A X=C
4B X=Si
Scheme 1. Synthetic scheme of Sila-Cyflumetofen: Reagents and conditions: a. n-BuLi,
tetrahydrofuran, -78 °C - r.t; b. 2 mol% [Pd2(allyl)2Cl2], 6 mol% S-Phos, mesitylene, 140 °C; c.
Diethyl carbonate, NaH, tetrahydrofuran, 56 °C; d. H2SO4, 2-methoxyethanol, 100 °C; e. NaH,
tetrahydrofuran, then 2-(trifluoromethyl)benzoyl chloride, 0 °C - r.t.
Scheme 2:
X
X
X
NC
O
O
COOH
CF3
g
f
O
O
O
h
HO
F3C
F3C
F3C
+
CF3
CN
CN
CN
X
7
8
AB-1
Sila-AB-1 X=Si
4A X=C
4B X=Si
X=C
9A X=C
9B X=Si
Scheme 2. Synthetic scheme of metabolites and acylated derivatives: Reagents and conditions: f.

H2SO4, ethanol, pressure, 120 °C; g. NaH, tetrahydrofuran, reflux; h. pivaloyl chloride,
triethylamine, dichloromethane, r.t.
2.2 Acaricidal activities
The acaricidal activity of Sila-Cyflumetofen (6B) was tested against the two spotted
spider mite (Tetranychus urticae). As shown in the Table 1, Sila-Cyflumetofen (6B)
exhibited as good acaricidal activity as the parent compound at 200 and 50 ppm. At
12.5 ppm Cyfumetofen (6A) still showed partial activity against T. urticae, whereas
Sila-Cyflumetofen (6B) was inactive. Although the silicon compound showed
somewhat lower activity than its carbon counterpart, our results have proven that silicon
is a valuable bioisosteric replacement for carbon with respect to the 4-t-Bu-phenyl
moiety and can lead to a highly active acaricide. The translation of this activity to field
situations and the influence of the differences in the physicochemical properties on the
field performance still need to be investigated.
X
O
CN
O
O
O
F3C
Table 1. Acaricidal activities of title compounds against T. urticae
Acaricidal activities at concn. of (ppm)
X
200
50
12.5
3
Cyflumetofen
6A
C
100
100
70-100
0
Sila-Cyflumetofen
6B
Si
100
100
0
0

2.3 Enzyme inhibition
Complex II or succinate: quinone oxidoreductase (SQR) is an essential component
of the tricarboxylic acid (or Krebbs) cycle and as such is required for energy
conservation from the oxidation of fat and carbohydrate. It catalyzes the oxidation of
succinate to fumarate, coupled to the reduction of ubiquinone to ubiquinol. Ubiquinol
is re-oxidized by molecular oxygen by electron transfer through Complex III
(cytochrome b/c1 complex), cytochrome c, and Complex IV (cytochrome a/a3).
Complex III, Complex IV and SQR are integral components of the inner mitochondrial
membrane and co-purify in mitochondrial preparations.53
The mode of action of Cyflumetofen, Cyenopyrafen and Pyflubumide and their
analogues was determined to be SQR inhibition by comparing effects on the oxidation
of succinate, pyruvate and α-glycerophosphate in polarographic assays.30 Because such
assays require relatively large amounts of mitochondrial protein, we instead used
cytochrome c as electron acceptor, blocking its re-oxidation by addition of KCN. This
provides a sensitive and convenient colorimetric assay that avoids the use of non-
specific artificial electron acceptors54 and allows assay of SQR inhibition in crude
extracts of Tetranychus urtice.
Cyflumetofen is a procide requiring conversion to its active principle AB-1 that
involves carboxylesterase activity55. The active metabolites AB-1 and Sila-AB-1 of
Cyflumetofen and Sila-Cyflumetofen were found to inhibit the succinate–cytochrome
c oxidoreductase activity at extremely low concentrations, confirming that carbon-
silicon replacement did not lead to alteration of the mode of action. The IC50 values of

AB-1 and the sila-analouge Sila-AB-1 for oxidoreductase activity were 0.0025 and
0.0016 μg.ml-1, respectively (Fig 1). Sila-AB-1 exhibited slightly stronger enzyme
inhibition than AB-1 from which we can conclude that the slightly lower acaricidal
activity of Sila-Cyflumetofen against T. urticae resulted from the changes in
physicochemical properties or pharmacological and pharmacodynamic properties.
Fig. 1. Inhibition profiling of succinate-cytochrome oxidoreductase activity.
2.4 Potential Surfaces and physicochemical properties analysis
Potential surfaces and physicochemical properties including clogP, clogS and TPSA
(Topological Polar Surface Area) were investigated to identify the potential changes in
physicochemical properties or pharmacological and pharmacodynamic properties
resulting from a carbon-silicon replacement. As shown in Fig.2 and Table 2, carbon-
silicon replacement gave little difference to the preferred energy-minimized
conformation, electrostatic potential surfaces and clogS values. However, Sila-
Cyflumetofen (6B) exhibited higher lipophilicity than Cyflumetofen (6A) in the

