Synthesis and antifungal activity of novel streptochlorin analogues

Article abstract of DOI:10.1016/j.ejmech.2015.01.043

Streptochlorin, first isolated as a new antibiotic in 1988 from the lipophilic extracts of the mycelium of a Streptomyces sp, is an indole natural products with a variety of biological activities. Based on the methods developed for the synthesis of pimpri

Full text of DOI:10.1016/j.ejmech.2015.01.043

European Journal of Medicinal Chemistry 92 (2015) 776e783
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antifungal activity of novel streptochlorin analogues
,
Ming-Zhi Zhang a, Qiong Chen a *, Cai-Hong Xie a, Nick Mulholland b, Sarah Turner b,
,
Dianne Irwin b, Yu-Cheng Gu b, Guang-Fu Yang a *, John Clough b
a Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China
b Syngenta, Jealott's Hill International Research Centre, Bracknell, Berkshire RG42 6EY, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Streptochlorin, first isolated as a new antibiotic in 1988 from the lipophilic extracts of the mycelium of a
Streptomyces sp, is an indole natural products with a variety of biological activities. Based on the methods
developed for the synthesis of pimprinine in our laboratory, we have synthesized a series of indole-
modified streptochlorin analogues and measured their activities against seven phytopathogenic fungi.
Some of the analogues displayed good activity in the primary assays, and the seven compounds 10b, 10c,
11e, 13e, 21, 22c and 22e (shown in Figure 1) were identified as the most promising candidates for
further study. Structural optimization is still ongoing with the aim of discovering synthetic analogues
with improved antifungal activity.
Received 25 October 2014
Received in revised form
20 January 2015
Accepted 21 January 2015
Available online 22 January 2015
Keywords:
Streptochlorin
Natural product
Antifungal activity
Synthesis
© 2015 Elsevier Masson SAS. All rights reserved.
Structureeactivity relationships
1. Introduction
replacement of Cl on the oxazole ring by Br or H [12], and
replacement of the oxazole ring by oxadiazole [13]. In a continua-
Streptochlorin 1, an indole alkaloid produced by many species of
marine actinomycetes [1], was first isolated as a new antibiotic in
1988 from the lipophilic extracts of the mycelium of a Streptomyces
sp. [2]. It belongs to the class of naturally occurring 5-(3-indolyl)
oxazoles, which also includes the natural product pimprinine 2 [3].
Streptochlorin has been claimed to have a variety of biological ac-
tivities, such as antibiotic [4], antiallergic [5], antiangiogenic [6,7],
anticancer [6,7] antitumor [8], antiproliferative [1], antityrosinase
[9], antinematodal [10] and pesticidal activity [11].
tion of our studies aimed at the discovery of novel analogues with
improved antifungal activity, we now describe work which has
focused on the optimization of the substituents on the indole ring
of streptochlorin (shown in Scheme 1). Jong Seok Lee and co-
workers have previously described the synthesis of two derivatives
[14,15], but, other than this, further indole ring modification and
biological activity of streptochlorin analogues have not been re-
ported before.
Biological activity screening conducted at Syngenta showed that
streptochlorin demonstrates antifungal activity against Pythium
spp., Botrytis cinerea, Zymoseptoria tritici, Pyricularia oryzae, Fusa-
rium culmorum and Rhizoctonia solani, and its analogue pimprinine
also exhibited weak antifungal activity. However, the potency of
these two compounds is too low to be used as agricultural
fungicides.
In our previous work, we have described various structural
modifications to streptochlorin, including the introduction of
different substituents at the nitrogen of the indole ring,
2. Experimental
2.1. Chemicals and instruments
2-Methyl-1H-indole-3-carbaldehyde (4a), 5-chloro-1H-indole-
3-carbaldehyde (4c), 5-bromo-1H-indole-3-carbaldehyde (4d), 7-
aza-1H-indole-3-carbaldehyde (4f), 1H-indole-5-carbaldehyde
(14) and other chemicals were purchased from commercial sour-
ces (e.g., Alfa Aesar Co.) and used without further purification un-
less otherwise stated. All solvents and liquid reagents were dried by
standard methods in advance and distilled before use. 1H NMR
spectra were recorded on a VARIAN Mercury-Plus 600 spectrom-
* Corresponding authors.
E-mail addresses: qchen@mail.ccnu.edu.cn (Q. Chen), gfyang@mail.ccnu.edu.cn
(G.-F. Yang).
eter in CDCl3 or DMSO-d6 with TMS as the internal reference. 13
NMR spectra were recorded in CDCl3 or DMSO-d6 on a Varian
C
http://dx.doi.org/10.1016/j.ejmech.2015.01.043
0223-5234/© 2015 Elsevier Masson SAS. All rights reserved.

M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 92 (2015) 776e783
777
Scheme 1. Modification strategy e streptochlorin derivatives.
Mercury 400/600 (100/150 MHz) spectrometer and chemical shifts
) are given in ppm relative to the center line of a triplet at
petroleum ether (60e90 ꢀC) to give the desired intermediate 5.
(d
77.0 ppm of CDCl3 or 39.5 ppm of DMSO-d6. Mass spectra were
determined using a Trace MS 2000 organic mass spectrometry (EI-
MS) or a ThermoFisher Mass platform DSQII by electrospray ioni-
zation (ESI-MS), and the signals are given in m/z. Melting points
were taken on a Büchi B-545 melting point apparatus and are un-
corrected. Reaction yields were not optimized.
2.2.2.1. Data for 2-methyl-1-(phenylsulfonyl)-1H-indole-3-
carbaldehyde (5a). White solid, yield 50%. 1H NMR (600 MHz,
DMSO-d6):
d
2.99 (s, 3H), 7.38 (d, J ¼ 7.2 Hz, 1H), 7.41 (d, J ¼ 8.4 Hz,
1H), 7.66 (t, J ¼ 7.8 Hz, 2H), 7.77 (d, J ¼ 7.8 Hz, 1H), 8.05 (d, J ¼ 7.8 Hz,
2H), 8.12 (d, J ¼ 8.4 Hz, 1H), 8.17 (d, J ¼ 7.8 Hz, 1H), 10.27 (s, 1H). ESI-
MS: m/z 300.2 (MHþ).
