A useful synthesis of 2-acylamino-1,3,4-oxadiazoles from acylthiosemicarbazides using potassium iodate and the discovery of new antibacterial compounds

Article abstract of DOI:10.3390/molecules24081490

A useful method for the synthesis of 2-acylamino-1,3,4-oxadiazoles was developed. By using potassium iodate as an oxidant in water at 60 ^?C, a wide range of 2-acylamino-1,3,4-oxadiazoles were afforded in moderate to excellent yields within two

Full text of DOI:10.3390/molecules24081490

molecules
Article
A Useful Synthesis of 2-Acylamino-1,3,4-oxadiazoles
from Acylthiosemicarbazides Using Potassium Iodate
and the Discovery of New Antibacterial Compounds
Tianlei Li 1,2,†, Gang Wen 1,†, Jishun Li 1,2,3, Wenxuan Zhang 1 and Song Wu 1,
*
1
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica,
Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China;
litianlei818@163.com (T.L.); wengang@imm.ac.cn (G.W.); 15286037616@163.com (J.L.);
wxzhang@imm.ac.cn (W.Z.)
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University,
Guiyang 550014, China
2
3
School of Pharmacy, Guiyang College of Traditional Chinese Medicine, Huaxi University town, Guiyang,
Guizhou 550025, China
*
Correspondence: ws@imm.ac.cn; Tel.: +86-10-83163542
†
These authors contributed equally to this work.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 5 March 2019; Accepted: 15 April 2019; Published: 16 April 2019
Abstract: A useful method for the synthesis of 2-acylamino-1,3,4-oxadiazoles was developed. By using
potassium iodate as an oxidant in water at 60 ◦C, a wide range of 2-acylamino-1,3,4-oxadiazoles were
afforded in moderate to excellent yields within two hours. This method could provide a facile shortcut
to generate a series of 2-acylamino-1,3,4-oxadiazoles in medicinal chemistry. Interestingly, some highly
potent antibiotic compounds were found through this synthetic method, and some of them displayed
a significant improvement in activity compared with the corresponding 1,4-diacylthiosemicarbazides.
Compound 2n was the most active against Staphylococcus aureus with MIC (minimum inhibitory
concentration) of 1.56 mg/mL, and compounds 2m and 2q were the most active against Bacillus subtilis
with MIC of 0.78 mg/mL. The preliminary cytotoxic activities of the most potent compounds 2m
and 2q against the androgen-independent (PC-3) prostate cancer cell line were more than 30
(IC50 > 30 µM).
, 2n,
µM
Keywords: heterocycles; synthetic method; 2-acylamino-1,3,4-oxadiazoles; antibacterial
1. Introduction
1,3,4-Oxadiazole, a pivotal five-membered nitrogen-containing heterocycle, is an interesting
pharmacophore in medicinal chemistry. In particular, 2-acylamino-1,3,4-oxadiazoles have a broad range
of biological activities such as anticoagulant [
1–
3], antibacterial [
4–
8], antifungal [
9
,
10], anticancer [11
,12],
anti-inflammatory [13 15], insecticidal [16
–
,
17], antihypertensive [18
,19], etc. [20,
21] (Figure 1). Thus,
the development of facile and efficient approaches to access these 2-acylamino-1,3,4-oxadiazoles is
highly valuable to early drug discovery.
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Figure 1. Biologically active compounds containing the 2-acylamino-1,3,4-oxadiazole core motif.
To date, different methods have been developed for the synthesis of these heterocyles.
The most straightforward synthesis relies on the cyclization of corresponding thiosemicarbazide
derivatives with several desulfurating agents [22], such as 1,3-dibromo-5,5-dimethylhydantoin [23];
p-tosyl chloride [24,25]; alkylating agents [26
,27], such as methyl iodide and ethyl bromoacetate;
carbodiimides [28,29]; mercury (II) acetate [30–32]; oxone [33]; and POCl3 [34] (Scheme 1).
Scheme 1. Intramolecular cyclodesulfurization of thiosemicarbazides.
the synthesis of 2-acylamino-1,3,4-oxadiazoles: ( ) Two-step procedure to synthesize 2-acylamino-
1,3,4-oxadiazoles by cyclization and amidization [22 35]; ( ) One-step procedure to synthesize
2-acylamino-1,3,4-oxadiazoles by desulfurated cyclization [11 36 41]. . Our new method for the
1. The previous methods for
a
–
b
,
–
2
preparation of 2-acylamino-1,3,4-oxadiazoles and the discovery of new antibacterial compounds.
Recently, Sureshbabu and Akamanchi [35] independently utilized hypervalent iodine (IBX) as
an oxidant to prepare 2-amino-1,3,4-oxadizale under mild conditions. Chang [36] reported a one-pot
procedure to synthesize 2-amino-substituted 1,3,4-oxadiazoles via the condensation of semicarbazide
and the corresponding aldehydes followed by I2-mediated oxidative cyclization. As is well known,
all of the mentioned methods are extremely dependent on the N-substituted group property, and when
the N-substituted groups are aryl, hydrogen, and alkyl groups, the reaction can occur smoothly. When