carbon-silicon replacement domain according to lipophilic potential surfaces (Fig.2, c
and d). The clogP value (5.40) of Sila-Cyflumetofen (6B) only increased about 0.28 as
compared to 6B (5.12). There was no difference in TPSA value, as carbon-silicon
replacement did not alter the polar groups. Fig.2 (e) depicts the physicochemical
properties of representative pesticides targeting sucking pests, mites and chewing pests.
The physicochemical properties of Sila-Cyflumetofen (6B) are situated in the suitable
range of commercial products (Fig.2, e). From the modelling and the analysis of
physicochemical properties, we can conclude that carbon-silicon isosteric replacement
did not result in major differences in the macroscopical characteristics confirming
trimethysilyl to be an ideal bioisosteric replacement of the tert-butyl group.
Fig. 2. Electrostatic potential surface of Cyflumetofen (a) and Sila-Cyflumetofen (b); lipophilic
potential surfaces of Cyflumetofen (c) and Sila-Cyflumetofen (d); The plot of physicochemical
properties for representative pesticides and Sila-Cyflumetofen (e)
Table 2. Physicochemical properties of title compounds
physicochemical properties
Compounds
clogP
5.12a
5.40
clogS
-5.58
-5.62
TPSA
76.39
76.39
Cyflumetofen
Sila-Cyflumetofen
a. The experimental value is 4.3

2.5 The Homology Model of T. cinnabarinus SQR
Up to present, the crystal structures of SQR were developed from E.coli56-59, Sus
scrofa60-62 and Gallus gallus63-64, no SQR crystal structure from spider mites has been
reported. Furthermore, the binding modes of acaricides targeting SQR are still not clear,
and further insights are highly desirable to enable further research on Complex II
acaricides. The binding characteristics cannot be correctly simulated with the present
SQR crystal structures because of different residues around the binding pocket.
Computational simulations including homology modeling and molecular docking were
applied to get insights into the binding modes of Cyflumetofen (6A) and the differences
in binding modes attribute to the carbon-silicon replacement.
The amino acid sequences of T. urticae SQR subunits were not available from
UniProt database (https://www.uniprot.org/ ). Therefore, the amino acid sequences of
SQR subunits from carmine spider mite (Tetranychus cinnabarinus) were subjected to
template search, to enable building a homology model. Taking the sequence identity,
crystal resolution values and residue completeness into account, the crystal structure of
porcine mitochondrial respiratory complex II co-crystalized with ubiquinone (PDB ID:
1ZOY60 at 2.4 Å resolution) was selected as the template to build the 3D structure of T.
cinnabarinus SQR. The final sequence alignment between target sequences and
template used for generating the 3D model of SQR is depicted in Fig.3 (a).
The overall identity and similarity of target sequences with the template were 56.0%

and 73.3%, respectively. The quality of the established homology model was assessed
by the PROCHECK Ramachandran plot,65 Profile-3D66 and Prosa-web z-score
approaches (https://prosa.services.came.sbg.ac.at/prosa.php). In the Ramachandran
plot evaluation (Fig.3, b), 91.6% of the residues were present in the most favored
regions, 7.7% in the additional regions, 0.5% in the generously allowed regions, and
only 0.2% in the disallowed regions. The Verify score by Profile-3D for T.
cinnabarinus SQR structure was 221.64, which was higher than the top score 221.54.
Moreover, most residues were reasonable with positive score values, and only a few
residues positioned far away from the binding site regions showed small negative
profile-3D values (Fig.3, d). Prosa-web z-score proves an interpretation of protein
quality, the plot contains the z-scores of all experimentally determined protein chains
in current PDB database. Structures from different sources (X-ray, NMR) are
distinguished by different colors. The z-score of T. cinnabarinus SQR structure was -
7.26, which was in the range of native conformations determined by NMR (Fig.3, c).
The above results indicated that the homology model of T. cinnabarinus SQR was
reliable and could be used for further molecular docking study. This is to the best of
our knowledge the first report on the development of a homology model of the spider
mite mitochondrial electron transport complex II (succinate ubiquinone oxidoreductase;
SQR) and is expected to stimulate further research in the area of silicon-containing
complex II acaricides as well as novel chemistries targeting this mode of action.

Fig. 3. Sequence alignment results of the template sequence (PDB ID: 1ZOY) with T. cinnabarinus
SQR subunits B, C and D (UniProt ID: A0A0K1SB10, A0A0K1SB53 and A0A0K1SAS9) (a), the

Ramachandran plots (c), the Z-Score plots (c), and the Profile-3D results (d) of T. cinnabarinus
Mitochondrial Respiratory Complex II
2.6 Binding mode analysis
Beta-ketoenoles like AB-1 and Sila-AB-1 are known to exist as tautomeric equilibria
between the keto-, ketoimine-, E-enol- and Z-enol forms which strongly dependents on
the solvents and substituents.67 It was found that in apolar solvents the equilibrium is
shifted towards the keto-form, and in polar solvents towards the enol (E or Z) isomer.
Due to the predominately hydrophobic nature of the binding pocket we selected the
keto forms of the active principles AB-1 and Sila-AB-1 for our further modeling studies.
AB-1 and Sila-AB-1 possess in the keto form chiral centers and consequently in the
tautomeric equilibria the R as well as the S configurations exist. Both these
configurations were included into our docking studies at the Qp site.
The superior poses were selected based on the Glide-Score values and from binding
mode analysis and it was found that binding of AB-1 and Sila-AB-1 to the Qp site in
the R configuration of the keto form is strongly preferred to binding in the
corresponding S configuration. Both compounds formed two hydrogen bonds with the
residues of Trp165 and Tyr433 and the corresponding distances are 2.2 Å and 2.0 Å,
respectively (Fig.4). The tert-butylbenzene or trimethylsilylbenzene moieties were
located in the flexible pocket. Furthermore cation-π interactions were observed in 2D
interaction diagrams (see Supporting imformation Fig. S1) between the
trifluoromethyl-benzene ring and the residue of Arg279.
Our work demonstrated that AB-1 and its sila-analogue Sila-AB-1 bind in the same