2.2. General procedure
2.2.2.2. Data for 4-methyl-1-(phenylsulfonyl)-1H-indole-3-
carbaldehyde (5b). White solid, yield 79%. 1H NMR (600 MHz,
2.2.1. General procedure for the synthesis of 4-methyl-1H-indole-3-
carbaldehyde (4b) and 6-methyl-1H-indole-3-carbaldehyde (4e)
(Schemes 2 and 3)
DMSO-d6):
d
2.71 (s, 3H), 7.18 (d, J ¼ 7.2 Hz, 1H), 7.35 (t, J ¼ 7.8 Hz,
1H), 7.67 (t, J ¼ 7.8 Hz, 2H), 7.76e7.81 (m, 2H), 8.14 (m, 2H), 8.84 (s,
1H), 10.07 (s, 1H). ESI-MS: m/z 300.6 (MHþ).
The Vilsmeier-Haack reagent was prepared by adding POCl3
(60 mmol, 6 mL) dropwise to ice-cold dry DMF (30 mL) whilst
stirring. The mixture was then stirred for 10e15 min at 0 ꢀC.
Compound 3b or 3e (10 mmol) was added as a solution in DMF
(5 mL) to the above Vilsmeier-Haack reagent. The stirred mixture
was then heated at 35 ꢀC for 1 h. After cooling, ice water (6 mL) and
a 30% aqueous solution of NaOH (13 mL) were added successively,
and the mixture was heated at reflux for 20 min and allowed to
cool. The mixture was extracted with CH2Cl2 (20 mL*3). The ex-
tracts were dried over Na2SO4, evaporated under reduced pressure
to remove the solvent, and the crude product was purified by flash
column chromatography using 15e25% acetone/petroleum ether
(60e90 ꢀC) as eluent to give the corresponding intermediate
compound 4b or 4e, respectively.
2.2.2.3. Data for 5-chloro-1-(phenylsulfonyl)-1H-indole-3-
carbaldehyde (5c). White solid, yield 96%. 1H NMR (600 MHz,
CDCl3):
d
7.38e7.40 (m, 2H), 7.53e7.55 (m, 2H), 7.65 (d, J ¼ 7.2 Hz,
1H), 7.89 (d, J ¼ 8.4 Hz, 1H), 7.96 (d, J ¼ 8.4 Hz, 1H), 8.24 (s, 1H), 8.27
(s, 1H), 10.09 (s, 1H). ESI-MS: m/z 320.2 (MHþ).
2.2.2.4. Data for 5-bromo-1-(phenylsulfonyl)-1H-indole-3-
carbaldehyde (5d). White solid, yield 96%. 1H NMR (600 MHz,
CDCl3):
d
7.37e7.39 (m, 2H), 7.49e7.51 (m, 2H), 7.71 (d, J ¼ 7.2 Hz,
1H), 7.90 (d, J ¼ 8.4 Hz, 1H), 7.95 (d, J ¼ 8.4 Hz, 1H), 8.24 (s, 1H), 8.27
(s, 1H), 10.07 (s, 1H). ESI-MS: m/z 365.9 (MHþ), 364.0 (MHþ).
2.2.2.5. Data for 6-methyl-1-(phenylsulfonyl)-1H-indole-3-
carbaldehyde (5e). White solid, yield 84%. 1H NMR (600 MHz,
2.2.1.1. Data
for
4-methyl-1H-indole-3-carbaldehyde
(4b).
DMSO-d6):
d
2.46 (s, 3H), 7.24 (d, J ¼ 7.8 Hz, 1H), 7.69 (t, J ¼ 7.8 Hz,
White solid, yield 74%. 1H NMR (600 MHz, DMSO-d6):
d
2.54 (s, 3H),
2H),7.76e7.79 (m, 2H), 7.99 (d, J ¼ 7.8 Hz,1H), 8.16 (d, J ¼ 7.8 Hz, 2H),
8.83 (s, 1H), 10.05 (s, 1H). ESI-MS: m/z 300.5 (MHþ).
6,88 (t, J ¼ 7.8 Hz, 1H), 7.03 (d, J ¼ 7.2 Hz, 1H), 7.37 (d, J ¼ 7.2 Hz, 1H),
7.55 (s, 1H), 9.83 (s, 1H), 10.52 (bs, 1H). ESI-MS: m/z 160.8 (MHþ).
2.2.2.6. Data for 1-acetyl-1H-7-aza-1H-indole-3-carbaldehyde (5f).
2.2.1.2. Data
for
6-methyl-1H-indole-3-carbaldehyde
(4e).
White solid, yield 78%. 1H NMR (600 MHz, CDCl3):
d 3.14 (s, 3H), 7.35
white solid, yield 79%. 1H NMR (600 MHz, CDCl3):
d
2.45 (s, 3H), 7.16
(m, 1H), 8.48 (d, J ¼ 7.8 Hz, 1H), 8.44 (m, 2H), 10.10 (s, 1H). ESI-MS:
(d, J ¼ 8.4 Hz, 1H), 7.24 (s, 1H), 7.78 (s, 1H), 8.19 (d, J ¼ 8.4 Hz, 1H),
m/z 189.3 (MHþ).
8.80 (s, 1H), 10.03 (s, 1H). ESI-MS: m/z 160.2 (MHþ).
2.2.3. General procedure for the synthesis of compounds 6e13
(Schemes 2 and 3)
The synthetic procedures for compounds 6e13 are the same as
those described in our previous work [12].
2.2.2. General procedure for the synthesis of compounds 5 (Schemes
2 and 3)
NaH (60% dispersion in mineral oil, 20.00 mmol, 0.48 g) was
added portionwise to
a stirred solution of the aldehyde 4
(10.00 mmol) in anhydrous THF (25 mL) cooled in an ice bath. The
resulting mixture was then slowly allowed to warm to r.t. After
stirring for 30 min, PhSO2Cl (12.00 mmol) (CH3COCl 12.00 mmol for
5f) in anhydrous THF (5 mL) was added dropwise. When TLC
monitoring showed that the starting material 4 had disappeared,
the reaction mixture was evaporated under reduced pressure to
remove the solvent and was then diluted with ice water (50 mL).
Solid products were filtered off and recrystallized from acetone/
2.2.3.1. Data
for
5-(2-methyl-1H-indol-3-yl)oxazole
(6a).