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the N-substituted groups are replaced by the acyl groups, these reactions often lead to undesirable
by-products. In fact, the preparation of 2-acylamino-substituted 1,3,4-oxadiazoles through the direct
oxidative cyclization of thiosemicarbazide is still limited. For example, the 2-acylamino-substituted
1,3,4-oxadiazoles were generated through the cyclodesulfurization of thiosemicarbazide in the presence
of I2 /aqueous NaOH as a desulfurization reagent with fair yields [37
,38]. Other desulfurization reagents
such as stoichiometric mercuric salts [11 39], or lead oxide [40] can be used to induce the cyclization to
,
form the 2-acylamino-substituted 1,3,4-oxadiazoles. More recently, Balalaie and co-workers [41] proved
that O-(benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium tetrafluoroborate (TBTU) as a uronium
coupling reagent can selectively activate the sulfur moiety to construct disubstituted 1,3,4-oxadiazoles
with good yields (Scheme 1). However, these methods suffer from several limitations, such as the
handing of harsh and toxic reagents, a poor functional group tolerance, multistep synthetic steps,
a long reaction time, and a tedious purified process.
Herein, we reported a useful method for the synthesis of 2-acylamino-1,3,4-oxadiazoles by the
direct oxidation of acylthiosemicarbazides using potassium iodate under mild conditions. A wide
range of 2-acylamino-substituted 1,3,4-oxadiazoles were afforded in moderate to excellent yields with a
short reaction time. We believe that this useful approach provides a facile shortcut for the construction
of diverse 2-acylamino-substituted 1,3,4-oxadiaxole libraries in a high throughput manner.
2. Results and Discussion
2.1. Optimization of the Reaction Conditions
We commenced with the reaction of 4-methyl-N-[2-(3-nitrobenzoyl)hydrazine-1-carbonothioyl]ben
zamide (1a) in the presence of 1.5 equivalent potassium persulfate or ammonium persulfate as the
oxidant in water at 100 ◦C, but the reaction did not give the corresponding product (Table 1, entry 1–2).
Switching to other oxidants such as 2-iodoxybenzoic acid (IBX) and oxone, the cyclodesulfurization
product was observed with a low conversion (entry 3–4). To our delight, the reaction obtained the
cyclodesulfurization product as 2-acylamino-1,3,4-oxadiazole in 53% yield by using KIO3 as the oxidant
(Table 1, entry 5). An encouraging result of an 83% isolated yield was afforded (entry 6) when the
reaction temperature was deceased to 80 ◦C. The screening of different temperatures showed that the
reaction temperature had a great influence on this oxidation reaction. The reaction could be performed
at a relatively low temperature (60 ◦C); the isolated yield of the reaction was up to 90% (Table 1, entry 8).
Subsequently, various aprotic solvents, such as dichloromethane (DCM) and acetone, were investigated
in the presence of 1.5 equivalent KIO3, and the reaction was fully inhibited when the reaction was
carried out in DCM and acetone. Thus, we concluded that the optimal condition was the use of KIO3
as the oxidant and water as the solvent at 60 ◦C (entry 8).
Table 1. Optimization of cyclization of the thiosemicarbazide.
Entry
Oxidant
Solvent
Temp. (◦C)
Yield (%)
1
2
3
4
5
6
7
8
K2S2O8
(NH4)2S2O8
IBX
Water
Water
Water
Water
Water
Water
Water
Water
100
100
100
100
100
80
N.O. a,c
N.O. a,c
<30 a
<40 a
53 b
Oxone
KIO3
KIO3
KIO3
83 b
46 b
40
60
90 b
KIO3