conformation to T. cinnabarinus SQR. Interestingly, also in the binding modes research
of SDHI fungicides, it was observed that two hydrogen bonds and a cation-π
interactions were found with the residues of Trp, Tyr and Arg, respectively.39, 62, 68 Our
results indicate that high similarities and conserved ligand binding regions among
acaricidal and fungicidal succinate dehydrogenase inhibitors and confirmed the
important roles of residues Trp, Tyr and Arg in ligand-receptor interaction.
Fig. 4. The 3D binding mode of AB-1 (a) and its sila-analogue (b) with T. cinnabarinus SQR
3. Conclusions
The application of a carbon-silicon bioisosteric replacement strategy has resulted in
the discovery Sila-Cyflumetofen, a novel and highly potent acaricide. We found that
the t-butyl group of the beta-ketonitrile acaricide Cyflumetofen can be replaced by a
trimethyl-silyl group with retention of high level acaricidal activity and favourable
pharmacological properties.
The carbon-silicon replacement in Cyflumetofen was rationalized by potential

surfaces modeling and physicochemical properties analysis. Sila-Cyflumetofen
retained similar preferred energy-minimized conformation, electrostatic potential
surface and clogS compare to the parent compound. Although there were some changes
in clogP values, the physicochemical properties of Sila-Cyflumetofen are still located
in the ideal range observed for the commercial products.
Furthermore, we developed as part of our research a new mode of action test for
Complex II acaricides using cytochrome c as electron acceptor and blocking its re-
oxidation by addition of KCN resulting in a sensitive and convenient colorimetric assay
that avoids the use of non-specific artificial electron acceptors and allows assay of SQR
inhibition in crude extracts of Tetranychus urtice.
The acaricidal activity indicated that Sila-Cyflumetofen showed somewhat lower
activity at 12.5 ppm than its carbon counterpart, however, in the enzyme inhibition
assay the intrinsically active form of Sila-Cyflumetofen Sila-AB-1, exhibited stronger
enzyme inhibition than the intrinsically active metabolite of Cyflumetofen AB-1,
demonstrating that the somewhat lower acaricidal activity of Sila-Cyflumetofen in
laboratory assays results from changes in physicochemical properties or
pharmacological and pharmacodynamic properties.
We also developed the first homology model of spider mite SQR. Our molecular
docking studies revealed that the active principles of Cyflumetofen and its sila-analogue
bind to the Qp site in same binding pose and that both compounds form two H-bonds
and a cation-π interaction with Trp 165, Tyr 433 and Arg 279, respectively. In summary,
our modeling work demonstrated that carbon-silicon replacement does not affect the

binding modes and offers basic insights for the design of novel analogues of Sila-
Cyflumetofen with improved activity as well as for the de-novo design of novel
chemistries targeting the Cyflumetofen binding pocket in Complex II. Our
pharmacophore model is expected to be instrumental for our ongoing further research
on Complex II acaricides as well as for other research groups in this area.
Although the value of carbon-silicon bioisosteric replacements has already been
demonstrated in the past, this is to the best of our knowledge the first report of a
successful application in crop protection research in the last two decades. It is hoped
that our data presented here will inspire scientists to think of employing such carbon-
silicon bioisosteric replacement strategy in their design of agrochemicals of the future.
4. Experimental section
4.1 Materials and methods
All the reagents were purchased from commercial vendors and used without further
purification. Anhydrous solvents were dried with standard methods before use. The
progresses of reactions were monitored by thin layer chromatography (TLC) analysis
on pre-coated plates (silica gel GF254), and spots were visualized under ultraviolet (UV)
light. All the compounds were purified by column chromatography on silica gel.
Melting points were determined on Büchi B540 (Büchi Labortechnik AG, Flawil,
Switzerland) melting point apparatus with an uncorrected thermometer. 1H NMR, and
13C NMR spectra were recorded on Bruker AM-400 spectrometer in CDCl3 or DMSO-
d6 solution with tetramethylsilane as internal standard. High-resolution mass spectra
(HRMS) were determined on XEVO G2 TOF (ESI) or GCT Premier (EI) instrument.
The yields obtained by the experiments were all isolated yields.
4.1.1 Synthesis of (4-bromophenyl)trimethylsilane 2