White solid, yield 34%. mp, 135e137 ꢀC. IR (KBr) cmꢁ1: 1092
(CeOeC), 1461 (-CH3), 1629 (C]N), 3180 (NH), 3413 (Pyrrolyl-CH).
1H NMR (600 MHz, DMSO-d6):
d
2.90 (s, 3H), 7.21 (t, J ¼ 7.2 Hz, 1H),
7.29 (t, J ¼ 7.2 Hz, 1H), 7.36e7.38 (m, 2H), 7.82 (s, 1H), 7.97 (s, 1H),
10.60 (s, 1H). 13C NMR (150 MHz, DMSO-d6):
13.0, 100.2, 111.1,
d
118.7, 119.3, 119.9, 121.3, 125.3, 134.4, 135.2, 148.1, 149.6. Anal.Calcd
for C12H10N2O: C, 72.71; H, 5.08; N, 14.13; Found: C, 72.59; H, 5.22;

778
M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 92 (2015) 776e783
Scheme 2. Synthetic routes for the preparation of analogues of streptochlorin.
Scheme 3. Structures of substituted indoles.
N, 14.10. EI-MS: m/z (%) 199.1 (MHþ).
DMSO-d6): d 21.9, 97.8, 107.8, 120.3, 121.2, 121.7, 122.4, 128.4, 135.0,
135.2, 148.4, 149.9. Anal.Calcd for C12H10N2O: C, 72.71; H, 5.08; N,
14.13; Found: C, 72.80; H, 5.14; N, 14.07. ESI-MS: m/z 199.2 (MHþ).
2.2.3.2. Data
White solid, yield 54%. mp, 124e126 ꢀC. 1H NMR (600 MHz, DMSO-
d6):
2.35 (s, 3H), 6.85 (d, J ¼ 6.6 Hz, 1H), 7.07 (d, J ¼ 7.8 Hz, 1H), 7.18
(s, 1H), 7.30 (t, J ¼ 8.4 Hz, 1H), 7.59 (s, 1H), 8.41 (s, 1H), 10.58 (s, 1H).
13C NMR (150 MHz, DMSO-d6):
20.3, 98.7, 108.1, 119.7, 121.5, 121.7,
121.9, 128.6, 134.0, 135.6, 149.9, 150.7. Anal.Calcd for C12H10N2O: C,
72.71; H, 5.08; N, 14.13; Found: C, 72.62; H, 5.23; N, 14.15. EI-MS: m/
z (%) 199.2 (MHþ).
for
5-(4-methyl-1H-indol-3-yl)oxazole
(6b).
d
2.2.3.6. Data for 5-(7-aza-1H-indol-3-yl)oxazole (6f). White solid,
yield 45%. mp, 157e159 ꢀC. 1H NMR (600 MHz, CDCl3):
d 7.25e7.26
d
(m, 1H), 7.29 (s, 1H), 7.73 (s, 1H), 7.93 (s, 1H), 8.24 (d, J ¼ 7.2 Hz, 1H),
8.43 (d, J ¼ 4.2 Hz, 1H), 8.70 (s, 1H). 13C NMR (150 MHz, DMSO-d6):
d
103.6, 116.6, 120.3, 123.6, 128.4, 142.5, 146.6, 148.7, 149.4, 151.1.
Anal.Calcd for C10H7N3O: C, 64.86; H, 3.81; N, 22.69; Found: C,
64.77; H, 3.90; N, 22.72. EI-MS: m/z (%) 185 (100), 156 (23), 145 (46),
130 (39), 103 (19).
2.2.3.3. Data for 5-(5-chloro-1H-indol-3-yl)oxazole (6c). White
solid, yield 65%. mp, 130e132 ꢀC. 1H NMR (600 MHz, CDCl3):
d 7.24
(s, 1H), 7.27 (s, 1H), 7.37 (d, J ¼ 7.8 Hz, 1H), 7.58 (d, J ¼ 7.8 Hz, 1H),
7.85 (s, 1H), 7.92 (s, 1H), 8.50 (s, 1H). 13C NMR (150 MHz, DMSO-d6):
2.2.3.7. Data for 5-(2-methyl-1-(phenylsulfonyl)-1H-indol-3-yl)oxa-
d
99.0, 114.7, 121.5, 121.7, 122.4, 125.6, 128.8, 129.9, 134.9, 149.7,
zole (7a). Grey solid, yield 77%. mp, 242e244 ꢀC. 1H NMR
151.3. Anal.Calcd for C11H7ClN2O: C, 60.43; H, 3.23; N, 12.81; Found:
(600 MHz, CDCl3):
d
2.77 (s, 3H), 7.25 (s, 1H), 7.31 (t, J ¼ 7.8 Hz, 1H),
C, 60.52; H, 3.28; N, 12.65. ESI-MS: m/z 219.5 (MHþ).
7.36 (t, J ¼ 7.8 Hz, 1H), 7.45e7.47 (m, 2H), 7.58 (t, J ¼ 7.8 Hz, 1H), 7.71
(d, J ¼ 7.8 Hz, 1H), 7.84e7.85 (m, 2H), 8.02 (s, 1H), 8.29 (d, J ¼ 8.4 Hz,
1H). ESI-MS: m/z 339.4 (MHþ).
2.2.3.4. Data
White solid, yield 57%. mp, 142e144 ꢀC. 1H NMR (600 MHz, CDCl3):
7.19 (s, 1H), 7.28 (s, 1H), 7.35 (d, J ¼ 7.2 Hz, 1H), 7.61 (d, J ¼ 7.2 Hz,
1H), 7.90 (s, 1H), 7.98 (s,1H), 8.46 (s,1H). 13C NMR (150 MHz, DMSO-
d6): 99.1, 113.9, 121.4, 122.8, 124.7, 126.2, 128.6, 130.7, 135.6, 149.2,
for
5-(5-bromo-1H-indol-3-yl)oxazole
(6d).
d
2.2.3.8. Data for 4-chloro-5-(2-methyl-1-(phenylsulfonyl)-1H-indol-
3-yl)oxazole (8a). White solid, yield 17%. mp, 253e255 ꢀC. 1H NMR
d
150.7. Anal.Calcd for C11H7BrN2O: C, 50.22; H, 2.68; N,10.65; Found:
(600 MHz, CDCl3):
d
: 2.63 (s, 3H), 7.30 (d, J ¼ 7.8 Hz, 1H), 7.38 (t,
C, 50.34; H, 2.73; N, 10.62. ESI-MS: m/z 263.4 (MHþ), 265.2 (MHþ).