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Table 1. Cont.
Entry
Oxidant
Solvent
Temp. (◦C)
Yield (%)
9
10
KIO3
KIO3
DCM
Acetone
60
60
5 a
N.O. a,c
All the reaction were carried out on a 0.4 mmol scale with 1.5 equiv. oxidants within 2 h; a the reaction conversions
were monitored by LC-MS; b Isolated yield; c N.O.: No observation.
2.2. Exploring the Substrates’ Scope
With the optimized reaction condition in hand, we next investigated the scope of
1,4-diacylthiosemicarbazides and the results are depicted in Table 2. Different substituents were
well-tolerated and most of the products were synthesized in high yields. The effects of the R2 groups’
properties are important in the cyclization reaction. When the R2 groups were the phenyl substituents,
the oxidative reaction resulted in higher yields than the alkyl groups (2b
higher yields of the 2-acylamino-1,3,4-oxadiazoles were observed when the phenyl group bearing an
electron-withdrawing substituent (-NO2) was presented on the R2 group (2i 2j 2k). Furthermore,
the reaction exhibited a good tolerance with the R1 groups in the 1,4-diacylthiosemicarbazides substrates
1b 1i 1k). When the R1 groups were replaced by a phenyl group, the reaction could generate
the desired products with moderate yields (2c 2f 2l). A large-scale reaction was conducted to
–e, 2i–k, 2n, 2o). Additionally,
,
,
(
–
e,
,
,
,
assess the scalability of this desulfurization and cyclization reaction. Under the standard conditions,
the thiosemicarbazide 1a (3.0 mmol, 1.07 g) was smoothly converted into the desired products with a
90% yield (See Supplementary Materials).
Table 2. Reaction scope of cyclization of the thiosemicarbazide.
Entry
R1
R2
Starting Material
1b
Product
2b
Yield (%)
1
89
2
3
1c
2c
65
90
1d
2d
4
5
6
1e
1f
2e
2f
95
50
57
1g
2g
7
1h
2h
62

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Table 2. Cont.
Entry
R1
R2
Starting Material
1i
Product
2i
Yield (%)
8
90
96
9
1j
2j
10
1k
2k
94
68
70
11
12
1l
2l
1m
2m
13
14
15
1n
1o
1p
2n
2o
2p
91
93
91
16
17
18
1q
1r
2q
2r
92
90
93
1s
2s
To gain an insight into the reaction mechanism, we set out the control reaction with the
semicarbazide (3a) and 2-acylamino-1,3,4-thiadiazoles (4a) under the standard conditions to validate
the reaction process. However, neither of them could be converted into the desired 2-acylamino-
1,3,4-oxadiazoles (2a, 2t) (Scheme 2). This may suggest that the oxidation and desulfurization step
is the key step in this process. Recent reports have proposed that the reaction may be initiated by
the nucleophilic attack of S on the electrophilic iodine of IBX, and subsequently, the cyclization and
desulfurization step occurred at the same time [42,43]. Very recently, Frederick and co-workers [44]
observed that 1-(2-hydroxybenzoyl)-thiosemicarbaziders existed as the keto–enol equilibrium in the
1H-NMR spectrum, and similar results have already been mentioned by Mostafa [45]. However,
the details of the corresponding oxidation and desulfurization mechanism remain to be ascertained
in this new reaction. On the basis of our studies and recent reports [35,42–45], a possible mechanism
for this reaction is illustrated in Scheme 2. Due to the keto–enol equilibrium of thiosemicarbaziders,
hydrosulphonyl could be oxidized by KIO3 to form sulfur dioxide which could be released from