1,4-dibromobenzene (1) (12.5mmol) was dissolved with anhydrous tetrahydrofuran
(100 mL) in pre-dried Schlenk tube (charged with Argon) and cooled to -78 °C, then n-
BuLi (2.5 M in hexane, 5 mL, 12.5mmol) was added dropwise. The solution was stirred
at -78 °C for 2 h, then chlorotrimethylsilane (15 mmol) was added and the reaction was
allowed to warm to room temperature gradually. Saturated NH4Cl solution was added
and the residue was taken up in ether twice. The combined organic layer was washed
with brine and dried with Na2SO4, filtered and concentrated under reduced pressure.
After column chromatography the target compound was obtained. Yield 64.7%,
colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.3
Hz, 2H), 0.25 (s, 9H) ppm.
4.1.2 Synthesis of 2-(4-(trimethylsilyl)phenyl)acetonitrile 3B
Pd2(allyl)2Cl2 (0.1 mmol), S-Phos (0.3 mmol), sodium cyanoacetate (7.5 mmol) were
added to a pre-dried two-necked bottle. The bottle was then evacuated and filled with
Argon. (4-bromophenyl)trimethylsilane (2) (5 mmol) and 15 mL anhydrous mesitylene
were added with a syringe. The reaction mixture was stirred at room temperature for 15
minutes, and then in a preheated oil bath at 140 °C for 5 h. Upon completion of the
reaction, the mixture was cooled to room temperature and filtered. The solvent was
removed under reduced pressure. After column chromatography the target compound
was obtained. Yield 73.2%, yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.1
Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 3.74 (s, 2H), 0.27 (s, 9H) ppm.
4.1.3 General procedure for the synthesis of the substituted ethyl phenylcyanoacetate
4A and 4B
NaH (60% in mineral oil, 15 mmol) was added to 20 mL tetrahydrofuran at 00C, then
the mixture was stirred under the same condition for few minutes. 10 mmol of
phenylacetonitrile 3A or 3B, respectively, was added dropwise under stirring at 00C.
After warming to room temperature, diethyl carbonate (12 mmol) was added slowly,
and then the solution was stirred at 56 °C. The reaction progress was monitored by
TLC. After complete disappearance of the starting material, the reaction was quenched

with water at 0°C. Diluted hydrochloric acid was added to keep the pH at 4-5. The
aqueous phase was extracted with ethyl acetate twice. The combined organic layer was
washed with brine and dried with Na2SO4, filtered and concentrated under reduced
pressure. After column chromatography the target compounds were obtained.
4.1.3.1 Ethyl 2-cyano-2-(4-(tert-butyl)phenyl)acetate (4A) Yield 43.2%, yellow oil. 1H
NMR (400 MHz, CDCl3) δ 7.48 – 7.35 (m, 4H), 4.69 (s, 1H), 4.24 (q, J = 7.1 Hz, 2H),
1.30 (d, J = 11.5 Hz, 12H) ppm
4.1.3.2 Ethyl 2-cyano-2-(4-(trimethylsilyl)phenyl)acetate (4B) Yield 72.8%, yellow
oil.1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H),
4.70 (s, 1H), 4.31 – 4.18 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 0.27 (s, 9H) ppm
4.1.4 General procedure for the synthesis of the substituted 2-methoxyethyl
phenylcyanoacetate 5A and 5B
Ethyl phenylcyanoacetate 4A or 4B (3 mmol), respectively, and catalytic amount of
H2SO4 were mixed in 10 mL 2-methoxyethanol. The reaction mixture was stirred at 120
°C and the reaction progress was monitored by TLC. Upon completion the reaction, the
mixture was poured into 20 mL water and extracted with ethyl acetate twice. The
organic layer was washed with saturated NaHCO3 solution and dried with Na2SO4,
filtered, and concentrated under reduced pressure. After column chromatography the
target compounds were obtained.
4.1.4.1 2-methoxyethyl 2-cyano-2-(4-(tert-butyl)phenyl)acetate (5A) Yield 55.3%, light
yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.41 (q, J = 8.6Hz, 4H), 4.75 (s, 1H), 4.41-
4.25 (m, 2H), 3.59 (t, J =5.3Hz, 2H), 3.33 (s, 3H), 1.32 (S, 9H) ppm
4.1.4.2 2-methoxyethyl 2-cyano-2-(4-(trimethylsilyl)phenyl)acetate (5B) Yield 73.2%,
light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.2 Hz, 2H), 7.45 (d, J =
8.0 Hz, 2H), 4.77 (s, 1H), 4.41 – 4.25 (m, 2H), 3.59 (t, J = 5.4 Hz, 2H), 3.33 (s, 3H),
0.27 (s, 9H) ppm
4.1.5 General procedure for the synthesis of cyflumetofen 6A and sila-Cyflumetofen 6B