J ¼ 7.8 Hz, 1H), 7.44e7.49 (m, 3H), 7.60 (t, J ¼ 7.8 Hz, 1H), 7.86 (d,
J ¼ 7.8 Hz, 2H), 7.97 (s, 1H), 8.26 (d, J ¼ 8.4 Hz, 1H). 13C NMR
2.2.3.5. Data
White solid, yield 60%. mp, 118e120 ꢀC. 1H NMR (600 MHz, DMSO-
d6):
2.42 (s, 3H), 6.98 (d, J ¼ 7.8 Hz, 1H), 7.25 (s, 1H), 7.41 (s, 1H),
7.70e7.73 (m, 2H), 8.31 (s, 1H), 11.42 (s, 1H). 13C NMR (150 MHz,
for
5-(6-methyl-1H-indol-3-yl)oxazole
(6e).
(150 MHz, DMSO-d6): d 22.6, 99.8, 114.5, 119.7, 121.2, 124.6, 125.8,
127.7, 128.4, 129.7, 133.9, 134.0, 135.5, 139.8, 151.4, 154.2. Anal.Calcd
for C18H13ClN2O3S: C, 57.99; H, 3.51; N, 7.51; Found: C, 57.85; H,
3.62; N, 7.50. ESI-MS: m/z 373.0 (MHþ).
d

M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 92 (2015) 776e783
779
2.2.3.9. Data for 4-bromo-5-(2-methyl-1-(phenylsulfonyl)-1H-indol-
124.2, 125.7, 128.1, 138.0, 142.8, 148.3, 150.7. Anal.Calcd for
3-yl)oxazole (9a). White solid, yield 28%, mp, 280e282 ꢀC. 1H NMR
C10H6BrN3O: C, 45.48; H, 2.29; N, 15.91; Found: C, 45.52; H, 2.31; N,
(600 MHz, CDCl3):
d
2.65 (s, 3H), 7.31 (d, J ¼ 7.8 Hz, 1H), 7.34 (t,
15.80. EI-MS: m/z (%) 263 (Mþ, 100), 265 (100), 184 (4), 145(32), 146
J ¼ 7.8 Hz, 1H), 7.45e7.50 (m, 3H), 7.60 (t, J ¼ 7.8 Hz, 1H), 7.83 (d,
(7).
J ¼ 7.8 Hz, 2H), 7.97 (s, 1H), 8.29 (d, J ¼ 8.4 Hz, 1H). 13C NMR
(150 MHz, DMSO-d6):
d
23.1, 98.9, 115.2, 118.8, 122.3, 124.4, 125.6,
2.2.3.17. Data for 2-chloro-1-(5-chloro-3-(4-chlorooxazol-5-yl)-1H-
126.9, 128.6, 129.7, 134.4, 134.8, 135.6, 138.7, 150.48, 152.1. Anal.-
Calcd for C18H13BrN2O3S: C, 51.81; H, 3.14; N, 6.71; Found: C, 51.68;
H, 3.16; N, 6.67. ESI-MS: m/z 419.2 (MHþ).
indol-1-yl)ethanone (12c). White solid, yield 43%.mp, 215e217 ꢀC.
1H NMR (600 MHz, CDCl3):
d
4.32 (s, 2H), 7.08 (d, J ¼ 7.8 Hz, 1H),
7.86 (d, J ¼ 7.8 Hz, 1H), 7.98 (s, 1H), 8.05 (s, 1H), 8.18 (s, 1H). 13C NMR
(150 MHz, CDCl3):
d 48.3, 112.5, 121.5, 121.9, 122.4, 125.4, 126.6,
2.2.3.10. Data for 4-chloro-5-(4-methyl-1H-indol-3-yl)oxazole (10b).
White solid, yield 29%, mp, 256e258 ꢀC. 1H NMR (600 MHz, CDCl3):
129.3, 123.0, 133.8, 138.1, 151.4, 160.9. Anal.Calcd for C13H7Cl3N2O2:
C, 47.38; H, 2.14; N, 8.50; Found: C, 47.45; H, 2.09; N, 8.51. EI-MS: m/
z (%) 329.1 (MHþ).
d
2.32 (s, 3H), 6.96 (d, J ¼ 7.2 Hz, 1H), 7.17 (t, J ¼ 7.2 Hz, 1H), 7.20 (t,
J ¼ 7.8 Hz, 1H), 7.30 (s, 1H), 8.07 (s, 1H), 8.56 (s, 1H). 13C NMR
(150 MHz, DMSO-d6):
d
19.5, 98.6, 108.1, 119.8, 121.8, 125.4, 128.2,
2.2.3.18. Data for 2-chloro-1-(3-(4-chlorooxazol-5-yl)-6-methyl-1H-
128.5, 132.9, 135.4, 138.1, 151.4. Anal.Calcd for C12H9ClN2O: C, 61.95;
H, 3.90; N, 12.04; Found: C, 62.05; H, 3.88; N, 12.05. ESI-MS: m/z
233.2 (MHþ).
indol-1-yl)ethanone (12e). White solid, yield 55%. mp, 202e204 ꢀC.
1H NMR (600 MHz, CDCl3):
d 2.32 (s, 3H), 4.52 (s, 2H), 7.21 (d,
J ¼ 7.8 Hz, 1H), 7.97 (s, 1H), 8.20 (s, 1H), 8.28 (s, 1H), 8.31 (d,
J ¼ 7.8 Hz, 1H). 13C NMR (150 MHz, CDCl3):
d 22.5, 46.5, 98.9, 111.2,
2.2.3.11. Data for 4-chloro-5-(5-chloro-1H-indol-3-yl)oxazole (10c).
White solid, yield 38%, mp, 243e245 ꢀC. IR (KBr) cmꢁ1: 642 (CeCl),
1131 (CeOeC), 1634 (C]N), 3035 (Ar-CH), 3210 (NH), 3450 (Pyr-
120.3, 122.0, 125.6, 126.2, 129.5, 132.1, 135.7, 138.2, 151.5, 160.5.