Molecules 2019, 24, 1490
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the corresponding semi-enol form. An activated carbodiimide intermediate A, generated from the
thiosemicarbazides, could subsequently occur to give the desired 2-acylamino-1,3,4-oxiadiazoles.
In this reaction, elemental iodine was isolated, and we found that the pH of the reaction solution
was less than 6 (pH = 5–6) after the reaction. The keto–enol equilibrium of thiosemicarbaziders
could be promoted by the increased reaction temperature, but the higher temperature may induce
the decomposition of 2-acylamino-1,3,4-oxadiazoles. Furthermore, the substituted R2 group had a
significant effect on this reaction, and when the phenyl groups were replaced by the alkyl groups,
the yields were dramatically decreased (2d, 2e, 2g, and 2h). It may suggest that the carbodiimide
intermediate A could be stabilized by the phenyl groups. The reaction has a high tolerance for the
property of the substituted R1 groups (2o–q).
Scheme 2. Postulated mechanism of desulfurization for the synthesis of 2-acylamino-1,3,4-oxadiazoles.
2.3. Evaluation of the Antibacterial Activity
The discovery of highly proficient chemical reactions that give functionalized bioactive heterocycles
with interesting pharmacophoric properties is a major challenge of medicinal chemistry [46,47]. The
development of new synthetic methods for the construction of new scaffolds is an efficient shortcut
to accelerate the rate of lead molecule identification [48]. The development of bacterial resistance
to currently available antibacterial agents is a growing global health problem [49,50]. The ESKAPE
pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii,
Pseudomonas aeruginosa, and Enterobacter species) are the cause of severe and difficult-to-treat nosocomial
infections due to their antibiotic resistance [50]. One of the most important solutions is the discovery
of new antibacterial compounds with a novel mechanism in medicinal chemistry. In our laboratory,
we are focusing on the development of new antibacterial agents to protect against the ESKAPE
pathogens [51]. As a continuation of our previous work, we further evaluated their antibiotic activity
against B. subtilis, S. aureus (Gram-positive bacteria) and E. coli (Gram-negative bacteria) and the results
are summarized in Table 3. By comparing the activities of the thiosemicarbazide (1a
2-acylamino-1,3,4-oxadiazoles (2a 2s) against B. subtilis, the potency of the major products (2a
have apparently improved. The activity of the compounds 2e 2k 2m 2n 2q, and 2s showed six
–
1s) and the
–
–2s)
,
,
,
,
times the potency of their corresponding 1,4-diacylthiosemicarbazides. Furthermore, the compound
2q even showed 64 times the potency of its 1,4-diacylthiosemicarbazides. There were another five
compounds, namely 2a, 2j, 2l, 2p, and 2r, which also exhibited better activity. As for antibiotic activity
against S. aureus, although some products displayed lower activities, compounds 2e and 2q were also
32 times better than compounds 1e and 1q. We found that the most potent compounds of all of the
compounds 1a–1s and 2a–2s were 2m, 2n, and 2q. However, all of the compounds 1a–1s and 2a–2s did