NaH (60% in mineral oil, 1.5 mmol) and 3 mL tetrahydrofuran were mixed
homogeneously at 0 °C, then 1 mmol of 2-methoxyethyl phenylcyanoacetate 5A or 5B,
respectively, and 2-(trifluoromethyl)benzoyl chloride (1.2 mmol) were added dropwise
to the suspension and the resulting reaction mixture was stirred overnight at room
temperature. The reaction was quenched with water at 00C, then diluted hydrochloric
acid was added to keep the pH at 6-7. The aqueous phase was extracted with ethyl
acetate twice. The combined organic layer was washed with brine and dried with
Na2SO4, filtered and concentrated under reduced pressure. After column
chromatography the target compounds were obtained.
1
4.1.5.1 Cyflumetofen (6A) Yield 62.5%, white solid, mp 77.3-80.7 °C. H NMR (400
MHz, CDCl3) δ 7.78 (d, J = 7.9 Hz, 1H), 7.60 (dd, J = 13.4, 8.2 Hz, 3H), 7.53 - 7.43
(m, 3H), 7.15 (d, J = 7.8 Hz, 1H), 4.54 - 4.35 (m, 2H), 3.64 (t, J = 4.8 Hz, 2H), 3.36 (s,
3H), 1.35 (s, 9H) ppm (mixture of conformers). 13C NMR (100 MHz, CDCl3) δ 189.8,
163.3, 153.2, 134.9, 131.4, 129.2,128.9, 128.6, 128.3(q, 2JCF = 32.4 Hz), 127.7, 127.3,
127.3, 127.2, 127.2(q, 3JCF = 4.8 Hz), 127.1, 126.2, 125.9, 124.4, 121.7 (d, 1JCF = 272.4
Hz), 115.2, 69.6, 66.93, 65.6, 59.0, 34.7, 31.2 ppm (mixture of conformers). HRMS
(ESI) Calcd. for C24H24F3NO4+Na+ [M+Na]+ 470.1554; found 470.1556.
1
4.1.5.2 Sila-Cyflumetofen (6B) Yield 38.7%, white solid, mp 56.3-58.8 °C. H NMR
(400 MHz, CDCl3,) δ 7.79 (d, J = 7.9 Hz, 1H), 7.66 – 7.56 (m, 5H), 7.49 (t, J = 7.6 Hz,
1H), 7.16 (d, J = 7.8 Hz, 1H), 4.54 – 4.35 (m, 2H), 3.64 (t, J = 4.8 Hz, 2H), 3.36 (s,
3H), 0.30 (s, 9H) ppm (mixture of conformers). 13C NMR (100 MHz, CDCl3) δ 190.9,
164.5, 144.3, 136.1, 135.5, 132.8, 130.6, 130.2, 129.9 (q, 2JCF = 32.3 Hz), 128.7, 128.6,
128.6, 128.5 (q, 3JCF = 4.8 Hz), 128.3, 125.6, 122.9 (d, 1JCF = 272.5 Hz), 116.3, 70.8,
68.2, 67.2, 60.3, 0.0 ppm (mixture of conformers). HRMS (ESI) Calcd. for
C23H24F3NO4Si+Na+ [M+Na]+ 486.1324; found 486.1325.
4.1.6 Synthetic procedure for ethyl 2-(trifluoromethyl)benzoate 8
In a 75 mL pressure tube, a mixture of 2-trifluoromethylbenzoic acid 7 (20 mmol),
ethanol (60 mL) and catalytic amount of H2SO4 was heated to 120 °C for 12 h. Then
the reaction mixture was cooled to room temperature and about 80% of the ethanol

solvent was removed under reduced pressure. The remaining mixture was then poured
into 30 mL water, neutralize with saturated NaHCO3 solution, and extracted with ethyl
acetate twice. The combined organic layer was washed with brine and dried with
Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by
column chromatography to afford 2-trifluoromethylethylbenzoate. Yield 87.2%,
colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.74 – 7.64 (m, 2H), 7.56 – 7.50 (m, 2H),
4.38 – 4.28 (m, 2H), 1.32 (d, J = 14.3 Hz, 3H).
4.1.7 General procedure for the synthesis of the active metabolites AB-1 and Sila-AB-1
NaH (60% in mineral oil, 2.5 mmol) was mixed with 10 mL tetrahydrofuran, then
the mixture was stirred in ice bath and 2mmol of phenylacetonitrile 4A or 4B,
respectively, was added dropwise. After warming up to room temperature, ethyl 2-
(trifluoromethyl)benzoate (8) (2.5 mmol) was added slowly, and then the solution was
stirred under reflux. The reaction progress was monitored by TLC. After complete
disappearance of the starting material, the reaction was quenched with water at 0 °C.
Diluted hydrochloric acid was added to keep the pH at 4-5. The aqueous phase was
extracted with ethyl acetate twice. The combined organic layer was washed with brine
and dried with Na2SO4, filtered and concentrated under reduced pressure. The target
compounds were obtained through recrystallization.
The metabolite AB-1 Yield 64.2%, white solid, mp 161.4-164.2 °C.1H NMR (400 MHz,
CDCl3) δ 7.76 (dd, J = 19.1, 7.8 Hz, 3H), 7.69 – 7.48 (m, 16H), 7.39 (d, J = 8.4 Hz,
2H), 7.24 (d, J = 8.4 Hz, 2H), 7.15 (s, 1H), 5.21 (s, 1H), 1.35 (s, 18H), 1.30 (s, 9H),
1.22 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 192.6, 162.6, 152.8, 151.9, 135.9, 132.40
132.3, 131.8, 131.2, 131.0, 128.3, 128.0, 127.9, 127.6, 127.1, 127.0, 126.9, 126.8, 126.8,
126.5, 126.3, 125.7, 118.4, 115.7, 93.1, 50.4, 34.7, 31.2, 31.2. HRMS (ESI) Calcd. for
C20H18F3NO+Na+ [M+Na]+ 368.1237; found 368.1239.
The metabolite Sila-AB-1 Yield 51.7%, white solid, mp 143.7-146.1 °C. 1H NMR (400
MHz, CDCl3) δ 7.79 (dd, J = 16.0, 7.7 Hz, 4H), 7.66 (q, J = 7.0 Hz, 17H), 7.56 (t, J =
8.8 Hz, 4H), 7.32 (d, J = 7.9 Hz, 2H), 7.19 (s, 1H), 5.25 (s, 1H), 0.32 (s, 18H), 0.29 (s,
10H), 0.21 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 193.7, 164.2, 143.8, 142.9, 137.1,