Anal.Calcd for C14H10Cl2N2O2: C, 54.39; H, 3.26; N, 9.06; Found: C,
54.37; H, 3.12; N, 9.11. EI-MS: m/z (%) 309.2 (MHþ).
rolyl-CH). 1H NMR (600 MHz, CDCl3):
d
: 7.25 (s, 1H), 7.38 (d,
J ¼ 9.0 Hz, 1H), 7.85 (d, J ¼ 9.0 Hz, 1H), 7.89 (s, 1H), 8.07 (s, 1H), 8.53
(s, 1H). 13C NMR (150 MHz, DMSO-d6):
99.2, 115.1, 121.4, 122.4,
125.2, 125.8, 127.9, 130.0, 134.8, 138.7, 150.9. Anal.Calcd for
2.2.3.19. Data for 4-bromo-5-(1-(cyclopropylmethyl)-6-methyl-1H-
d
indol-3-yl)oxazole (13e). White solid, yield, 63%. mp, 168e170 ꢀC.
1H NMR (600 MHz, CDCl3):
d
0.45 (d, J ¼ 7.2 Hz, 2H), 0.67 (d,
C
11H6Cl2N2O: C, 52.20; H, 2.39; N, 11.07; Found: C, 52.20; H, 2.39; N,
J ¼ 7.2 Hz, 2H),1.29e1.31 (m,1H), 2.32 (s, 3H), 4.11 (d, J ¼ 6.6 Hz, 2H),
11.07. ESI-MS: m/z 253.1 (MHþ).
7.31 (d, J ¼ 7.2 Hz, 1H), 7.43 (d, J ¼ 7.2 Hz, 1H), 7.89 (s, 1H), 7.95 (s,
1H), 8.08 (s, 1H). 13C NMR (150 MHz, CDCl3):
d 3.9, 4.0, 10.8, 22.3,
2.2.3.12. Data for 4-chloro-5-(5-bromo-1H-indol-3-yl)oxazole (10d).
White solid, yield 29%, mp, 252e254 ꢀC. 1H NMR (600 MHz, CDCl3):
51.2, 102.5, 107.8, 109.8, 120.7, 121.3, 122.3, 125.4, 126.5, 137.2, 148.0,
151.2. Anal.Calcd for C16H15BrN2O: C, 58.02; H, 4.56; N, 8.46; Found:
C, 58.11; H, 4.58; N, 8.50. EI-MS: m/z (%) 331.0 (MHþ).
d
7.25 (s, 1H), 7.31 (d, J ¼ 7.2 Hz, 1H), 7.78 (d, J ¼ 7.2 Hz, 1H), 7.82 (s,
1H), 8.12 (s, 1H), 8.44 (s, 1H). 13C NMR (150 MHz, DMSO-d6):
d
98.7,
114.2, 121.6, 122.8, 124.4, 125.6, 127.7, 131.1, 135.0, 137.7, 150.1.
Anal.Calcd for C11H6BrClN2O: C, 44.40; H, 2.03; N, 9.42; Found: C,
44.38; H, 2.13; N, 9.45. ESI-MS: m/z 299.4 (MHþ).
2.2.4. General procedure for the synthesis of compounds 15e21
(Scheme 4)
The synthetic procedures for compounds 15e21 are the same as
those described in our previous work [12].
2.2.3.13. Data for 4-chloro-5-(6-methyl-1H-indol-3-yl)oxazole (10e).
White solid, yield 75%. mp, 225e227 ꢀC. 1H NMR (600 MHz, CDCl3):
2.2.4.1. Data for 1-(phenylsulfonyl)-1H-indole-5-carbaldehyde (15).
White solid, yield 61%. IR (KBr) cmꢁ1: 731 (Pyrrolyl-HC]CH), 1699
d
2.47 (s, 3H), 7.09 (d, J ¼ 7.8 Hz, 1H), 7.41 (s, 1H), 7.75 (s, 1H), 7.87 (s,
1H), 7.97 (d, J ¼ 7.8 Hz, 1H), 8.37 (s, 1H). 13C NMR (100 MHz, CDCl3):
(C]O), 3435 (Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d 6.80 (t,
d
21.5, 102.1, 110.6, 119.6, 120.3, 121.3, 122.6, 123.2, 133.4, 134.7,
J ¼ 4.2 Hz, 1H), 7.46e7.49 (m, 2H), 7.59 (t, J ¼ 7.8 Hz, 1H), 6.69 (d,
J ¼ 3.6 Hz, 1H), 7.86e7.88 (m, 2H), 7.92 (d, J ¼ 7.2 Hz, 1H), 8.07 (s,
1H), 8.13 (d, J ¼ 8.4 Hz,1H), 10.03 (s,1H). 13C NMR (100 MHz, CDCl3):
146.5, 149.2. Anal.Calcd for C12H9ClN2O: C, 61.95; H, 3.90; N, 12.04;
Found: C, 61.87; H, 4.00; N, 12.11. ESI-MS: m/z 233.1 (MHþ).
d
109.5, 113.8, 124.7, 125.2, 126.7, 127.9, 129.4, 130.8, 132.2, 134.2,
2.2.3.14. Data for 4-chloro-5-(7-aza-1H-indol-3-yl)oxazole (10f).
White solid, yield 15%, mp, 234e236 ꢀC. 1H NMR (600 MHz, DMSO-
137.8, 138.0, 191.7. ESI-MS: m/z 286.1 (MHþ).
