New antifungal scaffold derived from a natural pharmacophore: Synthesis of α-methylene-γ-butyrolactone derivatives and their antifungal activity against Colletotrichum lagenarium

Article abstract of DOI:10.1016/j.bmcl.2013.05.073

Thirty new and thirty-four known analogues were designed and synthesized to improve the potential use of the α-methylene-γ-butyrolactone ring, a natural pharmacophore. All structures were confirmed by ¹H and ¹³C NMR, MS, and single-c

Full text of DOI:10.1016/j.bmcl.2013.05.073

Bioorganic & Medicinal Chemistry Letters xxx (2013) xxx–xxx
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Bioorganic & Medicinal Chemistry Letters
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New antifungal scaffold derived from a natural pharmacophore:
Synthesis of a-methylene-c-butyrolactone derivatives and their
antifungal activity against Colletotrichum lagenarium
,
⇑
⇑
Feng Jun-Tao , Wang De-Long , Wu Yong-Ling, Yan He, Zhang Xing
Research & Development Center of Biorational Pesticide, Key Laboratory of Plant Protection Resources and Pest Management of Ministry of Education, Northwest A&F University,
Yangling 712100, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Thirty new and thirty-four known analogues were designed and synthesized to improve the potential use
of the a-methylene-c H
-butyrolactone ring, a natural pharmacophore. All structures were confirmed by 1
Received 2 January 2013
Revised 17 May 2013
Accepted 21 May 2013
Available online xxxx
and 13C NMR, MS, and single-crystal X-ray diffraction analyses. The results of antifungal and cytotoxic
activity indicated that the synthesized analogues showed significant inhibitory activity and limited selec-
tivity. Compound 45 exhibited the highest antifungal activity with IC50 = 22.8
activity with IC50 = 28.5 M (against BGC823 cell line) and 7.7 M (against HeLa cell line). Analysis of
structure–activity relationships revealed that the incorporation of an aromatic ring into the b, positions
lM but moderate cytotoxic
l
l
Keywords:
Sesquiterpene lactones
c
of the lactone ring improved antifungal activity, and that the introduction of electron-withdrawing
groups into the aromatic rings increased the activity compared with electron-donating groups. The above
results identified 4-phenyl-3-phenyl-2-methylenebutyrolactone (33) as a lead scaffold for discovering
and developing novel and improved crop-protection agents.
a-Methylene-c-butyrolactone
Antifungal activity
Structure–activity relationships
Ó 2013 Elsevier Ltd. All rights reserved.
Growing public concern on food safety and environmental
health, combined with the global issue of emerging resistant pest
strains, is urging agrochemical industries to discover and develop
novel and improved crop-protection agents.1 Focus is mostly given
to the exploitation of bioactive natural sources to obtain new crop-
protection agents with novel modes of action (MoA). Many natural
products and their chemical analogues have been successfully
from the MoA of existing antifungal agents, thereby resulting in a
lack of cross-resistance to currently used fungicides.27 Thus, com-
pounds containing
a-methylene-c-butyrolactone can be used to
develop novel and improved crop-protection agents. To date, the
conspicuous biological activities of this class of compounds have
developed as crop-protection agents.2–4 The
a-methylene-c-buty-
rolactone ring is a central structural unit among numerous natural
products, most of which are sesquiterpenoids (Fig. 1).5–9 Com-
pounds containing an
a-methylene-c-butyrolactone functional
unit usually exhibit cytotoxic, allergenic, anti-inflammatory, phy-
totoxic, antioxidant, antimicrobial, and gastric-cytoprotection
activities.10–14 The small, less functionalized—‘stripped down’—
analogues of naturally occurring a-methylene-c-lactone are repre-
sented by tulipalin A and B (Fig. 2), which replicate the effective
antifungal ability of the natural product.15,16 Compounds contain-
ing the
a-methylene-c-butyrolactone moiety reportedly exert
their biological effects by acting as Michael acceptors in reactions
with thiol groups of bionucleophiles.5,17–26 This novel MoA differs
⇑
Corresponding authors. Tel./fax: +86 29 87092122 (F.J.-T.); tel.: +86 29
87092122; fax: +86 29 87093344 (Z.X.).
E-mail addresses: fengjt67@hotmail.com (F. Jun-Tao), zhxing1952@126.com (Z.
Xing).
