Design, Synthesis, and Biological Activities of Spirooxindoles Containing Acylhydrazone Fragment Derivatives Based on the Biosynthesis of Alkaloids Derived from Tryptophan

Article abstract of DOI:10.1021/acs.jafc.6b02683

On the basis of the biosynthesis of alkaloids derived from tryptophan and considering the wide use of spirooxindole in drug molecular design, a series of novel spirooxindole derivatives containing an acylhydrazone moiety were designed, synthesized, and first evaluated for their biological activities. The results of bioassays indicated that the target compounds possessed good activities against tobacco mosaic virus (TMV); especially compound 4, containing a tert-butyl at the benzene ring, exhibited the best antiviral activity in vitro and inactivation, curative, and protection activities in vivo (48.4%, 58 ± 0.4, 55.2 ± 2.3, and 49.7 ± 1.1% at 500 μg/mL, respectively) compared with ribavirin (38.2, 36.4 ± 0.2, 37.5 ± 0.2, and 36.4 ± 0.1% at 500 μg/mL, respectively) and harmine (44.6, 40.5 ± 0.2, 38.6 ± 0.8, and 42.4 ± 0.6% at 500 μg/mL, respectively). At the same time, these compounds exhibited fungicidal activity selectively against certain fungi; most of these derivatives exhibited >60% fungicidal activity against Physalospora piricola at 50 mg/kg. Additionally, compounds 25 and 14 displayed excellent insecticidal activities (60% motality against C. pipiens pallens at 0.25 mg/kg) even at very low concentrations.

Full text of DOI:10.1021/acs.jafc.6b02683

Article
pubs.acs.org/JAFC
Design, Synthesis, and Biological Activities of Spirooxindoles
Containing Acylhydrazone Fragment Derivatives Based on the
Biosynthesis of Alkaloids Derived from Tryptophan
†
†
,†
†
Δ
†
Linwei Chen, Jialin Xie, Hongjian Song,* Yuxiu Liu, Yucheng Gu, Lizhong Wang,
,†,§
and Qingmin Wang*
†State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, People’s Republic of China
§
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, People’s Republic of China
ΔSyngenta, Jealott’s Hill International Research Centre, Bracknell, Berks RG42 6EY, United Kingdom
*
S Supporting Information
ABSTRACT: On the basis of the biosynthesis of alkaloids derived from tryptophan and considering the wide use of
spirooxindole in drug molecular design, a series of novel spirooxindole derivatives containing an acylhydrazone moiety were
designed, synthesized, and first evaluated for their biological activities. The results of bioassays indicated that the target
compounds possessed good activities against tobacco mosaic virus (TMV); especially compound 4, containing a tert-butyl at the
benzene ring, exhibited the best antiviral activity in vitro and inactivation, curative, and protection activities in vivo (48.4%, 58 ±
0
0
.4, 55.2 ± 2.3, and 49.7 ± 1.1% at 500 μg/mL, respectively) compared with ribavirin (38.2, 36.4 ± 0.2, 37.5 ± 0.2, and 36.4 ±
.1% at 500 μg/mL, respectively) and harmine (44.6, 40.5 ± 0.2, 38.6 ± 0.8, and 42.4 ± 0.6% at 500 μg/mL, respectively). At the
same time, these compounds exhibited fungicidal activity selectively against certain fungi; most of these derivatives exhibited
60% fungicidal activity against Physalospora piricola at 50 mg/kg. Additionally, compounds 25 and 14 displayed excellent
>
insecticidal activities (60% motality against C. pipiens pallens at 0.25 mg/kg) even at very low concentrations.
KEYWORDS: tryptophan, biosynthesis, spirooxindole, acylhydrazone, antiviral activity, fungicidal activity, insecticidal activity
INTRODUCTION
As we all know, β-carbolines are synthesized in organisms
using tryptophan as a precursor via the catalysis of enzymes.
Furthermore, there are varieties of other fused or spiro indole
alkaloids such as spirotryprostatin A and paraherquamide A
■
Plant viral diseases cause enormous detrimental effects on
agriculture and horticulture worldwide. As one of the most
1
well-studied plant viruses, tobacco mosaic virus (TMV), which
is made up of a piece of nucleic acid (ribonucleic acid; RNA)
and a surrounding protein coat, is known to infect at least 125
individual species that are economically important plants, such
as tobacco, tomato, pepper, cucumber, and many ornamental
8
−12
(
Figure 1) using tryptophan as a precursor for biosynthesis.