d6):
1H),12.32 (s, 1H). 13C NMR (150 MHz, DMSO-d6):
122.2, 125.2, 127.5, 138.3, 143.5, 147.3, 151.4. Anal.Calcd for
d
: 7.36 (s, 1H), 7.69 (s, 1H), 8.33 (s, 1H), 8.43 (s, 1H), 8.51 (s,
2.2.4.2. Data for 5-(1H-indol-5-yl)oxazole (16). White solid, yield
82%, mp, 211e213 ꢀC. IR (KBr) cmꢁ1: 1114(CeOeC), 1622 (C]N),
3185 (NH), 3436 (Pyrrolyl-CH). 1H NMR (600 MHz, DMSO-d6):
d
99.4, 111.8, 115.6,
C
10H6ClN3O: C, 54.69; H, 2.75; N, 19.13; Found: C, 54.71; H, 2.69; N,
d
6.50 (s, 1H), 7.27 (s, 1H), 7.42 (d, J ¼ 7.2 Hz, 1H), 7.48e7.49 (m, 2H),
19.12. EI-MS: m/z (%) 219 (Mþ, 100), 221 (32), 184 (4), 143(5), 117(8).
7.53 (d, J ¼ 7.2 Hz, 1H), 7.92 (s, 1H), 11.29 (s, 1H). 13C NMR (150 MHz,
DMSO-d6):
d 101.8, 111.2, 115.8, 119.4, 121.7, 124.3, 128.3, 129.4,
2.2.3.15. Data for 4-bromo-5-(6-methyl-1H-indol-3-yl)oxazole (11e).
White solid, yield 18%, mp, 228e230 ꢀC. 1H NMR (600 MHz, CDCl3):
135.5, 149.8, 151.2. Anal.Calcd for C11H8N2O: C, 71.73; H, 4.38; N,
15.21; Found: C, 71.82; H, 4.50; N, 15.19. ESI-MS: m/z 185.3 (MHþ).
d
2.48 (s, 3H), 7.07 (d, J ¼ 7.8 Hz, 1H), 7.14 (s, 1H), 7.50 (s, 1H), 7.85 (d,
J ¼ 8.4 Hz, 1H), 8.00 (s, 1H), 8.31 (s, 1H). 13C NMR (150 MHz, DMSO-
2.2.4.3. Data for 5-(1-(phenylsulfonyl)-1H-indol-5-yl)oxazole (17).
White solid, yield 62%. mp, 218e220 ꢀC. 1H NMR (600 MHz, CDCl3):
d6):
d 22.2, 97.9, 107.8, 120.1, 121.7, 125.8, 128.5, 129.0, 133.3, 135.5,
137.9, 150.7. Anal.Calcd for C12H9BrN2O: C, 52.01; H, 3.27; N, 10.11;
d
6.71 (d, J ¼ 3.0 Hz, 1H), 7.33 (s, 1H), 7.43e7.46 (m, 2H), 7.47 (t,
Found: C, 52.11; H, 3.22; N, 10.09. ESI-MS: m/z 277.2 (MHþ).
J ¼ 7.8 Hz, 2H), 7.61 (d, J ¼ 3.6 Hz, 1H), 7.79 (s, 1H), 7.82e7.84 (m,
2H), 7.91 (s, 1H), 8.06 (d, J ¼ 9.0 Hz, 1H). ESI-MS: m/z 325.1 (MHþ).
2.2.3.16. Data for4-bromo-5-(7-aza-1H-indol-3-yl)oxazole (11f).
White solid, yield 27%, mp, 262e264 ꢀC. 1H NMR (600 MHz, DMSO-
2.2.4.4. Data for 4-chloro-5-(1-(phenylsulfonyl)-1H-indol-5-yl)oxa-
d6):
d
7.25 (s, 1H), 8.08 (s, 1H), 8.29 (s, 1H), 8.30 (s, 1H), 8.54 (s, 1H),
101.1, 115.7, 121.3,
zole (18). White solid, yield 24%. mp, 276e278 ꢀC. 1H NMR
12.39 (s, 1H). 13C NMR (150 MHz, DMSO-d6):
d
(600 MHz, CDCl3):
d
6.71 (d, J ¼ 7.2 Hz, 1H). 7.33 (s, 1H), 7.46 (t,

780
M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 92 (2015) 776e783
Scheme 4. Synthetic routes for “reversed” streptochlorin analogues.
J ¼ 7.8 Hz, 2H), 7.55 (t, J ¼ 7.8 Hz, 1H), 7.61 (d, J ¼ 7.2 Hz, 2H), 7.83 (s,
1H), 7.95e7.86 (m, 2H), 8.05 (d, J ¼ 8.4 Hz, 1H). ESI-MS: m/z 359.2
(MHþ).
removed under reduced pressure. The crude product was purified
by flash column chromatography using 15e25% acetone/petroleum
ether (60e90 ꢀC) as eluent to give the dichlorinated compounds 22.
2.2.5.1. Data for 2,4-dichloro-5-(5-chloro-1H-indol-3-yl)oxazole
2.2.4.5. Data for 4-bromo-5-(1-(phenylsulfonyl)-1H-indol-5-yl)oxa-
(22c). White solid, yield, 63%. mp, 257e259 ꢀC. 1H NMR (600 MHz,
zole (19). White solid, yield 26%, mp, 254e256 ꢀC. 1H NMR
DMSO-d6):
1H), 8.65 (s, 1H), 10.28 (bs, 1H). 13C NMR (150 MHz, DMSO-d6):
99.7, 115.2, 122.7, 124.5, 125.8, 126.6, 129.4, 130.8, 136.7, 142.1,
d
7.23 (d, J ¼ 7.2 Hz, 1H), 7.50 (d, J ¼ 7.2 Hz, 1H), 7.81 (s,
(600 MHz, CDCl3):
d
6.67 (d, J ¼ 7.2 Hz, 1H). 7.29 (s, 1H), 7.40 (t,
J ¼ 7.8 Hz, 2H), 7.51 (t, J ¼ 7.8 Hz, 1H), 7.57 (d, J ¼ 7.2 Hz, 2H), 7.80 (s,
1H), 7.89e7.91 (m, 2H), 8.02 (d, J ¼ 8.4 Hz, 1H). ESI-MS: m/z 402.9
(MHþ).
d
153.6. Anal.Calcd for C11H5Cl3N2O: C, 45.95; H, 1.75; N, 9.74; Found:
C, 46.01; H, 1.79; N, 9.68. EI-MS: m/z (%) 287.2 (MHþ).