Figure 1. Some reported sesquiterpenoids antifungal agents against plant pathogen
These authors contributed equally to this work.
(the content in round brackets is the compound class).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.05.073
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2
F. Jun-Tao et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
O
O
yields (72–93%) under markedly milder aqueous reaction condi-
tions than other reported methods.37–39 b,
-Substituted -methy-
lene- -butyrolactones (32–64) were also synthesized through
O
O
c
a
c
HO
indium-mediated Barbier addition (Scheme 2). Homoallylic alco-
hols were prepared according to a reported procedure involving
an indium-mediated Barbier-type reaction of corresponding alde-
hydes with cinnamyl bromides of Baylis–Hillman adducts.40,41 Ar-
gon as a gas protection was used during this reaction to reduce
the amounts of byproducts. Homoallylic alcohols were easily lact-
onized in the presence of a catalytic amount of p-TsOH instead of
pyridinium p-TsOH.40
All crude products were easily purified on silica gel upon elu-
tion with 0–40% ethyl acetate in petroleum ether using the Bio-
tageÒ Isolera™ Spektra One preparative chromatography system.
The structures of all compounds were confirmed by 1H and 13C
NMR, and HR-MS analyses. Single-crystal X-ray diffraction analysis
Tulipalin A
S-(-)-Tulipalin B
Figure 2. Two simplest compounds of naturally occurring
a
-methylene-
c
-lactone.
R1
H
OH
COOH
R1
O
O
R1CHO, In powder
THF/H2O, 24h
COOH
6M HCl
2-6 h
Br
Scheme 1. Synthetic route of compounds 1–31.
of 61 was performed to identify the trans-
a-methylene-c-butyro-
been extensively studied in the pharmaceutical field but not in the
agrochemical field.7
lactones of the b,
c
-substituted compounds (Fig. 3).42
The in vitro antifungal activities of all compounds against C.
lagenarium were evaluated for the first time by the spore germina-
tion assay method.32,43,44 The natural parent tulipalin A and carab-
rone were used as control compounds. The assay results are
summarized in Tables 1 and 2.
Compounds containing the bio-functional
a-methylene-c-lac-
tone moiety, especially sesquiterpene natural products that have
antifungal activity, play crucial roles in the agrochemical field
and are thus attracting our considerable attention. Our previous
study has shown that carabrone (Fig. 1) and its alcohol analogue,
carabrol, two natural sesquiterpene lactones isolated from Carpe-
sium macrocephalum, exhibited prominent antifungal activities
against C. lagenarium.28 A series of carabrone and carabrol deriva-
tives has been synthesized to understand structure–activity
relationships (SARs) and identify the active sites of these two
bioactive molecules. Results suggested that the activities of the
31 Analogues with different substituents at the c-position were
first prepared to explore the substituent effect on inhibitory po-
tency. Table 1 showed that all derivatives exhibited higher activity
than the natural lead compound tulipalin A. The following four
main SARs were obtained. First, the aromatic ring enhanced the
potency better than alkyl chains of different lengths from ethyl
to n-pentyl and (E)-pent-1-enyl, that is, the IC50 values of com-
compounds are mainly attributed to their complete
a-methy-
pounds 6, 8, and 9 (308.2, 261.6, and 255.4 lM, respectively) were
lene-c-lactone ring, which can be regarded as the core functional
group.29–32 Lee et al.33 reported similar results. However, limited
plant resources34 and complicated procedures for the total synthe-
sis35 of these highly active natural products hinder their develop-
ment and application.
Accordingly, the present study aimed to improve the potential
use of these compounds. Meanwhile, the cytotoxicity was tested
to ensure selectivity of the antifungal effects. The
a-methylene-
c-lactone ring (tulipalin A), a natural pharmacophore, was stripped
down from its parent compounds and developed as the lead com-
pound. Monosubstituted and bisubstituted compounds of the lead
compound were synthesized by incorporating different alkyl
groups and aromatic rings with electron-withdrawing and elec-
tron-donating groups into the lactone ring. A new bioactive scaf-
fold based on this natural pharmacophore was sought, and the
effect of this scaffold on antifungal and cytotoxic activity was
examined. Meanwhile, SARs were also studied.