Meanwhile, the spirooxindole scaffold is rather common in
drug design, and spirooxindole compounds frequently exhibit a
wide range of biological activities such as obviously analgesic
and antihypertensive effects, usually served as mammalian cell
2
,3
flowers. What is worse, although TMV can proliferate only
inside a living cell, it can survive in dead tissue in a dormant
state, retaining its ability to infect growing plants for years after
the infected plant part died. Because plants do not have the
same immune system as animals, the control of plant diseases is
13−15
cycle inhibitors, etc.
Furthermore, in an effort to break
through the limitation of the intrinsic structure and the
physicochemical property of natural product and make the
molecular structure simpler and more diverse, we intend to
select tryptophan to design and synthesize pseudo-spiro-indole
natural products with structural diversity, based on the
experience of β-carbolines’ antiviral inhibitor and the
4
still a challenge.
In the search for an effective agent to protect plants from
TMV infection, natural products from plants have been proved
to be a rich resource. In comparison to synthetic chemicals,
natural-product-based TMV inhibitors feature structural
diversity and complexity, low mammalian toxicity, friendliness
to the environment, specificity to targeted species, unique mode
16
preliminary results of tryptophan biological activity.
On the other hand, the biological activities of acylhydrazone
compounds have attracted more and more attention in recent
1
7−20
21
22
years;
for example, pymetrozine, metaflumizone, and
23
5
,6
diflufenzopyr (Figure 2) show desirable insecticidal or
of action, and so on. In our previous work, we found that
natural product harmine (Figure 1), one of the β-carboline
alkaloids isolated from Peganum harmala L., exhibited anti-
TMV activity (antiviral activity against TMV in vitro and
inactivation, curative, and protection activities in vivo were 44.6,
herbicidal activities. Our previous studies revealed that the
Received: June 14, 2016
Revised: August 12, 2016
Accepted: August 13, 2016
4
0.5 ± 0.2, 38.6 ± 0.8, and 42.4 ± 0.6%, respectively, at 500
7
μg/mL).
©
XXXX American Chemical Society
A
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Figure 1. Tryptophan and alkaloids using tryptophan as biosynthesis precursors.
Figure 2. Acylhydrazone compounds.
Figure 3. Synthesis of compounds 1−18.
introduction of an acylhydrazone fragment could dramatically
HRMS data were obtained on an FTICR-MS instrument (Ionspec 7.0
T). The melting points were determined on an X-4 binocular
microscope melting point apparatus and are uncorrected. Reaction
progress was monitored by thin-layer chromatography on silica gel
24
boost the antivirus activities. Reasonably, we speculate that
the hydrogen bond donor and acceptor of acylhydrazone could
obviously enhance the interaction between the agents and the
2
5,26
TMV receptor.
GF-254 with detection by UV.
General Synthesis. Reagents were purchased from commercial
On the basis of the above two points, here a series of
spirooxindole derivatives containing an acylhydrazone fragment
were designed, synthesized, and characterized in detail.
Meanwhile, their anti-TMV, fungicidal, and insecticidal
activities were evaluated for the first time. The structure−
activity relationship (SAR) study of these new spirooxindoles
was also discussed.
sources and were used as received. All anhydrous solvents were dried
and purified according to standard techniques just before use. The
synthetic routes are given in Figures 3 and 4.
The operating steps and physical data in detail of intermediates A−
H and target compounds 1−25 can be found in the Supporting
Information.
MATERIALS AND METHODS
■
Biological Assay. The anti-TMV, fungicidal, and insecticidal
Instruments. 1H NMR spectra and 13C NMR spectra were
activities of the synthesized compounds were tested using our
obtained at 400 MHz using a Bruker AV400 spectrometer in CDCl or
3
2
7,28
DMSO-d solution with tetramethylsilane as the internal standard.
previously reported methods.
6
B
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Figure 4. Synthesis of compounds 19−25.
Figure 5. Possible mechanism for the spirocyclization reaction.
RESULTS AND DISCUSSION
ester B, which was subsequently reacted with (Boc) O and
2
■
Et N to afford compound C in 94% yield. As a key step, the
3
Synthesis. The synthesis of the compound 1 is depicted in
Figure 3. Using L-tryptophan as starting material, the
tetrahydrocarboline skeleton was constructed via Pictet−
Spengler cyclization. Then the obtained carboxylic acid A was
reacted with thionyl chloride and methanol to form methyl
spirocyclization reaction of the tetrahydrocarboline skeleton
was carried out in the presence of N-bromosuccinimide (NBS)
and glacial acetic acid to successfully form the spirooxindole
architecture. It is worth mentioning that the reaction
C
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through reductive amination reaction gave F in 71% yield, and
then F was reacted with NBS using a similar procedure as for
the preparation of D, followed by hydrazinolysis and
condensation with benzaldehyde, to give 19 in 84% yield. To
investigate the influence of the spatial configuration and
substituents on bioactivities, compounds 24 and 25 were
synthesized using the method shown in Figure 4.