135.7, 135.5, 134.7, 133.6, 133.1, 133.0, 132.6, 132.3, 132.3, 132.1, 132.1, 130.3, 129.2,
129.0, 128.9, 128.6, 128.3, 128.3, 128.2, 128.1, 119.5, 116.7, 94.6, 52.0, 0.0, 0.0.
HRMS (ESI) Calcd. for C19H18F3NOSi+Na+ [M+Na]+ 384.1007; found 384.1006.
4.1.8 General procedure for the synthesis of acylated derivatives 9A and 9B
AB-1 or Sila-AB-1 (1 mmol), respectively, was dissolved in dichloromethane and
then triethylamine (1.2 mmol) was added dropwise. After stirring under room
temperature for 10 minutes, pivaloyl chloride (1.2 mmol) was added slowly. The
reaction progress was monitored by TLC. After complete disappearance of the starting
material, the reaction mixture was evaporated under reduced pressure, and the crude
product was poured into water and the resulting mixture was extracted with ethyl
acetate. The combined organic layer was washed with brine and dried with Na2SO4,
filtered and concentrated under reduced pressure. After column chromatography the
target compound was obtained.
4.1.8.1 (2E)-3-(2,2-Dimethypropanoyloxy)-2-(4-tert-butylphenyl)-3-(2-trifluoromethyl
1
phenyl)-acrylonitrile (9A) Yield 62.7%, white solid, mp 85.3-88.5°C. H NMR (400
MHz, CDCl3) δ 7.80 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.61 (t, J = 7.4 Hz,
1H), 7.54 (t, J = 7.6 Hz, 1H), 7.45 – 7.35 (m, 4H), 1.26 (s, 9H), 0.98 (s, 9H). 13C NMR
(100 MHz, CDCl3) δ 175.0, 157.5, 152.9, 132.9, 132.0, 131.3, 130.7, 128.9,128.5 (d,
2JCF = 32.2 Hz), 128.4, 127.2, 126.8, 126.8, 126.7, 126.7 (q, 3JCF = 4.9 Hz), 125.6, 125.0,
122.3 (d, 1JCF = 272.2 Hz), 116.8, 109.5, 39.1, 34.8, 31.2, 26.6. HRMS (EI): calcd for
C25H26F3NO2 [M]+ 429.1916, found 429.1917.
4.1.8.1 (2E)-3-(2,2-Dimethypropanoyloxy)-2-(4-trimethylsilylphenyl)-3-(2-trifluoromethyl
phenyl)-acrylonitrile (9B) Yield 64.3%, white solid, mp 78.1-81.8 °C.1H NMR (400
MHz, CDCl3) δ 7.68 (d, J = 7.5 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.40 (ddd, J = 40.4,
13
21.5, 7.8 Hz, 6H), 0.85 (s, 9H), 0.09 (s, 9H). C NMR (100 MHz, CDCl3) δ 176.2,
159.3, 144.0, 134.8, 134.1, 133.3, 132.4, 132.1, 131.7, 130.4, 130.1, 129.8, 129.5 (q,
3
2JCF = 31.2 Hz), 129.0, 128.9, 128.1, 128.1, 128.0, 128.0 (q, JCF = 4.8 Hz), 127.9,
1
126.2, 123.5, 120.8 (q, JCF = 272.2 Hz), 117.9, 110.9, 40.4, 27.8, 0.0. HRMS (EI):
calcd for C24H26F3NO2Si [M]+ 445.1685, found 445.1684.

4.2 Biological assay
4.2.1 Acaricidal activities against two-spotted spider mite (Tetranychus urticae)
Bean leaf discs on agar in 24-well microtiter plates were sprayed with aqueous test
solutions prepared from 10’000 ppm DMSO stock solutions. After drying the leaf discs
were infested with a mite population of mixed ages. The samples were assessed for
mortality on mixed population (mobile stages) 8 days after infestation.
4.2.2 Preparation of sub-mitochondrial particles from Tetranychus urticae
After 72 hours of infestation on bean plants, mites were collected by brushing,
immediately frozen in liquid nitrogen and stored at -80C. Sub-mitochondrial particles
(SMP) were prepared at 4C from 600 mg of mites. Mites were washed three times in
5 mM HEPES-KOH pH 7.4, 0.12 mM MgCl2, 320 mM sucrose (buffer A), resuspended
in 600 µl buffer A, and disrupted by sonication at 4C using a Qsonica Q700 equipped
with horn cup bath at amplitude 20, for 1 min. on 5 sec. on-off pulse cycle. The
homogenate was filtered through cotton wool and centrifuged for 15 min at 10000 rpm
in a Beckman Optima MAX-XP ultracentrifuge using a TLA-100.3 rotor. The
supernatant was collected and membranes containing the SMP were recovered by
centrifugation for 35 min. at 71000 rpm in a TLA-100.3 rotor. The resulting pellet was
resuspended in buffer A, supplemented with 2 mM EDTA.
4.2.3 Assay of succinate-cytochrome oxidoreductase activity
The assay was essentially as described for mammalian tissues69 and performed at
room temperature. Serial dilutions of test compounds were prepared in 100% dimethyl
sulfoxide (DMSO), and 1 µl dispensed from each dilution for each reaction. SMP were
diluted to 0.15 mg/ml in reaction buffer (20 mM KH2PO4 pH 8.0) and 50 µl added to
the reaction well followed by 50 µl 2 mM KCN in reaction buffer (to inhibit Complex
IV activity) and 50 µl 32 mM cytochrome c in reaction buffer. After 15 mins the
reaction was started by the addition of a further 50 µl of reaction buffer containing 12
mM succinate. The reduction of cytochrome c was monitored by the increase in optical