The synthetic route of
tones (1–31) is outlined in Scheme 1.
c
-substituted
a
-methylene-
c
-butyrolac-
-butyrolac-
a
-Methylene-
c
tones were prepared by the cyclization of c-hydroxy-a-methylene
esters, which were obtained through indium-mediated Barbier allyl
addition to aldehydes.36 This versatile and simple method was used
Figure 3. Crystal structure of 4-(4-hydroxyphenyl)-3-p-tolyl-2-methylenebutyro-
lactone (61).
to prepare
c
-substituted
a
-methylene-
c-butyrolactones in good
O
OH
O
O
R2CHO, DABCO
R2
OCH3
conc. H2SO4-HBr(48%)
R2
OCH3
OCH3
OCH3
neat
0 °C, overnight
Br
R3
R2
OH
R3
R2
R3CHO, In powder
H2O/THF, Ar air
p-TsOH
DCM, overnight
O
O
O
Scheme 2. Synthetic route of compounds 32–64.
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F. Jun-Tao et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
3
Table 1
The 50% inhibition concentration (IC50) of compounds 1–31 against spore germination of C. lagenarium
a
a
Compd
R1
IC50
(l
M)
Compd
R1
IC50 (lM)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ethyl
n-Propyl
n-Butyl
n-Pentyl
(E)-Pent-1-enyl
Phenyl
Benzyl
Thiophen-2-yl
Thiophen-3-yl
4-Fluorophenyl
3-Fluorophenyl
2-Fluorophenyl
4-Chlorophenyl
3-Chlorophenyl
2-Chlorophenyl
4-Bromophenyl
741.4 21.8
492.2 13.0
444.4 3.8
694.9 18.2
671.5 11.0
308.2 9.8
425.2 2.9
261.6 6.8
255.4 9.3
235.3 8.9
57.9 3.1
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3-Bromophenyl
2-Bromophenyl
4-Cyanophenyl
p-Tolyl
m-Tolyl
4-Hydroxyphenyl
3-Hydroxyphenyl
2-Hydroxyphenyl
4-Methoxyphenyl
3-Methoxyphenyl
2-Methoxyphenyl
2,3-Dichlorophenyl
2,4-Dichlorophenyl
4-Hydroxy-3-methoxyphenyl
2,4-Dimethoxyphenyl
93.8 5.0
169.2 1.0
203.7 6.2
311.9 7.7
345.2 11.4
409.8 7.8
231.3 6.7
287.2 3.5
379.2 3.2
264.9 9.2
302.5 8.0
84.9 3.4
77.9 2.9
204.4 6.9
223.4 4.0
220.4 9.4
158.5 2.3
1369.5 23.2
81.5 1.4
197.4 10.5
394.8 9.6
Tulipalin Ab
Carabronec
33.4 2.1
a
b
c
Note: All 50% inhibition concentration (IC50) values are presented as the means SD (n = 3), lM.
Natural lead compound tulipalin A was used as the positive control.
Sesquiterpene lactone carabrone reported with high antifungal activity was used as the positive control.
Table 2
The 50% inhibition concentration (IC50) of compounds 32–64 against spore germination of C. lagenarium
R3
Compd (R2 = Phenyl)
IC50
(
lM)
Compd (R2 = 4-Chlorophenyl)
IC50
(
lM)
Compd (R2 = p-Tolyl)
IC50
(
lM)
a
a
a
(E)-Pent-1-enyl
Phenyl
32
33
34
35
36
37
38
39
40
41
42
284.9 5.7
177.6 10.7
172.1 9.3
115.6 1.0
85.0 4.0
136.8 13.0
217.3 9.9
224.8 8.7
115.7 3.6
219.7 2.6
335.0 2.8
43
44
45
46
47
48
49
50
51
52
53
186.3 10.2
89.8 3.5
22.8 1.3
35.7 2.3
25.7 1.2
54.0 1.3
81.5 1.6
86.4 3.1
80.3 7.6
80.9 3.9
90.6 2.4
54
55
56
57
58
59
60
61
62
63
64
240.7 11.7
220.5 12.6
86.6 7.4
118.2 2.3
63.3 3.9
140.2 4.3
125.9 6.1
175.8 5.0
78.6 1.6
4-Fluorophenyl
4-Chlorophenyl
4-Bromophenyl
4-Cyanophenyl
p-Tolyl
4-Hydroxyphenyl
4-Methoxyphenyl
4-Hydroxy-3-methoxyphenyl
4-Isopropylphenyl
85.5 1.8
268.6 2.6
a
Note: All 50% inhibition concentration (IC50) values are presented as the means SD (n = 3), lM.