2.2.4.6. Data for 4-chloro-5-(1H-indol-5-yl)oxazole (20). White
solid, yield 40%, mp, 238e240 ꢀC. 1H NMR (600 MHz, CDCl3):
d 7.32
2.2.5.2. Data for 2,4-dichloro-5-(6-methyl-1H-indol-3-yl)oxazole
(22e). White solid, yield, 63%. mp, 243e245 ꢀC. 1H NMR (600 MHz,
(d, J ¼ 7.2 Hz, 1H), 7.40 (s, 1H), 7.54 (d, J ¼ 7.2 Hz, 1H), 7.61 (d,
J ¼ 8.4 Hz, 1H), 7.98 (s, 1H), 8.02 (s, 1H), 8.53 (s, 1H). 13C NMR
DMSO-d6):
1H), 7.75 (s, 1H), 8.35 (s, 1H), 10.57 (bs, 1H). 13C NMR (150 MHz,
DMSO-d6): 20.9, 98.5, 114.9, 122.6, 124.6, 125.4, 126.2, 128.8, 130.9,
d
2.41 (s, 3H), 7.11 (d, J ¼ 7.2 Hz, 1H), 7.42 (d, J ¼ 7.2 Hz,
(150 MHz, DMSO-d6):
d 102.6, 111.7, 116.8, 119.2, 124.3, 125.7, 128.8,
d
129.7, 135.2, 149.8, 152.7. Anal.Calcd for C11H7ClN2O: C, 60.43; H,
3.23; N, 12.81; Found: C, 60.47; H, 3.31; N, 12.78. ESI-MS: m/z 219.1
(MHþ).
135.3, 139.1, 153.4. Anal.Calcd for C12H8Cl2N2O: C, 53.96; H, 3.02; N,
10.49; Found: C, 54.01; H, 3.09; N, 10.52. EI-MS: m/z (%) 267.0
(MHþ).
2.2.4.7. Data for 4-bromo-5-(1H-indol-5-yl)oxazole (21). White
solid, yield 48%, mp, 246e248 ꢀC. 1H NMR (600 MHz, CDCl3):
d 7.31
2.3. Biological assays
(d, J ¼ 7.2 Hz, 1H), 7.38 (s, 1H), 7.43e7.47 (m, 1H), 7.58 (d, J ¼ 8.4 Hz,
1H), 7.91 (s,1H), 7.96 (s,1H), 8.46 (s,1H). 13C NMR (150 MHz, DMSO-
The materials and methods used in the biological assays con-
ducted at Syngenta are the same as those described in our earlier
work [12]. Screening consists of seven different high throughput
assays covering a selection of economically important plant path-
ogenic fungi and is performed using both leaf pieces and artificial
media. The results of the biological testing are shown in Table 1.
d6): d 101.7, 111.6, 116.4, 120.1, 124.5, 125.6, 128.3, 129.9, 135.4, 148.3,
151.8. Anal.Calcd for C11H7BrN2O: C, 50.22; H, 2.68; N,10.65; Found:
C, 50.31; H, 2.69; N, 10.68. ESI-MS: m/z 263.0 (MHþ).
2.2.5. General procedure for the synthesis of dichlorinated
compounds 22 (Scheme 5)
To a stirred solution of 6 (4.10 mmol) in THF-CCl4 (50 mL, 1:1)
was added 2 equivalents of NCS (8.20 mmol) and the resulting
mixture was heated at 50 ꢀC until 6 had been completely
consumed. The mixture was allowed to cool and the solvent was
3. Results and discussion
3.1. Synthetic chemistry
A series of indole-substituted streptochlorin analogues was
efficiently synthesized based on the methods we had developed in
our previous work. The synthetic routes to the streptochlorin an-
alogues are shown in Scheme 2, and the indole substituents are
shown in Scheme 3. The required substituted indole-3-
carboxaldehydes 4 were either commercially available, or could
be made by Vilsmeier-Haack formylation of the corresponding
substituted indoles 3 [16,17]. The indole nitrogen was then sulfo-
nylated to give the protected indole-3-carboxaldehydes 5. In the
key step of this sequence, the 5-linked oxazole was then installed
by Van Leusen's [3 þ 2] cyclisation with TosMIC, under the catalytic
influence of the ion exchange resin Ambersep® 900(OH) [18,19], to
Scheme 5. Synthesis of dichlorinated analogues of streptochlorin.

M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 92 (2015) 776e783
781
Table 1
Antifungal activities of streptochlorin analogues. Data are presented as means of the assessment scores across two or three replicates unless otherwise stated.
Species
PHYa
SEPa
UROa
PYTa
ALTa
BOTa
GIBa
Compound
Streptochlorin
Pimprinine
6a
6b
7a
8a
9a
10b
10c
10d
10e
10f
11d
11e
11f
12c
12e
13e
16
18
20
21
22c
22e
Rate
200
0b
0
49
0
0
0
49
0
60
49
0
0
0
27
0
0
0
0
100
36
51
0
0
0
0
0
0
0
100
55
27
0
77
27
49
27
49
77
e
20
99
0
99
99
27
0
2
0
0
55
0
0
0
0
0
e
e
0
e
e
0
20
99
0
0
27
0
0
0
27
77
e
2
99
0
0
0
27
0
0
0
0
20
99
0
0
0
0
0
0
49
e
e
e
e
e
e
e
0
2
0
0
0
0
0
0
0
0
e
e
0
e
e
0
20
99
0
0
0
0
0
0
0
99
e
99
e
e
99
e
0
0
55
0
0
0
2
0
0
0
0
0
0
0
0
0
e
0
e
e
0
e
0
0
0
0
0
0
0
0
0
0
99
e
0
ec
e
e
e
e
0
0
0
0
e
e
0
e
0
e
e
0
e
e
0
e
e
0
e
55
0
0
0
0
0
e
e
e
0
e
e
e
0
e
0
e
99
e
e
e
e
e
e
0
0
49
0
0
0
99
0
0
0
0
0
0
0
0
0
55
0
99
0
0
0
0
99
27
0
0
0
0
0
0
0
0
e
0
0
0
0
27
0
0
0
0
0
27
0
0
55
77
55
0
77
77
e
0
e
99
99
0
55
55
99
99
e
0
0
0
0
0
0
0
0
66
0
0
0
99
99
e
e
0
0
e
e
e
e
a
PHY, Phytophthora infestans (on tomato leaf pieces); SEP, Zymoseptoria tritici (on wheat leaf pieces); URO, Uromyces viciae-fabae (on bean leaf pieces); PYT, Pythium
dissimile; ALT, Alternaria solani; BOT, Botryotinia fuckeliana; GIB, Gibberella zeae (all in artificial media).
b
0 means 0e49% control of disease or pathogen; 55 means 50e80% control of disease or pathogen; 99 means 81e100% control of disease or pathogen.