absorption at 550 nm. The initial rate of the reaction was fitted to a linear function. The
IC50 values were calculated by fitting the dependence of the initial rates on compound
concentration to
a
dose response model (y
=
min
+
((max-
min)/(1+10^(Hill(Log10(IC50))))) by nonlinear regression.
4.3 Potential Surfaces modeling and physicochemical properties analysis
Preferred energy-minimized conformations of Cyflumetofen and Sila-Cyflumetofen,
optimized by Ligprep Module in Maestro 10.2 (Schrödinger, LLC, 2015), were used as
inputs into Sybyl (Tripos Inc.). Potential Surfaces were created by MOLCAD Module.
The color ramp for lipophilic potential surfaces range from brown (highest lipophilic
area of the molecule) to blue (highest hydrophilic area). The color ramp for electrostatic
potential surfaces range from red (most positive) to purple (most negative).
The clogP, clogS and TPSA of title compounds and commercial products were
predicted by Canvas （ Schrödinger, LLC, 2015 ） , ALOGPS 2.1 online server
(http://www.vcclab.org/web/alogps/) and MOE (Molecular Operating Environment,
version 2014). The experimental data of commercial products were retrieved from The
Pesticide Manual and corresponding literature.70 The detailed data were listed in Table
S1 in Supporting information.
4.4 Homology modeling and molecualr docking
The target sequences of T. cinnabarinus SQR subunits B, C and D (UniProt ID:
A0A0K1SB10, A0A0K1SB53 and A0A0K1SAS9) were retrieved from UniProt
(http://www.uniprot.org/). The sequences were submitted to the National Center for
Biotechnology Information (NCBI) (http://www.ncbi.nlm.nih.gov/) for template search
using the BLAST program. The crystal structure of porcine heart Complex II co-
crystalized with ubiquinone (PDB ID: 1ZOY, 2.4 Å resolution) was chosen as the
template to build the 3D structures of T. cinnabarinus SQR eventually. The Prime
program encoded in Maestro 10.2 was used to modulate sequence alignment manually.
The Align Sequence to Template and Build Homology Models Modules encoded in the
Discovery Studio 3.5 software package (Accelrys Inc., 2013) were applied to perform

the final sequence alignment and generate the T. cinnabarinus SQR structure. The iron-
sulfur clusters, ubiquinone in Qp site and heme group were retained from the original
template. Final geometric evaluation was performed on PROCHECK Ramachandran
plot, Profile-3D and Prosa-web z-score approaches.
Preferred energy-minimized conformations of the two active principles were
optimized by Ligprep Module in Maestro 10.2. Since the optimized conformations of
the active forms AB-1 and Sila-AB-1 contained chiral centers, the R and S
configurations were docked into the homology model simultaneously by Glide program
with default settings in standard precision (SP) mode. The binding site was set around
the centroid of the ubiquinone retained from the original template with a size of 15 Å.
100 conformations were output and ranked by Glide-Score in the ligand docking. The
superior poses were selected for the further binding mode analysis.71-72
Acknowledgments
This work was financially supported by National Key Research and Development
Plan (2017YFD0200300), the National Natural Science Foundation of China
(21572059, 21977030), and Innovation Program of Shanghai Municipal Education
Commission (201701070002E00037). Acaricidal activities and enzyme inhibition were
measured at Syngenta. The authors would like to thank Patrik Hoegger and Gemma
Hough for performing the biological testing.
Notes
The authors declare no competing financial interest.
Reference
1. Maienfisch, P.; Stevenson, T. M. Modern agribusiness-markets, companies, benefits
and challenges. In Discovery and Synthesis of Crop Protection Products, ACS Symp.
Ser.; Maienfisch, P., Stevenson, T. M., Eds.; American Chemical Society: Washington,
DC, 2015; Vol. 1204, pp 1-13.