lower than those of 1–5 (741.4, 492.2, 444.4, 694.9, and 671.5
respectively). Furthermore, the introduction of a benzyl group to
the -position (7,425.2 M) did not increase the potency compared
with the addition of a phenyl group (6). This result indicated that
an aromatic substituent directly fused to the -position more
lM,
c
l
c
effectively improved the potency than an alkyl group. Second,
the introduction of the electron-withdrawing groups F, Cl, Br, and
CN to the benzene ring dramatically increased the potency, and
11, 12, and 17 exhibited inhibitory activities approximately three
to fivefold higher than 6, with IC50 values of 57.9, 77.9, and
93.8
CH3, CH3O, and OH introduced to the benzene ring to give 20–22
(IC50 = 311.9, 345.2, and 409.8 M, respectively) and that of 24–
27 (IC50 = 287.2, 379.2, 264.9, and 302.5 M, respectively) slightly
lM, respectively. Meanwhile, the electron-donating groups
l
l
weakened the potency. This result suggested that the introduction
of electron-withdrawing groups to the aromatic rings increased the
activity compared with electron-donating groups. Third, meta-sub-
stitution on the benzene ring by F, Br, OH, and CH3O to give 11, 17,
23, and 26 were found to improve potency significantly compared
with ortho- and para-substitutions. Thus, the inhibitory potency
can be attributed to the positional selectivity of substituents.
Moreover, the addition of one more electron-withdrawing group
exerted an incremental effect on the activity, but the addition of
one more electron-donating group exerted a detrimental effect
on the activity. These phenomena were confirmed by comparing
Figure 4. The substituent effect on antifungal activity. The data reflects the effect of
different substituents at b position on the antifungal activity. #Lines with different
letters are significantly different (ANOVA and Tukey’s HSD, p <0.05).
the IC50 values of the bisubstituted compounds (28, 84.9
lM; 29,
81.5 M) with those of the monosubstituted compounds (13,
l
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F. Jun-Tao et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
Figure 5. Graphical depiction of the general SAR for antifungal activity based on the IC50 results on C. lagenarium. EWGs: electron-withdrawing groups; EDGs: electron-
donating groups.
of a benzene ring with the Cl (electron-withdrawing) group into the
b-position provided a series of highly potent inhibitors. In particu-
lar, 45 exhibited approximately 60-fold higher inhibitory activity
Table 3
The 50% inhibition concentration (IC50) of 22 representative compounds against spore
germination of C. lagenarium in comparison with cytotoxicity data against two human
than the natural lead compound tulipalin A (IC50 = 1369.5
IC50 = 22.8 M, which was higher than that of carabrone reported
with high activities (IC50 = 33.4 M). These results indicated that
lM) with
cell lines (BGC823 and HeLa)
l
Compd
IC50
(lM) (against
IC50
(
l
M) (against
IC50 (lM) (against
HeLa cell line)
l
C. lagenarium)
BGC823 cell line)
both electron-withdrawing and electron-donating groups contrib-
uted to improving activity, and electron-withdrawing groups were
more preferable.
1
2
3
7
741.4
492.2
444.4
425.2
158.5
203.7
311.9
84.9
93.8
>142.9
53.7
>103.5
51.4
100.5
93.7
36.6
21.1
59.7
22.1
20.6
21.2
32.8
28.0
28.5
26.0
19.0
22.5
31.3
6.9
8.8
68.9
28.9
12.1
4.84
29.2
10.1
9.5
0.7
3.2
2.5
2.5
5.5
20.1
2.0
7.7
11.2
2.2
2.1
2.5
1.9
1.9
The SARs of the natural lead compound (tulipalin A) analogues
are summarized in Figure 5. The direct fusion of aromatic ring A
with lactone ring C appeared to be essential in improving activity
against C. lagenarium. Such inhibitory activity can synergize with
the incorporation of aromatic ring B into the b-position. Using R0
as an electron-withdrawing group led to higher inhibitory activity
than using R0 as an electron-donating group. meta-Substitution was
found to improve the potency more significantly than ortho- and
para-substitutions. This result can be explained by the fact that
16
19
20
28
29
31
34
35
36
43
44
45
46
47
53
55
63
64
Carabrone
81.5
394.8
172.1
115.6
85.0
186.3
89.8
22.8
35.7
25.7
90.6
the
a,b-unsaturated carbonyl system (Michael acceptor), which
had higher electron deficiency induced by electron-withdrawing
groups, can be easily attacked by bionucleophiles.45–47 Subse-
quently, meta-substituted groups contributed more to the electron
deficiency. The activity trend of double-point substitution on the
benzene ring confirmed this explanation. However, both elec-
tron-withdrawing (R00) and electron-donating (R00) groups were
favorable for the improvement of potency, but electron-withdraw-
ing groups were more efficient than electron-donating groups. An-
other plausible explanation was the greater contribution made by
electron-withdrawing groups than electron-donating groups in
decreasing the electron density of the exocyclic-methylene and
220.5
85.5
268.6
33.4
15.1
23.7
14.9
204.4
values of the bisubstituted 31 (394.8
substituted 25 (379.2 M), 26 (264.9
also support this point.