Molecules 2019, 24, 1490
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not show good antibiotic activity against E. coli (Gram-negative bacteria). At the moment, there is no
clear trend regarding activity against E. coli, and the most active compounds (2m 2n, and 2q) against
,
Gram-positive pathogens do not show the same trend of activity against Gram-negative bacteria. In the
literature, some of the 1,3,4-oxadiazoles have been reported to possess cytotoxic activities (PC-3 cell
line) [21]. We tested the cytotoxicity of the most potent compounds 2m, 2n, and 2q against the human
tumor cell line (androgen-independent prostate cancer cell line, PC-3) to evaluate their potential as
antibacterial drugs. The results showed that the in vitro IC50 (median growth inhibitory concentration)
of 2m, 2n, and 2q was more than 30 µM (IC50 > 30 µM). Their lower cytotoxic activities may suggest
that the compounds 2m, 2n, and 2q are interesting drug-like antibacterial molecules.
Table 3. The antibiotic activity of compounds 1a–1s and 2a–2s.
MIC (µm/mL)
MIC (µm/mL)
Comp. ID
Comp. ID
B.subtilis
S. aureus
E. coli
B.subtilis
S. aureus
E. coli
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
12.5
12.5
6.25
6.25
25
12.5
25
6.25
3.12
100
50
25
>100
50
>100
50
25
>100
>100
12.5
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
3.12
50
6.25
3.12
1.56
100
100
50
25
6.25
1.56
1.56
0.78
1.56
>100
6.25
0.78
1.56
3.12
>100
6.25
25
25
12.5
3.12
>100
>100
100
>100
>100
100
>100
>100
100
25
12.5
>100
25
25
50
3.12
6.25
12.5
25
12.5
50
6.25
25
0.05
12.5
100
100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
0.02
100
25
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
25
100
6.25
3.12
12.5
50
3.12
100
3.12
12.5
0.20
6.25
6.25
3.12
1.56
>100
12.5
3.12
6.25
3.12
>100
1s
LEV
2s
3a
Levofloxacin (LEV) was used as a positive control.
3. Materials and Methods
3.1. Reagent and Methods
Reagents: unless otherwise indicated, all solvents and organic reagents were obtained from
commercially available sources and were used without further purification. Acetone was dried by a
molecular sieve. Potassium iodate (99%, Innochem) was used in this oxidative reaction.
Instrument: The reaction process was monitored by thin-layer chromatography (TLC, Yantai
Jiangyou Co.Ltd, Tsingdao, Shandong, China) with silica gel plates (thickness = 0.20 mm, GF254) under
UV light and LC-MS (Waters Acquity UPLC/SQD, Waters Acquity UPLC/SQD, Milford, MA, USA).
Mass spectra were obtained using a Waters Acquity UPLC-SQD mass spectrometer. High-resolution
mass spectra (HRMS, Thermo Scientific Exactive. Plus, 81 Wyman Street, Waltham, MA, USA) were
recorded on an Agilent Technologies LC/MSD TOF spectrometer. The 1H-NMR spectra were recorded
on a Varian Mercury 400 or 500 MHz instrument, and 13C-NMR spectra were recorded at 400 or 500 MHz
on a Varian Mercury using dimethyl sulfoxide-d6 (DMSO-d6), methanol-d4 (CD3OD), chloroform-d
(CDCl3) as the solvents and tetramethylsilane (TMS) as an internal standard.

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3.2. Synthesis of 1,4-Diacylthiosemicarbazide Substrates (1a–1s)
To a solution of acyl chloride (1.0 equiv.) in 20 mL dry acetone, potassium thiocyanate (1.1 equiv.)
was added at room temperature. The solution was stirred at room temperature for 0.5 h. Then, relevant
acylhydrazine (1.05 equiv.) was added. The reaction was stirred at 60 ◦C for 2 h until the reaction was
complete based on TLC (thin-layer chromatography) (DCM:MeOH = 15:1). Then, it was cooled to
room temperature, and concentrated under reduced pressure. The resulting residue was washed by
water and recrystallized in MeOH to give the corresponding intermediate as a white solid.
3.3. Synthesis of 2-acylamino-1,3,4-oxadiazole substrates (2a–2s)
A mixture of 1,4-diacylthiosemicarbazides substrates (0.4 mmol, 1.0 equiv.) and KIO3 (0.6 mmol,
1.5 equiv.) with 20 mL water in a three-necked flask (50 mL) was heated and stirred at 60 ◦C for 1.5 h.
After the reaction was completed, the reaction mixture was cooled to room temperature, and the
precipitate was removed by filtration. The aqueous phase was extracted with EtOAc. The combined
organic layers were dried by anhydrous Na2SO4, and concentrated under reduced pressure. The residue
and the former precipitate were recrystallized in EtOAc to give the desired products.
3.4. Antibacterial Activity and Cell Viability Assay
Microorganisms used for the antibiotic assay were S. aureus ATCC 29213, B. subtilis ATCC
63501, and E. coli ATCC 25922. The MIC (minimum inhibitory concentration) of the compounds was
determined according to the macrodilution broth method (National Committee for Clinical Laboratory
Standards 2000) in Mueller–Hinton Broth (MHB, Difco, Detroit, MI, USA).
Stock solutions of all compounds were prepared in dimethylsulfoxide. The stock solution was
then two-fold diluted in MHB to give an initial concentration of 100 µg/mL, and further dilution was
performed until a final concentration of 0.05 µg/mL was obtained.
The microorganisms were incubated overnight in MHB at 37 ◦C and matched to a 0.5 MCFarland
standard and added to make a final volume of 200 µL in each microliter well. A volume of bacterial
suspension equal to the volume of diluted antimicrobial solution was added to each well of antimicrobial
agent [52]. The 96-well plates were incubated for 18 h under aerobic conditions. The MIC was recorded
as the lowest concentration of the test compound which inhibited the growth of bacteria in the broth.
Standard drug, media, and bacterial growth control wells were included in each plate. Levofloxacin
was used as a positive control. The assay was done in duplicate to confirm results.
The PC-3 cells were kindly provided by the cell bank of the Chinese Academy of Sciences and
were maintained in F12K (Wisent) supplemented with 10% fetal bovine serum (Biosera) and 1 unit/mL
penicillin−streptomycin (Wisent) at 37 ◦C under humidified conditions.
Cytotoxicity assays: The in vitro cytotoxicity of the compounds (2m, 2n, and 2q) against PC-3
cells (the androgen-in) was measured by the MTT assays. This assay was based on the cleavage of the
yellow tetrazolium salt [3-(4,5-dimethyl-thiazol-2yl]-2,5-diphenyl-tetrazolium bromide, MTT, Sigma)
forming purple formazan crystals by viable cells [53]. The cells were plated in 96-well culture plates at a
density of 3
×
103 cells per well and incubated for 24 h at 37 ◦C in a 5% CO2 incubator. The compounds