2. Sieburth, S. M.; Manly, C. J.; Gammon, D. W. Organosilane insecticides. Part I:
biological and physical effects of isosteric replacement of silicon for carbon in
etofenprox and MTI 800. Pestic. Sci. 1990, 28, 289-307.
3. Sieburth, S. M.; Langevine, C. N.; Dardaris, D. M. Organosilane insecticides. Part
II: chemistry and structure-activity relationships. Pestic. Sci. 1990, 28, 309-319.
4. Koyanagi, T.; Haga, T. Bioisosterism in agrochemicals. In Synthesis and Chemistry
of Agrochemicals IV, ACS Symp. Ser.; Don R. B., Joseph G. F., Gregory S. B., Eds.;
American Chemical Society: Washington, DC, 1995; Vol. 584, pp 15-24.
5. Meanwell, N. A. Synopsis of some recent tactical application of bioisosteres in drug
design. J. Med. Chem. 2011, 54, 2529-2591.
6. Langdon, S. R.; Ertl, P.; Brown, N. Bioisosteric Replacement and Scaffold Hopping
in Lead Generation and Optimization. Molecular informatics. 2010, 29, 366-385.
7. Patani, G. A.; LaVoie, E. J. Bioisosterism: A rational approach in drug design. Chem.
Rev. 1996, 96, 3147-3176.
8. Zhu, X.-Y.; Mardenborough, L. G.; Li, S.; Khan, A.; Zhang, W.; Fan, P.; Jacob, M.;
Khan, S.; Walker, L.; Ablordeppey, S. Y. Synthesis and evaluation of isosteres of N-
methyl indolo[3,2-b]-quinoline (cryptolepine) as new antiinfective agents. Biorg. Med.
Chem. 2007, 15, 686-695.
9. Stockdale, D. P.; Beutler, J. A.; Wiemer, D. F. Synthesis of amide isosteres of
schweinfurthin-based stilbenes. Biorg. Med. Chem. 2017, 25, 5483-5489.
10. Stockdale, D. P.; Titunick, M. B.; Biegler, J. M.; Reed, J. L.; Hartung, A. M.;
Wiemer, D. F.; McLaughlin, P. J.; Neighbors, J. D. Selective opioid growth factor
receptor antagonists based on a stilbene isostere. Biorg. Med. Chem. 2017, 25, 4464-
4474.
11. Pasteris, R. J.; Hanagan, M. A.; Bisaha, J. J.; Finkelstein, B. L.; Hoffman, L. E.;
Gregory, V.; Shepherd, C. P.; Andreassi, J. L.; Sweigard, J. A.; Klyashchitsky, B. A.;
Henry, Y. T.; Berge, R. A. The discovery of oxathiapiprolin: a new, highly-active
oomycete fungicide with a novel site of action. In Discovery and Synthesis of Crop
Protection Products, ACS Symp. Ser.; Maienfisch, P., Stevenson, T. M., Eds.;
American Chemical Society: Washington, DC, 2015; Vol. 1204, pp 149-161.

12. Pasteris, R. J.; Hanagan, M. A.; Bisaha, J. J.; Finkelstein, B. L.; Hoffman, L. E.;
Gregory, V.; Andreassi, J. L.; Sweigard, J. A.; Klyashchitsky, B. A.; Henry, Y. T.;
Berge, R. A. Discovery of oxathiapiprolin, a new oomycete fungicide that targets an
oxysterol binding protein. Biorg. Med. Chem. 2016, 24, 354-361.
13. Mutahi, M. W.; Nittoli, T.; Guo L.; Sieburth, S. M. Silicon-Based Metalloprotease
Inhibitors: Synthesis and Evaluation of Silanol and Silanediol Peptide Analogues as
Inhibitors of Angiotensin-Converting Enzyme. J. Am. Chem. Soc. 2002, 124, 7363-
7375.
14. Showell, G. A.; Mills, J. S. Chemistry challenges in lead optimization: silicon
isosteres in drug discovery. Drug Discov. Today. 2003, 8, 551-556.
15. Showell, G. A.; Barnes, M. J.; Daiss, J. O.; Mills, J. S.; Montana, J. G.; Tacke, R.;
Warneck, J. B. (R)-sila-venlafaxine: a selective noradrenaline reuptake inhibitor for the
treatment of emesis. Bioorg. Med. Chem. Lett. 2006, 16, 2555-2558.
16. Sieburth, S. M.; Chen, C.-A. Silanediol protease inhibitors: From conception to
validation. Eur. J. Org. Chem. 2006, 37, 311-322.
17. Tacke, R.; Popp, F.; Muller, B.; Theis, B.; Burschka, C.; Hamacher, A.; Kassack,
M. U.; Schepmann, D.; Wunsch, B.; Jurva, U.; Wellner, E. Sila-haloperidol, a silicon
analogue of the dopamine (D2) receptor antagonist haloperidol: synthesis,
pharmacological properties, and metabolic fate. Chemmedchem. 2008, 3, 152-164.
18. Arnold, S. M.; Rinehart, J. J.; Tsakalozou, E.; Eckardt, J. R.; Fields, S. Z.; Shelton,
B. J.; DeSimone, P. A.; Kee, B. K.; Moscow, J. A.; Leggas, M. A phase I study of 7-t-
butyldimethylsilyl-10-hydroxycamptothecin in adult patients with refractory or
metastatic solid malignancies. Clin. Cancer. Res. 2010, 16, 673-680.
19. Franz, A. K.; Wilson, S. O. Organosilicon molecules with medicinal applications.
J. Med. Chem. 2013, 56, 388-405.
20. Ramesh, R.; Reddy, D. S. Quest for Novel Chemical Entities through Incorporation
of Silicon in Drug Scaffolds. J. Med. Chem. 2018, 61, 3779-3798.
21. Moberg, W. K. Fungicidal 1-(silylmethyl)-1,2,4-triazole derivatives. EP Patent
4510136A, 1985.
22. Moberg, W. K. Fungicidal 1,2,4-triazole and imidazole derivatives. EP Patent