Configuration. Interestingly, the H and 13C NMR spectra
of compounds 1−18 exhibited two sets of signals (the ratio
approximately was 1:1), whereas compounds 20−23 showed
mostly one set of signals (dr was more than 10:1), which
aroused our attention. At first, it should be noted that in both
kinds of compounds the carbon at the spiro center was
stereospecific with one enantiomer, which had been inves-
1
Figure 6. Compound 6 and its rotamer.
30−32
temperature and the dosage of NBS are crucial to the desired
tigated by elegant work,
and the reaction mechanism
29
product. The brominated byproduct , featuring a bromo
substituent on the benzene ring, was inevitably obtained when
the temperature was >0 °C or the NBS was in excess. The
possible mechanism that characterized an oxidative rearrange-
ment of indole C mediated by NBS is shown in Figure 5. We
surmised that the oxindole would have arisen from the
depicted in Figure 5 could also make sense. Second, in both
kinds of compounds the imine bond was always in trans
position not a mixture of cis and trans. Third, there were also
two sets of signals for 19 in which N−H bond was substituted
by a methyl group, whereas there was mostly one set of signals
for compounds 20−23 in which a new ring formed. On the
basis of the above information we speculate reasonably that the
NMR phenomenon of compounds 1−18 may be attributed to
the rotamers induced by the amide bond: there were two stable
configurations (Figure 6); after further cyclization, the
orientation of the carbonyl group was fixed, therefore giving
one set of peaks in the NMR spectra. However, a newly
generated stereocenter (C3′) in compounds 20−23 resulted in
a pair of diastereoisomers, and the diastereoisomeric mixture
ratio was more than 10:1. To investigate the absolute
configuration of the main diastereoisomer, compound 20 was
taken, for example, to carry out a NOESY experiment (Figure
7). As depicted in the 2D NOE spectrum, there were no
obvious correlation signals between δ 4.42 and 5.76, so we
speculated that the H of δ 4.42 and 5.76 were trans to each
other. Indirectly, δ 4.42 had correlation signals with δ 2.48, not
δ 2.80, so the H of δ 4.42 and 2.48 is cis and trans, respectively,
with the H of δ 2.80; there was a weak correlation signal
30−32
rearrangement of a bromohydrin derivative J.
Satisfac-
torily, compound D was prepared in excellent yield with
stereospecificity due to self-chirality induction of the L-
tryptophan moiety. Next the hydrazide 1 was formed from
the spirooxindole D by deprotection and hydrazinolysis
reaction sequentially. Compounds 2−25 containing the
acylhydrazone fragment can be synthesized from the
condensation of compound 1 with the corresponding aldehydes
under different reaction conditions (Figures 3 and 4). To be
specific, when the usage of aldehyde was 1 equiv at room
temperature for 6 h, compounds 2−18 could be easily obtained
in moderate to good yields when the aldehyde was in excess,
and when the reactions were carried out in ethanol under reflux
conditions, compounds 20−23 with a new N-heteroacetal ring
were obtained efficiently. To study the effect of hydrogen
bonding of the amino on the anti-TMV activity, compound 19
was designed and synthesized. First, the methylation of B
Figure 7. NOE spectra and chemical shift assignment of compound 20.
D
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Table 1. In Vitro and in Vivo Antiviral Activity of Compounds 1−25 against TMV
between δ 5.76 and 2.80, thus indicating they are on the same
side of the ring, and therefore δ 4.42 and 5.76 are on the
opposite side accordingly. In conclusion, we presume the
absolute configuration of 20 to be (3S,3′R,7a′S), and the
chemical shift assignment is given in Figure 7. However, this is
only reasonable speculation yet to be confirmed by crystal
structure determination. As for compounds 24 and 25, they
were mixtures of rotamers and diastereoisomers deduced from
the analysis of NMR spectra and the structure.
ribavirin, most of the newly designed compounds displayed
desirable antiviral activity in vitro, of which 4, 5, 9−11, 13, 19,
and 22 exhibited higher inhibition than ribavirin (38.2%, 500
μg/mL); especially, compounds 4 (48.4%, 500 μg/mL) and 19
(45.9%, 500 μg/mL) exhibited higher activities than harmine
(44.6%, 500 μg/mL).