Molecules 2019, 24, 1490
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(
2m
,
2n, and 2q) were dissolved in DMSO and diluted with culture medium. A total of 20
µL of the
compound solution was added 24 h post-plating at the indicated concentrations. Cell viability was
determined 72-h post-compound treatment. The total number of viable cells was determined using the
MTT (biosharp) with the Envision (PekinElmer).
4. Conclusions
To conclude, we have developed an efficient, convenient, and environmentally friendly method to
synthesize 2-acylamino-1,3,4-oxadiazoles by the direct oxidation of 1,4-diacylthiosemicarbazides. This
oxidative protocol has also shown good functional group tolerance. By mixing the substrates with KIO3,
a series of 2-acylamino-1,3,4-oxadiazoles were obtained within two hours. Compared with the classical
strategies, this reaction provides a direct approach to construct 2-acylamino-1,3,4-oxadiazoles. Various
substituted 2-acylamino-1,3,4-oxadiazoles were synthesized, and evaluated for antibacterial activity.
The screening of those compounds revealed that several compounds were active against B. subtilis and
S. aureus. The compound 2n is the most active compound with MIC of 1.56 mg/mL against S. aureus, and
the compounds 2m and 2q are the most active compounds with MIC of 0.78 mg/mL against B. subtilis.
Interestingly, some of the 2-acylamino-1,3,4-oxadiazoles display a significant improvement in activity
compared with the corresponding 1,4-diacylthiosemicarbazides. The preliminary cytotoxic effect of the
most potent compounds 2m, 2n, and 2q was determined by an MTT assay on an androgen-independent
(PC-3) prostate cancer cell line. The results showed that the median growth inhibitory concentrations of
2m
2m
,
,
2n, and 2q are more than 30
2n, and 2q are interesting drug-like antibacterial molecules. Further study of this project is
µM. Their lower cytotoxic activities may suggest that the compounds
currently underway in our laboratory.
Supplementary Materials: The supplementary materials are available online.
Author Contributions: Conceptualization, S.W., T.L., and W.Z.; Methodology, G.W., T.L., and J.L.; Data Curation,
G.W., J.L., and T.L.; Writing-Original Draft Preparation, T.L. and G.W.; Writing-Review and Editing, S.W. and T.L.
All authors read and approved the final manuscript.
Funding: This work was supported by National Natural Science Foundation of China (Grant No: 81703364),
Chinese Academy of Medical Sciences-CAMS Innovation Fund for Medical Sciences (Grant No: 2017-I2M-1-011
and 2017-I2M-1-012).
Acknowledgments: The authors are grateful to Jie Xia for his assistance in this study.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 2m, 2n and 2q are available from the authors.
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