Accordingly, the aromatic ring was introduced to directly attach
onto the b-position of the lactone ring, and then the effect of sub-
stituents was determined. 33 b,
thesized according to Scheme 2. Figure 4 showed the b,
substituted data from Table 2 with corresponding -substituted
data from Table 1. One-way ANOVA was performed and Tukey’s
HSD were used to determine significant differences between sub-
stituents at the b-position (Fig. 4). Table 2 and Figure 4 clearly
showed that the replacement of H atom with phenyl retained most
of the potency, whereas the replacement of H atom with p-tolyl re-
sulted in a modest increase in potency. Moreover, the incorporation
l
M; 14, 223.4
l
M; 15, 220.4
l
M). A comparison of the IC50
M) with those of the mono-
M), and 27 (302.5 M) can
l
l
l
l
making the a,b-unsaturated carbonyl system more electron defi-
cient. Overall, the substituent effect on antifungal activity was con-
firmed. Consequently, the SAR results established the importance
of maintaining electron deficiency in the aryl ring and revealed
that aromatic rings A and B (containing electron-withdrawing
groups) significantly contributed to biological activity. Thus, 4-
phenyl-3-phenyl-2-methylenebutyrolactone (33) can be a basic
scaffold for discovering and developing novel and improved crop-
protection agents.
c-Substituted derivatives were syn-
c
-
c
As a matter of fact, compounds with
a-methylene-c-lactone
structures often exhibit considerable toxicity against mammalian
cells.7,48,49 In order to ensure selectivity of the antifungal effects,
the cytotoxicity of 22 representative derivatives was therefore
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F. Jun-Tao et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
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Acknowledgments
We greatly appreciate the funding support for this research pro-
vided by the National Natural Science Foundation of China (NSFC
No. 30971934) and the National Department Public Benefit Re-
search Foundation of China (Grant No. 200903052). We also thank
Professor Du-qiang Luo for the HR-MS spectral data and Kunming
Institute of Botany, Chinese Academy of Science for the testing
cytotoxicity.
42. Crystallographic data of 4-(4-hydroxyphenyl)-3-p-tolyl-2-methylenebutyrolactone
(61):
C
18H16O3, MW = 280.31; monoclinic, space group P21/n; a = 5.75720
= 90°, b = 97.71°, = 90°;
d = 1.265
mg/m3,
(4) Å, b = 11.6775 (3) Å, c = 19.3379(5) Å,
a
c
V = 1472.27
(9) Å3,
Z = 4,
calculated
density
crystaldimensions 0.48 ꢀ 0.40 ꢀ 0.12 mm3, were used for measurement on a
Bruker APEXII CCD diffractometer with a graphite monochromater, Cu K
a R
radiation. The total number of reflections measured was 6164, of which 2670
were observed, I >2 (I). Final indices: R1 = 0.0542, wR2 = 0.1409.
Supplementary data
r
The crystal structure of compound 61 was solved by direct method SHELXS-97
and expanded using the difference Fourier techniques, refined by the program
SHLXL-97 and the full-matrix least-squares calculations. Crystallographic data
for the structure of compound 61 have been deposited on the Cambridge
Crystallographic Data Centre (deposition no. CCDC 914927). Copies of these
data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.htm (or from the Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB21EZ, UK; fax: +44 1223 336 033; or
desposit@ccdc.cam.ac.uk).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.
05.073.
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Please cite this article in press as: Jun-Tao, F.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2013.05.073