Furthermore, it was noteworthy that the substituents of the
acylhydrazone moiety had a significant impact on the anti-TMV
activity, indicated by a set of representative compounds (2−12)
containing different substituted benzyl structures. The result
demonstrated that the electronic effect of substituents on the
benzene ring did have an effect on anti-TMV activity. For
Antiviral Activities. The results of antiviral activities, in
vitro and in vivo (inactivation, curative, and protection), of
these compounds are listed in Table 1. Overall, compared with
E
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a
Table 2. Fungicidal Activity of Compounds 1−9, 12, 14−19, 21, 22, 24, and 25 against 14 Kinds of Phytopathogens
a
F.C., Fusarium oxysporum sp. cucumeris; C.H., Cercospora arachidicola Hori; P.P., Physalospora piricola; R.C., Rhizoctonia cerealis; B.M., Bipolaris
maydis; C.O., Colletotrichum orbiculare; F.M., Fusarium moniliforme; A.S., Alternaria solani; F.G., Fusarium graminearum; P.I., Phytophthora infestans;
P.C., Phytophthora capsici; S.S., Sclerotinia sclerotiorum; B.C., Botrytis cinerea. R.S., Rhizoctonia solani.
instance, it was advantageous to anti-TMV activity when the
electron-withdrawing group (nitro, 5 (40.8%, 500 μg/mL)) was
introduced to the benzene ring compared with the activity of
compounds bearing an electron-donating group (methoxyl, 3
exhibited significantly higher activity. The position of the
substituent also affected the anti-TMV activity; the order of
activities of chloro-substituted compounds was ortho > para >
meta. It was noteworthy that the antivirus activity was
tremendously improved when a sterically hindered group was
introduced on the benzene ring (14.7%, 500 μg/mL), such as 4
(tert-butyl, 48.4% at 500 μg/mL), partly due to the increase of
the molecular lipid solubility.
(
0, 500 μg/mL)). Additionally, monosubstitution or multi-
substitution on the benzene ring affected anti-TMV activity to a
certain extent; for example, compared with compounds 6
(
28.9%, 500 μg/mL), 7 (25.5%, 500 μg/mL), and 8 (32.1%,
00 μg/mL), the multisubstituted compounds 9 (38.1%, 500
μg/mL), 10 (37.2%, 500 μg/mL), and 11 (43.4%, 500 μg/mL)
5
When the benzene ring was changed to other aromatic (13−
16) or aliphatic (17−18) substituents, their activities were
F
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Table 3. Larvacidal Activities against Oriental Armyworm
compounds 6−8, and 17. For example, 22 (44.2%, 500 μg/mL)
displayed obviously higher activity than most of the other
compounds. Additionally, the SAR demonstrated that the
chirality at the 3,5′-position of spirooxindole affected the
antiviral activity slightly. For instance, compound 24 (3S,5′S,
(
Mythimna separata), Cotton Bollworm (Helicoverpa
armigera), Corn Borer (Ostrinia nubilalis), and Mosquito
C. pipiens pallens) of Compounds 1−9, 12, 14−19, 21, 22,
4, and 25
(
2
2
5.2%, 500 μg/mL) derived from L-tryptophan was more active
than 25 (3R,5′R, 14.3%, 500 μg/mL) derived from D-
tryptophan. With regard to compounds 2 and 24, the result
indicated that the introduction of a substituent at the 2′-
position had little influence on the bioactivity.
Further anti-TMV bioassay was conducted to investigate
their inactivation, curative, and protection effects in vivo (Table
1
). The result showed that most of the compounds exhibited
good antiviral activity and similar SAR to the activity in vitro.
The activities of compounds 4, 5, 8−11, 13, 18, 19, and 22
were much superior to those of ribavirin (36.4 ± 0.2, 37.5 ±
0
3
.2, and 36.4 ± 0.1% at 500 μg/mL) and harmine (40.5 ± 0.2,
8.6 ± 0.8, and 42.4 ± 0.6% at 500 μg/mL); especially
compounds 4 (58 ± 0.4, 55.2 ± 2.3, and 49.7 ± 1.1% at 500
μg/mL), 9 (53.8 ± 3.3, 46.2 ± 2.0, and 51.4 ± 1.7% at 500 μg/
mL), and 22 (51.4 ± 1.0, 48.1 ± 3.7, and 54 ± 0.8% at 500 μg/
mL) displayed higher activities than the others. Interestingly,
compound 18 showed moderate activity in vitro but desirable
activities in vivo. Of all, compound 4, the N′-benzylidene-2-
oxospiro[indoline-3,3′-pyrrolidine]-5′-carbohydrazide contain-
ing a tert-butyl at the benzene ring, exhibited the best antiviral
activity both in vitro and in vivo. Considering its good
solubility, stability, and simple chemical structure, it is worthy
of further research and exploitation.