On testing or not tested.
c
give the 5-(30-indolyl)-oxazoles 6, with the sulfonyl protecting
group lost during this cyclisation. For compounds with the indole
substitution patterns b, c, d, e and f, varying from electron-donating
groups to electron-withdrawing groups (shown in Scheme 3),
compounds 6 could be treated with NCS/NBS to directly afford the
chlorinated or brominated streptochlorin analogues 10/11, respec-
tively (Route 2 shown in Scheme 2) [12,20]. Some dichlorinated
analogues of streptochlorin were also obtained when two equiva-
lents of NCS were employed (Scheme 5). For compounds with the
indole substitution patterns a (2-methylindole) and 14 (5-indolyl),
streptochlorin analogues were synthesized by a sequence of pro-
tection, cyclization, reprotection, halogenation and hydrolysis
(Route 1 shown in Scheme 2 and Scheme 4). On the basis of our
previous work, further substituents were introduced to the indole
NH of some streptochlorin derivatives.
Although the yields were not optimized, we noted that the step
that led to the formation of the oxazole ring was sensitive to the
nature of the steric effect of substituents on indole. For example, for
a methyl substituent, the yields of oxazoles 6 from aldehydes 5
were highly dependent on the position of the methyl group, namely
17%, 43% and 50% for 5-(2-methyl-1H-indol-3-yl)oxazole 6a, 5-(4-
methyl-1H-indol-3-yl)oxazole 6b and 5-(6-methyl-1H-indol-3-yl)
oxazole 6e, respectively. These results show that a methyl group at
the 2-position of the indole offers greater steric hindrance than a
methyl at the 4- or 6-positions.
streptochlorin analogue 16 with NCS or NBS was also a problem,
because halogenation also occurred at the 2- and 3-positions of the
indole. Again, the solution was to add a phenylsulfonyl group to the
indole nitrogen, after which halogenation took place exclusively on
the oxazole ring. Hydrolysis of the phenylsulfonyl group then gave
the required reversed analogues 20 and 21.
3.2. Antifungal activity and the structureeactivity relationships
(SAR)
The results of the biological testing against seven phytopatho-
genic fungi are given in Table 1. For the purposes of an analysis of
structureeactivity relationships, the antifungal activities of com-
pounds 6e13, 16, 18 and 20e22 were compared to the lead com-
pounds, the natural products streptochlorin and pimprinine.
It was noticeable that where compounds were active it was
most commonly against Pythium dissimile, Uromyces viciae-fabae
and Alternaria solani, but the activity lacked potency, as illustrated
by the absence of activity at the lower rates tested. Although the
antifungal activity of some of the compounds has not yet been
determined, making it difficult for a detailed structureeactivity
relationship analysis, some broad conclusions can still be drawn.
Some indole-modified derivatives 10 showed antifungal activity.
For example, compounds 10b and 10e showed clear activity on
P. dissimile and Gibberella zeae, respectively. 10c exhibited clear
activity on three out of five fungal species tested at the higher rates
only (U. viciae-fabae, A. solani, G. zeae), therefore displaying a
broader spectrum of activity. For the effect of indole ring sub-
stituents, compared to antifungal activity of electron-donating 4-
methyl and 6-methyl equivalents (10b and 10e), the electron-
withdrawing 5-Cl derivative (10c) and the dichloro equivalent
(22c) displayed higher antifungal activity on three out of five fungal
species, though 10b demonstrated a broader spectrum. Compound
21, the reversed brominated analogue of streptochlorin, showed
clear activity on Phytophthora infestans and P. dissimile and
It is worth noting that the 2-methyl streptochlorin derivatives
10a and 11a could not be synthesized using halogenation as the
final step, since chlorination or bromination of the 2-methyl-indole
6a using NCS or NBS afforded complex mixtures. A phenylsulfonyl
group was therefore added to the indole nitrogen of 6a to give in-
termediate 7a, after which halogenation proceeded smoothly to
generate the N-protected streptochlorin derivatives 8a and 9a.
Hydrolysis of the phenylsulfonyl group from these intermediates to
afford the final compounds 10a, 11a then proved to be problematic.
Direct halogenation on the oxazole ring of the reversed

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M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 92 (2015) 776e783
Fig. 1. Structures of the most active synthetic streptochlorin analogues.
structure determination of streptochlorin, an antiproliferative agent from a
marine-derived Streptomyces sp. 04DH110, J. Microbiol. Biotechnol. 17 (2007)
1403e1406.
moderate control of Zymoseptoria tritici, and A. solani. However, the
indole-modified derivatives 10 were less active than the lead
compound streptochlorin.
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dron 19 (1963) 1437e1439;
In our previous work we showed that antifungal activity could
be improved by introducing a halogen atom (Cl, Br) at the 4-
position of the oxazole ring. An additional halogen atom intro-
duced at the 2-position of the oxazole ring can also further improve
the antifungal activity. For example, the compound 10c showed
good control of G. zeae, U. vicae-fabae and A. solani, while the
dichloro equivalent 22c exhibited effective control of U. viciae-
fabae, A. solani, and G. zeae. The situation is similar with compounds
10e and its dichloro equivalent 22e. A derivative with substitution
on the nitrogen of the indole ring was also tested for the antifungal
activity; compound 13e showed effective control of U. viciae-fabae,
P. dissimile, A. solani, and moderate control of G. zeae, but the ac-
tivity lacks potency.
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4. Conclusions
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In summary, we have efficiently synthesized a novel series of
indole-modified streptochlorin analogues based on the methods
developed in our previous work. Biological testing showed that
some of the derivatives have good antifungal activity in a series of
primary assays. The compounds 10b, 10c, 11e, 13e, 21, 22c and 22e
were identified as the most active and therefore the most prom-
ising candidates for further study (shown in Fig. 1). Further struc-
tural optimization of indole-modified streptochlorin derivatives is
well under way, with the aim of preparing analogues with
improved antifungal activity.
Acknowledgements
We are grateful to the financial support for this work from the
National Key Technologies R&D Program (2011BAE06B05). We
thank the Biology Team at Syngenta for their kind help in screening
the compounds for biological activity.
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Supplementary data related to this article can be found at http://
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