Through the modification of the spirooxindole skeleton, as
we can see, the introduction of an acylhydrazone moiety favors
the antiviral activities. These results indicate that the hydrogen
bond donor and acceptor of acylhydrazone could obviously
enhance the interaction between the agents and the TMV
receptor and then improve the activities. This verified that our
initial design ideas are reasonable.
Fungicidal Activity. Overall, these derivatives exhibited
broad-spectrum fungicidal activities against 14 kinds of plant
fungi (Table 2). Most of these derivatives exhibited >60%
fungicidal activity against Physalospora piricola at 50 mg/kg. To
our surprise, the compound containing a hydrazide structure
(
1) showed low anti-TMV activity but excellent fungicidal
activity against Physalospora piricola (96.6% at 50 mg/kg).
Noteworthily, those compounds containing aryl groups
exhibited fungicidal activities to certain fungi selectively: they
showed apparently higher activities against Physalospora
piricola, Rhizoctonia cerealis, and Sclerotinia sclerotiorum than
the others. Addtionally, the chlorinated compounds 6−9
generally showed good fungicidal activities against Physalospora
piricola and Rhizoctonia cerealis.
Insecticidal Activity. Some derivatives also showed broad-
spectrum insecticidal activities (Table 3). It was noteworthy
that the chirality played an important role in the insecticidal
activities. For example, compound 25, which derived from D-
tryptophan, displayed excellent activities (60% against C. pipiens
pallens at 0.25 mg/kg) compared with 24 (20% against
C. pipiens pallens at 5 mg/kg) derived from L-tryptophan.
Although the antivirus activities of compound 14 was far less
effective, the insecticidal activities were extremely higher than
those of other tested compounds even at very low
concentration (60% against C. pipiens pallens at 0.25 mg/kg
and 100% against M. separata at 600 mg/kg).
slightly higher than or comparable to that of compound 2.
However, the activity was greatly improved when the
naphthalene ring was introduced to the molecules, maybe
also attributed to the molecular lipid solubility. For the aliphatic
substituent, the number of branched chains affected anti-TMV
activity; the more branched was the aliphatic chain, the better
was the activity. For example, compound 17 (16.3%, 500 μg/
mL) containing a cyclohexyl displayed lower anti-TMV
activities than 18 (36%, 500 μg/mL) containing a tert-butyl
group.
To investigate the role of the N−H bond to the bioactivity,
we designed and synthesized compound 19, which has a methyl
at the nitrogen. To our delight, it showed better antivirus
activities (45.9%, 500 μg/mL) than compound 2, ribavirin, and
harmine. Thus, the result turned out that the N−H bond is not
indispensable. Similarl results can be found for the imidazolone
compounds 20−23; the activity could be kept or increased
substantially compared with the corresponding acylhydrazone
G
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In summary, according to the biosynthesis of alkaloids
derived from tryptophan and the wide use of spirooxindole in
drug molecular design, as well as by drawing from the
experience of our previous study on derivatives containing
acylhydrazone fragment, we designed and synthesized a series
of novel spirooxindole derivatives containing an acylhydrazone
moiety and first evaluated their biological activities. The results
of bioassays indicated that most of the target compounds
showed good anti-TMV activity both in vitro and in vivo
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3
±
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ASSOCIATED CONTENT
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jafc.6b02683.
(
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AUTHOR INFORMATION
■
*
(16) Huang, Y. Q.; Liu, Y. X.; Liu, Y. X.; Song, H. J.; Wang, Q. M. C
Corresponding Authors
ring may be dispensable for β-carboline: design, synthesis, and
bioactivities evaluation of tryptophan analog derivatives based on the
biosynthesis of β-carboline alkaloids. Bioorg. Med. Chem. 2016, 24,
(H.S.) Phone/fax: +86-(0)22-23503952. E-mail:
songhongjian@nankai.edu.cn.
(Q.W.) Phone/fax: +86-(0)22-23503952. E-mail: wangqm@
*
4
(
62−473.
nankai.edu.cn.
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of chromanone and chromone analogues of diacylhydrazines. Bioorg.
Med. Chem. 2007, 15, 1888−1895.
Funding
We are grateful to the National Natural Science Foundation of
China (21132003, 21421062, 21372131, 21602117), the
Specialized Research Fund for the Doctoral Program of Higher
Education (20130031110017), and the Tianjin Natural Science
Foundation (16JCZDJC32400).
(
18) Chen, Q.; Liu, Z. M.; Chen, C. N.; Jiang, L. L.; Yang, G. F.
Synthesis and fungicidal activities of new 1,2,4-triazolo[1,5-a]-
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The authors declare no competing financial interest.
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